Current Issue - Journal of Clinical and Basic Research

Supplementary 3 Article: 10-127-11

| Post date: 2025/12/29 |

Supplementary 3
Amino Acid Conservation Scores
The layers for assigning grades are as follows.
from -1.299 to -1.010 the grade is 9
from -1.010 to -0.722 the grade is 8
from -0.722 to -0.433 the grade is 7
from -0.433 to -0.144 the grade is 6
from -0.144 to 0.288 the grade is 5
from 0.288 to 0.865 the grade is 4
from 0.865 to 1.442 the grade is 3
from 1.442 to 2.019 the grade is 2
from 2.019 to 2.596 the grade is 1
If the difference between the colors of the Confidence interval colors is more than 3 or the msa number (Under the column titled MSA) is less than 6, there is insufficient data and an * appears in the COLOR column.
- POS: The position of the AA in the SEQRES derived sequence.
- SEQ: The SEQRES derived sequence in one letter code.
- 3LATOM: The ATOM derived sequence in three letter code, including the AA's positions as they appear in the PDB file and the chain identifier.
- Score: The normalized conservation scores.
- Color: The color scale representing the conservation scores (9 - conserved, 1 - variable).
- Confidence interval: When using the bayesian method for calculating rates, a confidence interval is assigned to each of the inferred evolutionary conservation scores.
- Confidence interval colors: When using the bayesian method for calculating rates. The color scale representing the lower and upper bounds of the confidence interval.
- MSA DATA: The number of aligned sequences having an amino acid (non-gapped) from the overall number of sequences at each position.
- Residue variety: The residues variety at each position of the multiple sequence alignment.

Supplementary 3. Consurf grade scores for each amino acid of PAH protein

POS	SEQ	3LATOM	Score (Normalized)	Color	Confidence interval	Confidence interval colors	B/E	Function	MSA DATA	Residue variety
1	M	MET:1:A	-0.46	7*	-1.100, -0.093	9,5	e	NA	2/150	M
2	S	SER:2:A	-0.822	8*	-1.211, -0.635	9,7	e	f	4/150	S
3	T	THR:3:A	0.278	5*	-0.575, 0.994	7,3	e	NA	3/150	T,A
4	A	ALA:4:A	0.271	5*	-0.635, 0.994	7,3	e	NA	3/150	A,V
5	V	VAL:5:A	-0.502	7*	-1.100, -0.193	9,6	e	NA	3/150	V
6	L	LEU:6:A	-0.471	7*	-1.100, -0.093	9,5	e	NA	3/150	L
7	E	GLU:7:A	-0.669	7*	-1.175, -0.439	9,7	e	NA	4/150	E
8	N	ASN:8:A	0.846	4*	-0.093, 1.453	5,2	e	NA	4/150	N,S,E
9	P	PRO:9:A	0.931	3*	-0.093, 1.453	5,2	e	NA	4/150	P,G,R
10	G	GLY:10:A	0.026	5*	-0.746, 0.473	8,4	e	NA	5/150	G,S
11	L	LEU:11:A	0.081	5*	-0.692, 0.473	7,4	e	NA	5/150	L,T
12	G	GLY:12:A	0.554	4	-0.364, 0.994	6,3	e	NA	6/150	G,S,E
13	R	ARG:13:A	1.504	2	0.473, 2.658	4,1	e	NA	11/150	R,Q,G,K,D,P,N,S,E
14	K	LYS:14:A	0.394	4	-0.282, 0.696	6,4	e	NA	10/150	K,R,H,G,D
15	L	LEU:15:A	1.035	3	0.019, 1.453	5,2	e	NA	8/150	L,F,E,P
16	S	SER:16:A	0.873	3	0.019, 1.453	5,2	b	NA	9/150	S,D,K,E,A,N
17	D	ASP:17:A	0.808	4	0.019, 1.453	5,2	e	NA	8/150	D,E,K,V
18	F	PHE:18:A	1.405	3	0.473, 2.658	4,1	e	NA	8/150	F,G,A,S,K,D
19	G	GLY:19:A	2.073	1	0.994, 2.658	3,1	e	NA	11/150	G,R,Q,Y,D,S,T
20	Q	GLN:20:A	2.042	1	0.994, 2.658	3,1	e	NA	17/150	Q,L,Y,R,T,H,N,S,P,E
21	E	GLU:21:A	2.24	1	0.994, 2.658	3,1	e	NA	21/150	E,G,R,S,K,Q,H
22	T	THR:22:A	1.784	2	0.696, 2.658	4,1	b	NA	32/150	T,S,G,H,N,Q,D,E,L
23	S	SER:23:A	1.143	3	0.473, 1.453	4,2	e	NA	40/150	S,M,N,T,F,K,E,Q,A,G,P,R
24	Y	TYR:24:A	0.396	4	-0.093, 0.696	5,4	b	NA	45/150	Y,G,E,S,L,I,F,K
25	I	ILE:25:A	1.183	3	0.473, 1.453	4,2	b	NA	45/150	I,L,V,H,M,R,A,K,S,T,G,E
26	E	GLU:26:A	2.292	1	0.994, 2.658	3,1	e	NA	51/150	E,K,H,A,R,D,V,M,G,C,F,L,P,S,N,Q
27	D	ASP:27:A	0.315	4	-0.093, 0.473	5,4	b	NA	53/150	D,E,N,Q,I,V,K,P,S,H
28	N	ASN:28:A	2.558	1	1.453, 2.658	2,1	e	NA	56/150	N,H,E,G,Y,P,D,T,S,A,V,R,F,I
29	C	CYS:29:A	2.509	1	1.453, 2.658	2,1	e	NA	57/150	C,S,T,I,D,K,R,F,E,N,V,P,Q,Y,L,H
30	N	ASN:30:A	0.918	3	0.473, 1.453	4,2	e	NA	59/150	N,S,T,D,E,A,P,C,G,L
31	Q	GLN:31:A	2.269	1	0.994, 2.658	3,1	e	NA	71/150	Q,E,K,M,S,D,G,C,N,P,R,A,V,T,L
32	N	ASN:32:A	2.005	2	0.994, 2.658	3,1	e	NA	81/150	N,S,D,G,E,A,T,P,I,R,K,Q,Y,L
33	G	GLY:33:A	2.527	1	1.453, 2.658	2,1	b	NA	87/150	G,S,N,E,K,R,T,A,I,Q,D,V,P,L
34	A	ALA:34:A	1.468	2	0.696, 1.453	4,2	b	NA	94/150	A,F,R,V,T,S,C,N,L,K,Q,H,M,I
35	I	ILE:35:A	0.89	3	0.473, 0.994	4,3	b	NA	104/150	I,V,M,S,T,A,L,F,N,R
36	S	SER:36:A	0.031	5	-0.193, 0.147	6,5	b	NA	113/150	S,T,E,C,H,Y,L,W,A,N,R,I,K,D
37	L	LEU:37:A	0.973	3	0.473, 1.453	4,2	b	NA	117/150	L,C,V,I,F
38	I	ILE:38:A	0.977	3	0.473, 1.453	4,2	b	NA	117/150	I,L,T,C,V,F,H,Y,S,M,A,Q,E
39	F	PHE:39:A	-0.408	6	-0.635, -0.282	7,6	b	NA	117/150	F,Y,L,I,V,M
40	S	SER:40:A	-0.185	6	-0.439, -0.093	7,5	e	NA	117/150	S,T,G,A,R,M,E,H,K,N
41	L	LEU:41:A	0.267	5	-0.093, 0.473	5,4	b	NA	117/150	L,V,P,M,S,I,F,A,T
42	K	LYS:42:A	1.058	3	0.473, 1.453	4,2	e	NA	120/150	K,P,R,Q,H,E,A,N,T,V,I,G,D,S,C
43	E	GLU:43:A	-0.444	7	-0.635, -0.364	7,6	e	NA	120/150	E,D,Q,S,N,K,A,T,P,R
44	E	GLU:44:A	0.894	3	0.473, 0.994	4,3	e	NA	122/150	E,Q,K,S,R,N,T,D,A,H,G,C,V
45	V	VAL:45:A	0.479	4	0.147, 0.696	5,4	e	NA	122/150	V,A,S,I,P,T,N,L,G,F,K,M,C,Q
46	G	GLY:46:A	0.089	5	-0.193, 0.295	6,4	e	NA	122/150	G,S,D,T,P,N,A,E,L,K
47	A	ALA:47:A	0.875	3	0.473, 0.994	4,3	e	NA	122/150	A,I,S,C,T,D,E,G,V,H,N,P,R,M
48	L	LEU:48:A	-0.91	8	-1.062, -0.797	9,8	e	f	123/150	L,F,V,I
49	A	ALA:49:A	0.318	4	0.019, 0.473	5,4	e	NA	123/150	A,V,S,G,I,E,D,K,P,F,Q,N,H,W,L,T,C,R
50	K	LYS:50:A	0.894	3	0.473, 0.994	4,3	e	NA	124/150	K,R,E,S,A,D,T,N,G,Q,L,F,H
51	V	VAL:51:A	0.467	4	0.147, 0.696	5,4	b	NA	124/150	V,A,M,S,T,I,Y,F,C,L
52	L	LEU:52:A	-0.683	7	-0.847, -0.575	8,7	e	NA	124/150	L,F,V,M,N,G,T,A,I
53	R	ARG:53:A	0.292	4	0.019, 0.473	5,4	e	NA	124/150	R,K,N,H,S,Q,G,M,A,D,E
54	L	LEU:54:A	1.61	2	0.994, 1.453	3,2	b	NA	125/150	L,I,V,M,Y,T,C,A,R,F,H,E,P,K,S
55	F	PHE:55:A	-0.549	7	-0.746, -0.439	8,7	b	NA	125/150	F,L,I,V,S
56	E	GLU:56:A	-0.056	5	-0.282, 0.147	6,5	e	NA	126/150	E,Q,K,T,S,N,A,R,W,D,P
57	E	GLU:57:A	0.75	4	0.295, 0.994	4,3	e	NA	126/150	E,D,S,A,R,N,K,G,T,V,M,Y
58	N	ASN:58:A	1.073	3	0.696, 1.453	4,2	e	NA	124/150	N,K,R,H,Y,F,G,M,L,D,C,V,A,E
59	D	ASP:59:A	1.197	3	0.696, 1.453	4,2	e	NA	126/150	D,G,K,N,S,H,E,Q,A
60	V	VAL:60:A	0.059	5	-0.193, 0.147	6,5	b	NA	127/150	V,I,A,F,S,E,T,G,C
61	N	ASN:61:A	-0.296	6	-0.509, -0.193	7,6	e	NA	128/150	N,S,T,D,Q,K,R,A,I,C,H
62	L	LEU:62:A	-0.33	6	-0.575, -0.193	7,6	e	NA	128/150	L,I,M,V,T
63	T	THR:63:A	1.146	3	0.696, 1.453	4,2	e	NA	128/150	T,Y,H,M,L,A,K,V,F,I,R,S,Q,D,C,E
64	H	HIS:64:A	-0.782	8	-0.938, -0.692	8,7	e	f	128/150	H,K,Y,L,R,S,D,E,Q

Supplementary 3 (Continued)

65	I	ILE:65:A	-0.76	8	-0.893, -0.692	8,7	e	f	128/150	I,M,L,F,Y,V
66	E	GLU:66:A	-1.178	9	-1.281, -1.138	9,9	b	s	128/150	E,H,Q,L,A
67	S	SER:67:A	-1.081	9	-1.175, -1.022	9,9	e	f	128/150	S,T,V,N
68	R	ARG:68:A	-1.223	9	-1.318, -1.175	9,9	e	f	128/150	R,H,K
69	P	PRO:69:A	0.223	5	-0.093, 0.473	5,4	e	NA	127/150	P,S,L,A,K,R,Q,T,D
70	S	SER:70:A	0.142	5	-0.093, 0.295	5,4	e	NA	127/150	S,A,G,M,V,C,P,K,N,R,T,D
71	R	ARG:71:A	1.145	3	0.696, 1.453	4,2	e	NA	128/150	R,Q,K,T,S,V,H,E,A,L,N,P
72	L	LEU:72:A	1.43	3	0.994, 1.453	3,2	e	NA	127/150	L,V,T,M,A,R,N,D,Q,K,S,H,E,G,I,F,Y
73	K	LYS:73:A	2.37	1	1.453, 2.658	2,1	e	NA	127/150	K,N,S,D,G,L,I,V,F,Q,R,H,M,A,P,E,Y,W,T
74	K	LYS:74:A	2.279	1	0.994, 2.658	3,1	e	NA	127/150	K,Q,R,A,P,S,H,N,E,T,V,D,G
75	D	ASP:75:A	1.863	2	0.994, 2.658	3,1	e	NA	119/150	D,E,S,N,G,K,Q,T,W,A,P,R,Y,M,I,V
76	E	GLU:76:A	1.228	3	0.696, 1.453	4,2	e	NA	127/150	E,Q,H,S,G,R,D,K,V,C,L,N,I,A,T,Y
77	Y	TYR:77:A	0.416	4	0.019, 0.696	5,4	e	NA	127/150	Y,F,H,V,I,L,A,M,T,P,R
78	E	GLU:78:A	-0.636	7	-0.797, -0.509	8,7	e	NA	127/150	E,Q,D,S,F,N,A,T
79	F	PHE:79:A	-0.132	5	-0.364, 0.019	6,5	b	NA	127/150	F,I,V,M,Y,L,A,C,G
80	F	PHE:80:A	0.665	4	0.295, 0.994	4,3	b	NA	127/150	F,L,Y,M,V,D,Q,H
81	T	THR:81:A	-0.118	5	-0.364, 0.019	6,5	b	NA	127/150	T,I,V,A,F,L,M
82	H	HIS:82:A	0.266	5	-0.093, 0.473	5,4	b	NA	128/150	H,Y,N,S,R,D,A,E,T,V,Q,K,C
83	L	LEU:83:A	0.423	4	0.019, 0.696	5,4	b	NA	129/150	L,V,F,C,S,I,T,A
84	D	ASP:84:A	0.272	5	0.019, 0.473	5,4	e	NA	129/150	D,A,E,S,K,N,I,M,L,Q,F,P,H,Y
85	K	LYS:85:A	0.867	3	0.473, 0.994	4,3	e	NA	129/150	K,S,N,P,T,A,H,E,C,I,G,V,L,R,M,Y,W
86	R	ARG:86:A	1.721	2	0.994, 2.658	3,1	e	NA	122/150	R,K,N,T,S,E,P,Q,A,G,M,D,H,V
87	S	SER:87:A	2.523	1	1.453, 2.658	2,1	b	NA	39/150	S,N,C,Y,D,A,E,G,R,Q,L,P,V,K,I,F
88	L	LEU:88:A	1.944	2	0.994, 2.658	3,1	e	NA	129/150	L,M,T,I,S,A,K,N,P,G,D,H,R,C,Q,E,V,F
89	P	PRO:89:A	2.053	1	0.994, 2.658	3,1	e	NA	129/150	P,Q,A,G,T,K,I,D,E,S,R,L,F,N,V,C
90	A	ALA:90:A	1.265	3	0.696, 1.453	4,2	e	NA	129/150	A,S,G,Q,N,E,D,K,R,H,L,I,T,F,V
91	L	LEU:91:A	0.761	4	0.295, 0.994	4,3	b	NA	129/150	L,M,V,I,F,K,T,A
92	T	THR:92:A	1.573	2	0.994, 1.453	3,2	e	NA	129/150	T,E,D,K,H,G,L,A,S,Y,N,Q,P,R,C,I,V,M
93	N	ASN:93:A	2.202	1	0.994, 2.658	3,1	e	NA	128/150	N,D,K,E,S,Q,A,V,R,T,G,H,L,I,P,F
94	I	ILE:94:A	0.258	5	-0.093, 0.473	5,4	b	NA	129/150	I,V,A,T,L,M,F
95	I	ILE:95:A	1.143	3	0.696, 1.453	4,2	b	NA	129/150	I,V,L,M,T,F,S,Q,G,D,E
96	K	LYS:96:A	1.529	2	0.994, 1.453	3,2	e	NA	129/150	K,Q,R,E,D,N,A,P,L,H,S,T,G,I,Y
97	I	ILE:97:A	1.336	3	0.696, 1.453	4,2	e	NA	129/150	I,T,C,G,S,A,D,E,N,K,V,Q,R,H,L,M
98	L	LEU:98:A	-0.588	7	-0.797, -0.439	8,7	b	NA	130/150	L,I,V,F
99	R	ARG:99:A	0.508	4	0.147, 0.696	5,4	e	NA	130/150	R,K,Q,E,A,N,S,G,I,P,T,C
100	H	HIS:100:A	1.418	3	0.994, 1.453	3,2	e	NA	130/150	H,N,T,S,A,E,K,D,G,Q,F,R,I,P
101	D	ASP:101:A	0.35	4	-0.364, 0.696	6,4	e	NA	12/150	D,E,Q
102	I	ILE:102:A	1.348	3	0.696, 1.453	4,2	e	NA	130/150	I,T,K,Y,Q,N,R,E,S,M,D,H,C,L,V,A
103	G	GLY:103:A	1.409	3	0.696, 1.453	4,2	e	NA	131/150	G,S,A,E,C,V,T,I,W,M,L,N,Q,K
104	A	ALA:104:A	2.463	1	1.453, 2.658	2,1	b	NA	127/150	A,G,C,E,S,T,K,H,N,L,Q,D,I,V,R,P
105	T	THR:105:A	1.713	2	0.994, 2.658	3,1	e	NA	128/150	T,Q,H,P,S,K,N,Y,V,I,L,M,D,A,G,E,R,C,F
106	V	VAL:106:A	0.438	4	0.147, 0.696	5,4	b	NA	128/150	V,A,L,F,H,M,I,T,C
107	H	HIS:107:A	1.218	3	0.696, 1.453	4,2	b	NA	128/150	H,Q,T,N,K,S,V,L,D,M,R,E,A,G
108	E	GLU:108:A	1.025	3	0.473, 1.453	4,2	e	NA	129/150	E,L,V,I,M,P,T,S,F,Y,A,G
109	L	LEU:109:A	1.162	3	0.696, 1.453	4,2	b	NA	130/150	L,M,H,I,F,Q,N,E,D,K,V,T,R,P,A,S,Y,G,C
110	S	SER:110:A	1.129	3	0.696, 1.453	4,2	b	NA	131/150	S,T,A,L,D,P,G,E,R,K,H,Q,N,C
111	R	ARG:111:A	1.091	3	0.473, 1.453	4,2	b	NA	76/150	R,L,K,H,F,P,W,A,T,S,D,Q,G
112	D	ASP:112:A	1.335	3	0.696, 1.453	4,2	e	NA	76/150	D,T,N,C,K,S,E,A,G,P,V,H,F,Q
113	K	LYS:113:A	1.643	2	0.994, 2.658	3,1	e	NA	86/150	K,S,T,N,E,D,R,G,Q,H,C,F,V,A,L
114	K	LYS:114:A	1.501	2	0.696, 1.453	4,2	e	NA	88/150	K,Q,C,T,E,G,N,V,L,D,A,R,S,I,H
115	K	LYS:115:A	1.448	2	0.994, 1.453	3,2	e	NA	134/150	K,C,E,G,T,L,R,D,S,Q,M,N,P,V,F,I,A,H
116	D	ASP:116:A	1.458	2	0.994, 1.453	3,2	e	NA	137/150	D,V,N,G,A,E,T,S,K,H,R,Q,Y,W,P,M
117	T	THR:117:A	0.956	3	0.473, 0.994	4,3	e	NA	140/150	T,A,K,E,S,V,C,N,G,D,Q,P,L
118	V	VAL:118:A	0.522	4	0.147, 0.696	5,4	b	NA	143/150	V,I,G,F,M,L,T,S,A,P,N,D,C,E
119	P	PRO:119:A	0.112	5	-0.193, 0.295	6,4	b	NA	145/150	P,A,C,H,R,V,T,I,S,L,Q,E
120	W	TRP:120:A	-0.671	7	-0.847, -0.575	8,7	b	NA	146/150	W,M,Q,S,I,G,D
121	F	PHE:121:A	-0.974	8	-1.100, -0.893	9,8	b	NA	146/150	F,V,R,Y,I
122	P	PRO:122:A	-1.278	9	-1.338, -1.246	9,9	b	s	146/150	P
123	R	ARG:123:A	0.15	5	-0.093, 0.295	5,4	b	NA	145/150	R,N,Y,V,T,A,K,M,Q,L,H
124	T	THR:124:A	-0.146	6	-0.364, 0.019	6,5	b	NA	146/150	T,S,D,G,K,R,A,M,H,C,V,Q,N
125	I	ILE:125:A	-0.538	7	-0.692, -0.439	7,7	b	NA	146/150	I,M,L,A,V,K,R,P,T
126	Q	GLN:126:A	0.354	4	0.019, 0.473	5,4	e	NA	146/150	Q,P,D,S,K,R,N,A,T,V,G,Y,C,W

Supplementary 3 (Continued)

127	E	GLU:127:A	-0.509	7	-0.692, -0.364	7,6	b	NA	146/150	E,D,S,G
128	L	LEU:128:A	-0.971	8	-1.100, -0.893	9,8	b	NA	146/150	L,A,I,T,F
129	D	ASP:129:A	-1.235	9	-1.318, -1.211	9,9	e	f	146/150	D,Q,N
130	R	ARG:130:A	1.468	2	0.994, 1.453	3,2	e	NA	146/150	R,K,D,E,N,Q,L,T,S,F,M,I,H,V,C,Y,G
131	F	PHE:131:A	-0.135	5	-0.364, 0.019	6,5	b	NA	140/150	F,Y,L,C,T,S,A,I,V,H
132	A	ALA:132:A	-0.209	6	-0.439, -0.093	7,5	b	NA	145/150	A,L,S,I,H,T,Q,N,V,P,C,D,G,X
133	N	ASN:133:A	-0.125	5	-0.364, 0.019	6,5	e	NA	146/150	N,S,D,R,Q,I,H,E,C,A,K,L,M,V
134	Q	GLN:134:A	-0.069	5	-0.282, 0.019	6,5	b	NA	146/150	Q,L,H,R,S,K,N,E,V,M,T,A
135	I	ILE:135:A	-0.413	6	-0.635, -0.282	7,6	e	NA	146/150	I,V,S,T,L,M,N
136	L	LEU:136:A	-0.597	7	-0.797, -0.509	8,7	e	NA	146/150	L,S,V,F,T,W,M,I,Y,D
137	S	SER:137:A	-0.711	7	-0.847, -0.635	8,7	e	NA	146/150	S,T,N,G,M,L,A,E,K,D,Q
138	Y	TYR:138:A	-0.458	7	-0.635, -0.364	7,6	b	NA	146/150	Y,N,A,C,M,F,S,V,G,L
139	G	GLY:139:A	-0.642	7	-0.847, -0.509	8,7	b	NA	146/150	G,V,A,D,E,T,Q
140	A	ALA:140:A	0.271	5	0.019, 0.473	5,4	e	NA	145/150	A,S,G,D,N,E,L,P,T,I,V,K
141	E	GLU:141:A	-0.219	6	-0.439, -0.093	7,5	e	NA	146/150	E,F,D,R,S,H,N,A,G,L,V,T
142	L	LEU:142:A	-0.868	8	-1.022, -0.797	9,8	b	NA	146/150	L,F,I,M,E
143	D	ASP:143:A	-0.522	7	-0.692, -0.439	7,7	e	NA	146/150	D,E,H,S,N,K,Q,A
144	A	ALA:144:A	-0.066	5	-0.282, 0.019	6,5	e	NA	146/150	A,V,S,H,L,E,Q,M,C,K,F,D,Y,T,P,G
145	D	ASP:145:A	-0.743	8	-0.893, -0.635	8,7	e	f	146/150	D,C,E,G,A,N,R,T,M,K
146	H	HIS:146:A	-1.202	9	-1.281, -1.175	9,9	b	s	146/150	H,A,Y
147	P	PRO:147:A	-1.066	9	-1.175, -0.981	9,8	e	f	149/150	P,Q,D,V
148	G	GLY:148:A	-1.014	9	-1.138, -0.938	9,8	b	s	149/150	G,D,S,K
149	F	PHE:149:A	-0.581	7	-0.746, -0.439	8,7	e	NA	149/150	F,S,A,Y,H,W,C
150	K	LYS:150:A	0.073	5	-0.193, 0.147	6,5	e	NA	148/150	K,T,R,A,P,H,S,N,Q,G,V
151	D	ASP:151:A	-1.236	9	-1.318, -1.211	9,9	e	f	148/150	D,N,S
152	P	PRO:152:A	2.596	1	1.453, 2.658	2,1	e	NA	148/150	P,A,E,V,Q,L,S,M,N,H,D,K,T,I
153	V	VAL:153:A	0.562	4	0.147, 0.696	5,4	e	NA	148/150	V,E,L,T,A,I,S,Q,D,G
154	Y	TYR:154:A	-1.154	9	-1.246, -1.100	9,9	b	s	149/150	Y,I,F
155	R	ARG:155:A	-1.018	9	-1.138, -0.938	9,8	e	f	149/150	R,H,C,Q,K,D,I
156	A	ALA:156:A	1.244	3	0.696, 1.453	4,2	e	NA	149/150	A,S,I,T,E,Q,K,R,L,D,N,H
157	R	ARG:157:A	-1.199	9	-1.281, -1.175	9,9	b	s	149/150	R,A,H,G
158	R	ARG:158:A	-1.164	9	-1.246, -1.138	9,9	b	s	149/150	R,E,K,M,Q
159	K	LYS:159:A	0.337	4	0.019, 0.473	5,4	e	NA	149/150	K,T,Q,M,A,S,I,E,C,R,N,G,D,L,H
160	Q	GLN:160:A	1.294	3	0.696, 1.453	4,2	e	NA	149/150	Q,E,V,Y,H,L,F,A,I,K,T,D,M,S,N,R
161	F	PHE:161:A	-0.781	8	-0.938, -0.692	8,7	b	NA	149/150	F,I,V,L
162	A	ALA:162:A	-0.419	6	-0.635, -0.282	7,6	b	NA	149/150	A,V,T,S,F,G,H,C,E,D,L,N
163	D	ASP:163:A	0.49	4	0.147, 0.696	5,4	e	NA	149/150	D,R,E,A,K,S,Q,N,G,T,M
164	I	ILE:164:A	0.152	5	-0.093, 0.295	5,4	e	NA	149/150	I,V,L,K,S,Y,F,M,A,N,H
165	A	ALA:165:A	-1.186	9	-1.281, -1.138	9,9	b	s	148/150	A,X,S,L,P
166	Y	TYR:166:A	1.468	2	0.994, 1.453	3,2	e	NA	148/150	Y,F,L,H,A,M,K,T,N,R,I,E,Q,S,V
167	N	ASN:167:A	0.843	4	0.473, 0.994	4,3	e	NA	148/150	N,S,H,K,L,T,D,A,G,V,I,R,Q,E,F,M
168	Y	TYR:168:A	-0.564	7	-0.746, -0.439	8,7	b	NA	148/150	Y,H,F,W
169	R	ARG:169:A	-0.163	6	-0.364, 0.019	6,5	e	NA	148/150	R,K,S,N,Y,A,V,H
170	H	HIS:170:A	0.317	4	0.019, 0.473	5,4	e	NA	148/150	H,F,Y,Q,T,S,L,E,A,D,W
171	G	GLY:171:A	-0.953	8	-1.100, -0.847	9,8	e	f	149/150	G,C,N,D
172	Q	GLN:172:A	0.667	4	0.295, 0.994	4,3	e	NA	149/150	Q,T,E,D,H,N,M,L,R,G,C,K
173	P	PRO:173:A	1.266	3	0.696, 1.453	4,2	e	NA	149/150	P,V,I,T,A,Q,K,L,R,E,Y,S,D
174	I	ILE:174:A	-0.726	8	-0.893, -0.635	8,7	b	NA	149/150	I,L,H,V,F,M
175	P	PRO:175:A	-1.013	9	-1.138, -0.938	9,8	e	f	149/150	P,T,S,A,E
176	R	ARG:176:A	0.97	3	0.473, 0.994	4,3	e	NA	149/150	R,Q,E,H,Y,P,T,K,W,V,I,S,C,D,F
177	V	VAL:177:A	-0.226	6	-0.439, -0.093	7,5	b	NA	149/150	V,M,I,A,L
178	E	GLU:178:A	0.632	4	0.295, 0.696	4,4	e	NA	149/150	E,T,D,A,N,V,Q,K,S,H
179	Y	TYR:179:A	-1.156	9	-1.246, -1.100	9,9	b	s	149/150	Y,S,F,H
180	M	MET:180:A	-0.651	7	-0.797, -0.575	8,7	e	NA	149/150	M,T,S,I,L,N,V,R,F
181	E	GLU:181:A	1.226	3	0.696, 1.453	4,2	e	NA	149/150	E,K,S,N,T,P,A,I,D,Q,V,L
182	E	GLU:182:A	0.477	4	0.147, 0.696	5,4	e	NA	149/150	E,D,V,A,I,S,Q,N,K,T,L,R,G
183	E	GLU:183:A	-1.256	9	-1.318, -1.246	9,9	b	s	149/150	E,S,V
184	K	LYS:184:A	0.819	4	0.473, 0.994	4,3	e	NA	149/150	K,I,V,R,S,T,L,N,Y,A
185	K	LYS:185:A	1.295	3	0.696, 1.453	4,2	e	NA	149/150	K,A,N,G,E,P,S,R,D,I,Q,T,H
186	T	THR:186:A	-1.13	9	-1.211, -1.100	9,9	b	s	149/150	T,C,I,A,V
187	W	TRP:187:A	-1.199	9	-1.318, -1.138	9,9	b	s	149/150	W,C
188	G	GLY:188:A	1.006	3	0.473, 1.453	4,2	b	NA	150/150	G,R,S,N,A,K,Q,F,E,D,T

Supplementary 3 (Continued)

189	T	THR:189:A	1.545	2	0.994, 1.453	3,2	e	NA	150/150	T,I,K,V,H,S,E,Q,A,L,M,R,N,D,W,Y
190	V	VAL:190:A	-0.433	7	-0.635, -0.282	7,6	b	NA	150/150	V,I,M,T,C,L,S
191	F	PHE:191:A	-0.12	5	-0.364, 0.019	6,5	b	NA	150/150	F,Y,A,L,W
192	K	LYS:192:A	2.362	1	1.453, 2.658	2,1	e	NA	149/150	K,R,Q,T,N,A,E,G,D,S,X,V,P,L,C,I
193	T	THR:193:A	0.373	4	0.019, 0.473	5,4	e	NA	150/150	T,E,S,N,K,Q,H,R,M,Y,G,A
194	L	LEU:194:A	-1.017	9	-1.138, -0.938	9,8	b	s	149/150	L,G,V,M
195	K	LYS:195:A	0.92	3	0.473, 0.994	4,3	e	NA	149/150	K,R,T,V,S,I,N,C,M,A,H,E,Q,L,F
196	S	SER:196:A	1.404	3	0.994, 1.453	3,2	e	NA	149/150	S,T,K,D,R,Q,E,V,M,A,N,G,L,P
197	L	LEU:197:A	-0.689	7	-0.847, -0.575	8,7	b	NA	150/150	L,T,M,Y,I,V,C,A,R
198	Y	TYR:198:A	-0.202	6	-0.439, -0.093	7,5	b	NA	150/150	Y,H,F,S,L,W,M,T,I,R
199	K	LYS:199:A	1.348	3	0.696, 1.453	4,2	e	NA	150/150	K,N,P,S,V,A,T,Q,F,I,E,R,G,H,D
200	T	THR:200:A	-0.063	5	-0.282, 0.019	6,5	e	NA	150/150	T,S,A,K,L,V,D,E,R,N,Q,G
201	H	HIS:201:A	-0.449	7	-0.635, -0.364	7,6	e	NA	150/150	H,W,Y,N,K,R,L,F
202	A	ALA:202:A	-1.186	9	-1.281, -1.138	9,9	b	s	150/150	A,R,S,F,T
203	C	CYS:203:A	-1.14	9	-1.246, -1.062	9,9	b	s	150/150	C,T,S
204	Y	TYR:204:A	1.402	3	0.994, 1.453	3,2	e	NA	148/150	Y,R,K,Q,S,A,E,H,X,N,T,L,D,M,V,P
205	E	GLU:205:A	-1.013	9	-1.100, -0.938	9,8	e	f	150/150	E,Q,H,V
206	Y	TYR:206:A	0.024	5	-0.282, 0.147	6,5	b	NA	149/150	Y,H,F,M
207	N	ASN:207:A	-0.47	7	-0.635, -0.364	7,6	e	NA	149/150	N,L,I,Q,C,R,K,V
208	H	HIS:208:A	1.022	3	0.473, 1.453	4,2	e	NA	149/150	H,R,Y,N,K,Q,D,E,S,A,V,W,L,G
209	I	ILE:209:A	-0.194	6	-0.439, -0.093	7,5	b	NA	149/150	I,V,M,N,H,A,G,S,T,Y
210	F	PHE:210:A	0.087	5	-0.193, 0.295	6,4	b	NA	149/150	F,L,I,W,K,V,P,M,C
211	P	PRO:211:A	0.737	4	0.295, 0.994	4,3	e	NA	149/150	P,R,T,Q,H,N,K,S,E,G,A
212	L	LEU:212:A	-0.044	5	-0.282, 0.147	6,5	e	NA	149/150	L,I,Q,K,E,V,M,D,N,R,S
213	L	LEU:213:A	-0.811	8	-0.981, -0.692	8,7	b	NA	149/150	L,M,F,W
214	E	GLU:214:A	0.242	5	-0.093, 0.473	5,4	e	NA	149/150	E,M,I,V,Q,S,T,R,H,K,L
215	K	LYS:215:A	0.909	3	0.473, 0.994	4,3	e	NA	150/150	K,E,D,Q,A,R,V,S,N,T,L,I,G
216	Y	TYR:216:A	0.148	5	-0.093, 0.295	5,4	e	NA	150/150	Y,N,T,H,Q,F,E,K,A,S,G,I
217	C	CYS:217:A	-0.336	6	-0.575, -0.193	7,6	b	NA	150/150	C,S,F,G,D,K,A,V,Q
218	G	GLY:218:A	0.219	5	-0.093, 0.473	5,4	e	NA	150/150	G,A,S,E,D,K,N,L,I,V,C
219	F	PHE:219:A	-0.379	6	-0.575, -0.282	7,6	b	NA	150/150	F,Y,V,C,L,I
220	H	HIS:220:A	0.636	4	0.295, 0.696	4,4	e	NA	150/150	H,R,C,N,K,Q,G,S,T,A,V,D
221	E	GLU:221:A	0.067	5	-0.193, 0.147	6,5	e	NA	150/150	E,Q,P,A,D,K,V,R,S
222	D	ASP:222:A	0.251	5	-0.093, 0.473	5,4	e	NA	150/150	D,N,Q,T,K,S,H,G,E
223	N	ASN:223:A	-0.341	6	-0.509, -0.193	7,6	e	NA	150/150	N,Q,I,K,C,H,R,S,V,E,F,D,A
224	I	ILE:224:A	-0.915	8	-1.022, -0.847	9,8	b	NA	149/150	I,V,L,M
225	P	PRO:225:A	-1.278	9	-1.338, -1.246	9,9	b	s	149/150	P
226	Q	GLN:226:A	-1.213	9	-1.281, -1.175	9,9	b	s	150/150	Q,K,S,G
227	L	LEU:227:A	-0.878	8	-1.022, -0.797	9,8	b	NA	150/150	L,C,I,Q,A,G,M,S,V,T
228	E	GLU:228:A	-0.293	6	-0.509, -0.193	7,6	e	NA	149/150	E,Q,D,A,K,R,G,S,N,L
229	D	ASP:229:A	-0.447	7	-0.635, -0.364	7,6	e	NA	150/150	D,E,S,Q,A,R,K,H
230	V	VAL:230:A	-0.547	7	-0.692, -0.439	7,7	b	NA	150/150	V,I,T,L,M,C
231	S	SER:231:A	-1.114	9	-1.211, -1.062	9,9	b	s	150/150	S,N,T,C,D,V
232	Q	GLN:232:A	1.976	2	0.994, 2.658	3,1	e	NA	150/150	Q,R,N,E,Y,C,L,D,I,K,V,A,H,T,S,G
233	F	PHE:233:A	-1.013	9	-1.138, -0.938	9,8	b	s	150/150	F,A,Y,V
234	L	LEU:234:A	-1.109	9	-1.211, -1.062	9,9	b	s	150/150	L,S,M,C
235	Q	GLN:235:A	0.124	5	-0.093, 0.295	5,4	e	NA	150/150	Q,K,R,I,M,C,S,E,H,L,P
236	T	THR:236:A	0.474	4	0.147, 0.696	5,4	e	NA	150/150	T,S,D,E,A,G,R,Q,Y,K
237	C	CYS:237:A	0.227	5	-0.093, 0.473	5,4	e	NA	150/150	C,S,R,Q,W,K,T,A,H,E,N,L
238	T	THR:238:A	-0.957	8	-1.062, -0.893	9,8	b	NA	150/150	T,S,Y
239	G	GLY:239:A	-1.14	9	-1.246, -1.062	9,9	e	f	150/150	G,Q,K
240	F	PHE:240:A	-1.01	8	-1.138, -0.938	9,8	b	NA	150/150	F,Y,W
241	R	ARG:241:A	0.088	5	-0.193, 0.295	6,4	e	NA	150/150	R,T,Q,S,I,L,C,K,V
242	L	LEU:242:A	-0.616	7	-0.797, -0.509	8,7	b	NA	150/150	L,V,I,M
243	R	ARG:243:A	-1.167	9	-1.246, -1.138	9,9	b	s	150/150	R,W,G,K
244	P	PRO:244:A	-1.231	9	-1.318, -1.211	9,9	b	s	150/150	P,S
245	V	VAL:245:A	-0.956	8	-1.062, -0.893	9,8	b	NA	150/150	V,T,S,I,A,C
246	A	ALA:246:A	-0.94	8	-1.062, -0.893	9,8	b	NA	150/150	A,M,S,Q,G,T
247	G	GLY:247:A	-1.208	9	-1.318, -1.175	9,9	b	s	150/150	G,N
248	L	LEU:248:A	-1.202	9	-1.281, -1.175	9,9	e	f	150/150	L,Y,H
249	L	LEU:249:A	-0.968	8	-1.100, -0.893	9,8	b	NA	150/150	L,I,V,T
250	S	SER:250:A	-1.005	8	-1.100, -0.938	9,8	b	NA	150/150	S,T,P,A,L

Supplementary 3 (Continued)

251	S	SER:251:A	-0.66	7	-0.797, -0.575	8,7	b	NA	149/150	S,P,A,T,V,F,Q,I
252	R	ARG:252:A	-1.27	9	-1.338, -1.246	9,9	b	s	149/150	R,I
253	D	ASP:253:A	-1.236	9	-1.318, -1.211	9,9	b	s	149/150	D,E,H
254	F	PHE:254:A	-1.286	9	-1.338, -1.281	9,9	e	f	149/150	F
255	L	LEU:255:A	-1.157	9	-1.246, -1.100	9,9	b	s	149/150	L,I,M
256	G	GLY:256:A	-0.934	8	-1.062, -0.847	9,8	b	NA	150/150	G,A,S,N,V,Y,Q,C
257	G	GLY:257:A	-0.664	7	-0.847, -0.575	8,7	b	NA	150/150	G,A,S,C,N
258	L	LEU:258:A	-1.111	9	-1.211, -1.062	9,9	b	s	150/150	L,I,F,V
259	A	ALA:259:A	-1.249	9	-1.318, -1.211	9,9	b	s	150/150	A,S,V
260	F	PHE:260:A	-1.063	9	-1.175, -0.981	9,8	b	s	150/150	F,Y,L
261	R	ARG:261:A	-1.2	9	-1.281, -1.175	9,9	e	f	149/150	R,K,S
262	V	VAL:262:A	-1.049	9	-1.138, -0.981	9,8	b	s	150/150	V,A,M,I,T,L
263	F	PHE:263:A	-1.287	9	-1.338, -1.281	9,9	b	s	150/150	F
264	H	HIS:264:A	-0.795	8	-0.938, -0.692	8,7	b	NA	150/150	H,Q,F,P,Y,S,N
265	C	CYS:265:A	-0.735	8	-0.893, -0.635	8,7	b	NA	150/150	C,S,A,T
266	T	THR:266:A	-1.282	9	-1.338, -1.246	9,9	b	s	150/150	T,S
267	Q	GLN:267:A	-1.265	9	-1.318, -1.246	9,9	b	s	150/150	Q,K,L
268	Y	TYR:268:A	-1.246	9	-1.318, -1.211	9,9	b	s	150/150	Y,K
269	I	ILE:269:A	-0.822	8	-0.938, -0.746	8,8	b	NA	150/150	I,V,L,K,T
270	R	ARG:270:A	-1.269	9	-1.338, -1.246	9,9	b	s	150/150	R,D
271	H	HIS:271:A	-1.272	9	-1.338, -1.246	9,9	b	s	150/150	H,D
272	G	GLY:272:A	1.395	3	0.994, 1.453	3,2	e	NA	150/150	G,C,S,H,P,Q,Y,A,D,F,E,V,T,N,W
273	S	SER:273:A	-0.927	8	-1.022, -0.847	9,8	e	f	149/150	S,A,K,T,X,N,G,V
274	K	LYS:274:A	0.38	4	0.019, 0.473	5,4	e	NA	150/150	K,R,N,S,Q,V,C,A,D,E,M,T
275	P	PRO:275:A	-1.064	9	-1.175, -0.981	9,8	e	f	150/150	P,A,V,C
276	M	MET:276:A	0.443	4	0.147, 0.696	5,4	e	NA	150/150	M,T,L,K,F,N,W,Y,D,S,H,E,Q
277	Y	TYR:277:A	-1.014	9	-1.138, -0.938	9,8	e	f	150/150	Y,F,H
278	T	THR:278:A	-1.079	9	-1.175, -1.022	9,9	e	f	150/150	T,S,L,C
279	P	PRO:279:A	-1.066	9	-1.175, -0.981	9,8	e	f	150/150	P,V,F
280	E	GLU:280:A	-1.285	9	-1.338, -1.281	9,9	b	s	150/150	E,S
281	P	PRO:281:A	-1.177	9	-1.281, -1.138	9,9	e	f	150/150	P,L,S
282	D	ASP:282:A	-1.299	9	-1.338, -1.281	9,9	b	s	150/150	D
283	I	ILE:283:A	-0.237	6	-0.439, -0.093	7,5	b	NA	150/150	I,V,T,C,A,R,M,L
284	C	CYS:284:A	-0.509	7	-0.692, -0.364	7,6	b	NA	150/150	C,V,I,L,G
285	H	HIS:285:A	-1.299	9	-1.338, -1.281	9,9	b	s	150/150	H
286	E	GLU:286:A	-1.285	9	-1.338, -1.281	9,9	b	s	150/150	E,D
287	L	LEU:287:A	-0.89	8	-1.022, -0.797	9,8	b	NA	150/150	L,V,I,F
288	L	LEU:288:A	-0.557	7	-0.746, -0.439	8,7	b	NA	150/150	L,M,I,F,V
289	G	GLY:289:A	-1.268	9	-1.338, -1.246	9,9	b	s	150/150	G
290	H	HIS:290:A	-1.272	9	-1.338, -1.246	9,9	b	s	150/150	H,N
291	V	VAL:291:A	-0.173	6	-0.364, -0.093	6,5	b	NA	150/150	V,A,C,M,I,F,L,T
292	P	PRO:292:A	-1.127	9	-1.246, -1.062	9,9	b	s	150/150	P,A
293	L	LEU:293:A	-0.807	8	-0.938, -0.746	8,8	b	NA	150/150	L,M,I,F
294	F	PHE:294:A	-0.878	8	-1.022, -0.797	9,8	b	NA	150/150	F,L,Y
295	S	SER:295:A	-1.066	9	-1.175, -1.022	9,9	b	s	150/150	S,A,C,L,G,T
296	D	ASP:296:A	-0.831	8	-0.981, -0.746	8,8	e	f	150/150	D,E,N,Y,H,F
297	R	ARG:297:A	0.093	5	-0.193, 0.295	6,4	e	NA	150/150	R,P,S,H,Q,V,K,A,T
298	S	SER:298:A	0.309	4	0.019, 0.473	5,4	e	NA	150/150	S,A,G,K,T,D,N,E,V,Q,Y,I,L
299	F	PHE:299:A	-1.103	9	-1.211, -1.062	9,9	b	s	150/150	F,Y,V,I
300	A	ALA:300:A	-1.246	9	-1.318, -1.211	9,9	b	s	150/150	A,S,I
301	Q	GLN:301:A	-0.796	8	-0.938, -0.692	8,7	e	f	150/150	Q,R,D,E,A,V,S,N,H,W
302	F	PHE:302:A	-1.108	9	-1.211, -1.062	9,9	b	s	150/150	F,L,Y
303	S	SER:303:A	-1.086	9	-1.175, -1.022	9,9	b	s	150/150	S,C,A,T
304	Q	GLN:304:A	-1.164	9	-1.246, -1.138	9,9	b	s	150/150	Q,H,F
305	E	GLU:305:A	-0.871	8	-0.981, -0.797	8,8	b	NA	150/150	E,V,D,N,Q,T,A,M,K
306	I	ILE:306:A	-0.735	8	-0.893, -0.635	8,7	b	NA	150/150	I,V,L,T,S
307	G	GLY:307:A	-1.268	9	-1.338, -1.246	9,9	b	s	150/150	G
308	L	LEU:308:A	-1.064	9	-1.175, -0.981	9,8	b	s	149/150	L,M,I,V
309	A	ALA:309:A	-1.024	9	-1.138, -0.981	9,8	b	s	149/150	A,L,S,T
310	S	SER:310:A	-1.241	9	-1.318, -1.211	9,9	b	s	150/150	S,T,A,E
311	L	LEU:311:A	-1.113	9	-1.211, -1.062	9,9	b	s	150/150	L,I,V

Supplementary 3 (Continued)

312	G	GLY:312:A	-0.943	8	-1.100, -0.847	9,8	b	NA	150/150	G,A,S,L
313	A	ALA:313:A	-1.034	9	-1.138, -0.981	9,8	b	s	150/150	A,S,T,V,F
314	P	PRO:314:A	-0.625	7	-0.797, -0.509	8,7	e	NA	150/150	P,S,L,T,C,N,A,G,H,K,D,R
315	D	ASP:315:A	-0.747	8	-0.893, -0.635	8,7	e	f	150/150	D,N,E,T,H
316	E	GLU:316:A	-0.135	5	-0.364, 0.019	6,5	e	NA	150/150	E,D,S,N,A,Q,K,R,V,H
317	Y	TYR:317:A	-0.183	6	-0.439, -0.093	7,5	e	NA	150/150	Y,F,V,M,A,D,E,S,T,Q,L,P
318	I	ILE:318:A	-0.522	7	-0.692, -0.439	7,7	b	NA	150/150	I,V,L,C
319	E	GLU:319:A	0.077	5	-0.193, 0.295	6,4	e	NA	150/150	E,M,Q,K,T,L,H,S,N,D,A,R,I,V
320	K	LYS:320:A	-0.431	6	-0.635, -0.282	7,6	e	NA	150/150	K,M,R,Q,E,H,N,S,P,L,F
321	L	LEU:321:A	-1.064	9	-1.175, -0.981	9,8	b	s	150/150	L,F,I
322	A	ALA:322:A	-0.733	8	-0.893, -0.635	8,7	b	NA	150/150	A,S,G,P,R
323	T	THR:323:A	-0.872	8	-0.981, -0.797	8,8	b	NA	150/150	T,A,S,R,K,Q,N
324	I	ILE:324:A	0.102	5	-0.193, 0.295	6,4	b	NA	150/150	I,V,L,C,M,F
325	Y	TYR:325:A	-0.926	8	-1.062, -0.847	9,8	b	NA	149/150	Y,F,G,C
326	W	TRP:326:A	-1.149	9	-1.246, -1.100	9,9	b	s	149/150	W,F,V
327	F	PHE:327:A	-0.968	8	-1.100, -0.893	9,8	b	NA	149/150	F,Y,V,W,H
328	T	THR:328:A	-1.104	9	-1.211, -1.062	9,9	b	s	149/150	T,I,S,A
329	V	VAL:329:A	-0.536	7	-0.692, -0.439	7,7	b	NA	149/150	V,A,I,F,L
330	E	GLU:330:A	-1.256	9	-1.318, -1.246	9,9	b	s	149/150	E,Q,G
331	F	PHE:331:A	-0.875	8	-1.022, -0.797	9,8	b	NA	149/150	F,Y,T
332	G	GLY:332:A	-1.205	9	-1.318, -1.175	9,9	b	s	148/150	G,V
333	L	LEU:333:A	-0.482	7	-0.692, -0.364	7,6	b	NA	148/150	L,I,M,V,Q
334	C	CYS:334:A	-0.81	8	-0.981, -0.692	8,7	b	NA	148/150	C,A,T,V,S,L
335	K	LYS:335:A	0.148	5	-0.093, 0.295	5,4	e	NA	148/150	K,R,N,V,L,E,I,Q,M,T,S,C,G
336	Q	GLN:336:A	-0.823	8	-0.938, -0.746	8,8	e	f	147/150	Q,E,T,D,V
337	G	GLY:337:A	1.297	3	0.696, 1.453	4,2	e	NA	147/150	G,D,E,Q,N,A,K,H,S,T,R
338	D	ASP:338:A	0.481	4	0.147, 0.696	5,4	e	NA	147/150	D,E,S,G,N,V,W,H,R,P
339	S	SER:339:A	1.371	3	0.994, 1.453	3,2	e	NA	147/150	S,K,D,E,A,Q,R,H,L,M,G,I,T,N
340	I	ILE:340:A	1.238	3	0.696, 1.453	4,2	e	NA	148/150	I,L,T,V,R,K,M,F,Y,N,A,W
341	K	LYS:341:A	-0.573	7	-0.746, -0.439	8,7	e	NA	148/150	K,R,G,I
342	A	ALA:342:A	-0.871	8	-0.981, -0.797	8,8	b	NA	148/150	A,V,I,C,D
343	Y	TYR:343:A	-0.392	6	-0.635, -0.282	7,6	b	NA	148/150	Y,F,C,W,T,I
344	G	GLY:344:A	-1.139	9	-1.246, -1.062	9,9	b	s	148/150	G,T,S
345	A	ALA:345:A	-1.245	9	-1.318, -1.211	9,9	b	s	148/150	A,G
346	G	GLY:346:A	-1.141	9	-1.246, -1.100	9,9	b	s	148/150	G,A,K
347	L	LEU:347:A	-1.063	9	-1.175, -0.981	9,8	b	s	148/150	L,I,E,F
348	L	LEU:348:A	-1.199	9	-1.281, -1.175	9,9	b	s	148/150	L,N,I
349	S	SER:349:A	-1.291	9	-1.338, -1.281	9,9	b	s	148/150	S,H
350	S	SER:350:A	-1.14	9	-1.211, -1.100	9,9	e	f	148/150	S,A,C,K
351	F	PHE:351:A	0.089	5	-0.193, 0.295	6,4	e	NA	148/150	F,Y,I,V,A,S,C,K
352	G	GLY:352:A	-0.815	8	-0.981, -0.692	8,7	e	f	148/150	G,S,A,Q,T
353	E	GLU:353:A	-1.285	9	-1.338, -1.281	9,9	b	s	148/150	E,P
354	L	LEU:354:A	-1.11	9	-1.211, -1.062	9,9	b	s	148/150	L,I,M,Y
355	Q	GLN:355:A	0.294	4	0.019, 0.473	5,4	e	NA	148/150	Q,K,E,R,S,I,D,G,L,V,N,M,T
356	Y	TYR:356:A	-0.595	7	-0.746, -0.509	8,7	e	NA	147/150	Y,H,W,R,V,A,N,F
357	C	CYS:357:A	-0.093	5	-0.364, 0.019	6,5	b	NA	144/150	C,S,A,V,T
358	L	LEU:358:A	-0.121	5	-0.364, 0.019	6,5	e	NA	144/150	L,K,V,I,M,C,S,F
359	S	SER:359:A	-0.422	6	-0.575, -0.282	7,6	e	NA	144/150	S,T,E,N,L,Q,G,A
360	E	GLU:360:A	0.829	4	0.473, 0.994	4,3	e	NA	144/150	E,G,S,D,N,R,A,T,P,Q,V
361	K	LYS:361:A	0.368	4	0.019, 0.473	5,4	e	NA	144/150	K,T,E,Q,N,H,S,R,P,Y,V,D,G
362	P	PRO:362:A	-0.38	6	-0.575, -0.282	7,6	b	NA	144/150	P,A,S,D,E,T,W,N
363	K	LYS:363:A	0.384	4	0.019, 0.473	5,4	e	NA	144/150	K,E,R,D,Q,S,N,I,C,T,P,H,V,A
364	L	LEU:364:A	2.578	1	1.453, 2.658	2,1	e	NA	144/150	L,Y,V,F,I,S,H,K,T,R,M
365	L	LEU:365:A	1.031	3	0.473, 1.453	4,2	e	NA	144/150	L,Q,K,M,R,A,Y,E,V,I
366	P	PRO:366:A	1.11	3	0.696, 1.453	4,2	e	NA	143/150	P,Q,A,E,D,T,V,R,K,M,I,H,G
367	L	LEU:367:A	-0.992	8	-1.138, -0.893	9,8	b	NA	143/150	L,F,W
368	E	GLU:368:A	-0.039	5	-0.282, 0.147	6,5	e	NA	143/150	E,D,V,N,S,I,L
369	L	LEU:369:A	-0.944	8	-1.100, -0.847	9,8	b	NA	143/150	L,M,P,C,S,A
370	E	GLU:370:A	1.508	2	0.994, 1.453	3,2	e	NA	143/150	E,D,V,A,Y,F,I,S,T,K,L,Q,P,W,N
371	K	LYS:371:A	1.631	2	0.994, 1.453	3,2	e	NA	144/150	K,N,V,Q,R,E,I,T,S,A,H,L,M,D,W
372	T	THR:372:A	-0.332	6	-0.509, -0.193	7,6	b	NA	144/150	T,I,M,A,C,V,R
373	A	ALA:373:A	-0.075	5	-0.282, 0.019	6,5	b	NA	144/150	A,S,C,G,I,T,V

Supplementary 3 (Continued)

374	I	ILE:374:A	2.174	1	0.994, 2.658	3,1	e	NA	144/150	I,V,K,L,E,S,D,Q,T,H,N,R,M,Y,A
375	Q	GLN:375:A	-0.57	7	-0.746, -0.509	8,7	e	NA	144/150	Q,T,E,A,H,M,C,L,N,R
376	N	ASN:376:A	0.456	4	0.147, 0.696	5,4	e	NA	144/150	N,E,P,K,Q,D,A,T,S,I,L
377	Y	TYR:377:A	-0.816	8	-0.981, -0.692	8,7	b	NA	144/150	Y,C,P,L,H,S,F,N
378	T	THR:378:A	-0.095	5	-0.364, 0.019	6,5	e	NA	143/150	T,P,N,L,I,M,R,Q,V,D,S,E,H
379	V	VAL:379:A	-1.02	9	-1.138, -0.981	9,8	e	f	143/150	V,I,D,S,Q
380	T	THR:380:A	-0.848	8	-0.981, -0.746	8,8	e	f	145/150	T,E,Q,M,A,N,P,L,S,Y,V
381	E	GLU:381:A	0.262	5	0.019, 0.473	5,4	e	NA	145/150	E,S,Q,K,C,D,G,T,A,N,R,P
382	F	PHE:382:A	-0.11	5	-0.364, 0.019	6,5	e	NA	145/150	F,Y,P,W,M,I
383	Q	GLN:383:A	-1.263	9	-1.318, -1.246	9,9	b	s	145/150	Q,F,N
384	P	PRO:384:A	0.289	4	0.019, 0.473	5,4	e	NA	145/150	P,E,D,K,N,L,S,T,C,Q,W,R,V
385	L	LEU:385:A	0.58	4	0.295, 0.696	4,4	b	NA	145/150	L,R,I,V,T,K,A,G,M,Q,N
386	Y	TYR:386:A	-1.147	9	-1.246, -1.100	9,9	b	s	144/150	Y,R,F,L
387	Y	TYR:387:A	-0.228	6	-0.439, -0.093	7,5	b	NA	144/150	Y,F,L,W,V
388	V	VAL:388:A	-0.255	6	-0.439, -0.093	7,5	b	NA	144/150	V,I,L,F,A,Y,T,C,D
389	A	ALA:389:A	-0.687	7	-0.847, -0.575	8,7	b	NA	144/150	A,S,T,G,L,C
390	E	GLU:390:A	0.036	5	-0.193, 0.147	6,5	e	NA	143/150	E,D,N,Q,K,A,X,R,F,T,S
391	S	SER:391:A	-0.874	8	-0.981, -0.797	8,8	e	f	144/150	S,N,D,T,Q,C,R
392	F	PHE:392:A	-0.698	7	-0.893, -0.575	8,7	b	NA	144/150	F,I,L,G,R,M
393	N	ASN:393:A	0.771	4	0.295, 0.994	4,3	e	NA	144/150	N,M,K,E,D,Q,G,A,L,T,S,P,I,V,F,R
394	D	ASP:394:A	-0.121	5	-0.364, 0.019	6,5	e	NA	144/150	D,S,N,K,E,Q,V,A,C,T,G,R
395	A	ALA:395:A	-0.968	8	-1.100, -0.893	9,8	b	NA	144/150	A,G,V,M,S
396	K	LYS:396:A	-0.697	7	-0.847, -0.635	8,7	b	NA	144/150	K,Q,R,I,A,M,E,T
397	E	GLU:397:A	1.012	3	0.473, 1.453	4,2	e	NA	144/150	E,D,Q,I,A,R,N,V,M,L,S,P,T,H,K
398	K	LYS:398:A	-0.26	6	-0.439, -0.093	7,5	e	NA	144/150	K,R,Q,L,D,M,E,P,N
399	V	VAL:399:A	-0.219	6	-0.439, -0.093	7,5	b	NA	144/150	V,L,M,T,I,F
400	R	ARG:400:A	-0.307	6	-0.509, -0.193	7,6	e	NA	144/150	R,K,V,I,S,L,T,M,W,Q,E
401	N	ASN:401:A	1.335	3	0.696, 1.453	4,2	e	NA	142/150	N,K,R,T,E,H,Q,A,S,D,L,I,G,V,M
402	F	PHE:402:A	-0.06	5	-0.364, 0.147	6,5	b	NA	142/150	F,W,Y
403	A	ALA:403:A	-0.291	6	-0.509, -0.193	7,6	b	NA	142/150	A,S,T,V,C,Y,G,I
404	A	ALA:404:A	1.011	3	0.473, 1.453	4,2	e	NA	142/150	A,S,G,H,N,K,Y,Q,D,F,L,M,E,R,T,C
405	T	THR:405:A	0.611	4	0.295, 0.696	4,4	e	NA	142/150	T,A,K,S,N,H,Q,R,G,D,V
406	I	ILE:406:A	-0.556	7	-0.746, -0.439	8,7	b	NA	142/150	I,V,T,L,Q,M,F,N
407	P	PRO:407:A	0.229	5	-0.093, 0.473	5,4	e	NA	142/150	P,E,S,K,N,T,D,Q,R,M,C,V
408	R	ARG:408:A	-0.879	8	-1.022, -0.797	9,8	e	f	142/150	R,K,H
409	P	PRO:409:A	-0.336	6	-0.575, -0.193	7,6	e	NA	142/150	P,S,K,D,N,L,R,T,C
410	F	PHE:410:A	-0.814	8	-0.981, -0.692	8,7	b	NA	142/150	F,Y,H,I,V,L
411	S	SER:411:A	0.606	4	0.295, 0.696	4,4	e	NA	142/150	S,T,G,M,Q,N,L,A,E,H,C,Y,F,K,V,P,I,W
412	V	VAL:412:A	-0.152	6	-0.364, 0.019	6,5	b	NA	142/150	V,I,L,M,A,P,N
413	R	ARG:413:A	-0.026	5	-0.282, 0.147	6,5	e	NA	142/150	R,H,T,K,Y,M,N,C,E,L,Q,A,V
414	Y	TYR:414:A	-0.774	8	-0.938, -0.692	8,7	b	NA	142/150	Y,F,L,H
415	D	ASP:415:A	-0.665	7	-0.797, -0.575	8,7	b	NA	142/150	D,N,E,H,R,S,I
416	P	PRO:416:A	0.109	5	-0.193, 0.295	6,4	e	NA	142/150	P,S,A,F,N,G,V
417	Y	TYR:417:A	0.196	5	-0.093, 0.473	5,4	e	NA	142/150	Y,L,F,C,H,I,V,N,Q,A,K
418	T	THR:418:A	-0.883	8	-1.022, -0.797	9,8	e	f	142/150	T,N,I,S,G,Q,A
419	Q	GLN:419:A	-0.18	6	-0.364, -0.093	6,5	e	NA	142/150	Q,R,H,E,A,V,K,L,C,Y,S,N,G,W,D
420	R	ARG:420:A	-0.659	7	-0.797, -0.575	8,7	e	NA	141/150	R,S,Q,N,T,A,I
421	I	ILE:421:A	0.158	5	-0.093, 0.295	5,4	b	NA	140/150	I,V,M,L,A
422	E	GLU:422:A	-0.157	6	-0.364, 0.019	6,5	b	NA	138/150	E,D,N,Q,R,K,I,M,S,W,H
423	V	VAL:423:A	0.296	4	0.019, 0.473	5,4	b	NA	136/150	V,I,T,F,M,L,E,A,S,Q
424	L	LEU:424:A	-0.302	6	-0.509, -0.193	7,6	b	NA	132/150	L,I,V,D,M,T,S,P,Y
425	D	ASP:425:A	-0.059	5	-0.282, 0.147	6,5	e	NA	131/150	D,E,N,R,K,T,Q,S,Y,P
426	N	ASN:426:A	0.107	5	-0.193, 0.295	6,4	e	NA	129/150	N,S,Q,R,G,K,D,A,T,E,V,H,M
427	T	THR:427:A	0.383	4	0.019, 0.473	5,4	e	NA	125/150	T,A,V,K,P,I,L,S,N,R,F,M,Q,Y,E
428	Q	GLN:428:A	1.305	3	0.696, 1.453	4,2	e	NA	124/150	Q,K,D,G,E,P,N,S,M,H,Y,R,T,A,C,L
429	Q	GLN:429:A	0.121	5	-0.193, 0.295	6,4	b	NA	124/150	Q,H,S,T,I,A,K,R,N,C,D,E,Y
430	L	LEU:430:A	0.331	4	0.019, 0.473	5,4	e	NA	124/150	L,I,V,M,T,A,C
431	K	LYS:431:A	1.418	3	0.994, 1.453	3,2	e	NA	124/150	K,M,R,S,V,L,I,G,E,N,Q,A,T,D,Y
432	I	ILE:432:A	1.573	2	0.994, 1.453	3,2	e	NA	124/150	I,N,S,D,G,H,Q,E,V,R,K,M,T,Y,A,L
433	L	LEU:433:A	0.805	4	0.295, 0.994	4,3	e	NA	125/150	L,M,V,A,F,Y,I,S,G,T,N
434	A	ALA:434:A	0.26	5	-0.093, 0.473	5,4	e	NA	125/150	A,T,M,V,L,I,S,K,W
435	D	ASP:435:A	1.682	2	0.994, 1.453	3,2	e	NA	125/150	D,N,G,A,K,S,T,R,Y,Q,I,H,E,C,W

Supplementary 3 (Continued)

436	S	SER:436:A	1.135	3	0.696, 1.453	4,2	e	NA	125/150	S,T,C,N,D,G,E,Q,L,H,K,A,M,R
437	I	ILE:437:A	0.271	5	-0.093, 0.473	5,4	e	NA	125/150	I,S,L,V,M
438	N	ASN:438:A	0.717	4	0.295, 0.994	4,3	e	NA	124/150	N,K,S,G,H,I,R,E,Q,C
439	S	SER:439:A	0.935	3	0.473, 0.994	4,3	e	NA	123/150	S,N,G,C,H,Q,T,R,Y,D,E,A,L,I
440	E	GLU:440:A	-0.31	6	-0.509,-0.193	7,6	e	NA	123/150	E,M,D,Q,N,H
441	I	ILE:441:A	0.783	4	0.295, 0.994	4,3	e	NA	122/150	I,V,M,L,Y,F,T,N
442	G	GLY:442:A	1.237	3	0.696, 1.453	4,2	e	NA	122/150	G,S,E,H,D,M,Q,A,N,F,C,K,L,T,R
443	I	ILE:443:A	1.011	3	0.473, 1.453	4,2	e	NA	122/150	I,K,C,L,V,M,T,E,R,A,S,N,H,Q
444	L	LEU:444:A	-0.733	8	-0.893, -0.635	8,7	e	f	121/150	L,C,I,V
445	C	CYS:445:A	0.949	3	0.473, 0.994	4,3	e	NA	120/150	C,S,V,E,Q,L,T,I,M,H,A,G,N,R,F
446	S	SER:446:A	1.285	3	0.696, 1.453	4,2	e	NA	119/150	S,N,E,Q,D,T,G,H,F,K,L,A,C,R
447	A	ALA:447:A	-0.92	8	-1.062, -0.847	9,8	e	f	119/150	A,S,T,V,I
448	L	LEU:448:A	-0.169	6	-0.439, 0.019	7,5	e	NA	119/150	L,F,V,I,M,A
449	Q	GLN:449:A	1.824	2	0.994, 2.658	3,1	e	NA	117/150	Q,R,K,T,S,D,E,A,H,M,G,N
450	K	LYS:450:A	-0.226	6	-0.439, -0.093	7,5	e	NA	105/150	K,R,Q,T,A,N,V,Y
451	I	ILE:451:A	0.882	3	0.473, 0.994	4,3	e	NA	89/150	I,N,L,V,F,M
452	K	LYS:452:A	-0.747	8	-1.022, -0.575	9,7	e	f	18/150	K,R

* Below the confidence cut-off - The calculations for this site were performed on less than 6 non-gaped homologue sequences, or the confidence interval for the estimated score is equal to- or larger than- 4 color grades.

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Supplementary 2 Article 10-127-11

| Post date: 2025/12/29 |

Supplementary 2. Putative pathogenic variants in the PAH gene listed in the Iranome genomic database

PAH missense variants	Number of heterozygotes	CADD Score	SIFT	Polyphen2	MutationTaster	MutationAssessor	FATHMM	FATHMM MKL	N/6 Damaging Prediction	Population with the most Frequency of Allele	Population with the Least Frequency of Allele
c.1169A>G	1	23.4	Damaging	Possibly damaging	Damaging	Predicted functional (Medium)	Damaging	Damaging	6	Persian (0.005)	Turkmen (0)
c.1157A>G	1	25.1	Damaging	Probably damaging	Damaging	Predicted functional (High)	Damaging	Damaging	6	Persian (0.005)	Turkmen (0)
c.1139C>T	5	26.3	Damaging	Probably damaging	Damaging	Predicted functional (High)	Damaging	Damaging	6	Azeri (0.015)	Turkmen (0)
c.1066T>C	1	9.756	Tolerated	Possibly damaging	Damaging	Predicted non-functional (Low)	Damaging	Damaging	4	Kurd (0.005)	Turkmen (0)
c.898G>T	4	34	Damaging	Probably damaging	Damaging	Predicted functional (Medium)	Damaging	Damaging	6	Azeri (0.005)	Persian Gulf Islander (0)
c.820A>G	2	18.93	Tolerated	Benign	Damaging	Predicted non-functional (Neutral)	Damaging	Damaging	3	Persian (0.005)	Turkmen (0)
c.728G>A	1	35	Damaging	Probably damaging	Damaging	Predicted functional (Medium)	Damaging	Damaging	6	Arab (0.005)	Turkmen (0)
c.688G>A	13	22.7	Tolerated	Benign	Damaging	Predicted non-functional (Neutral)	Damaging	Damaging	3	Kurd (0.03)	Turkmen (0)
c.533A>G	1	24	Damaging	Possibly damaging	Damaging	Predicted functional (Medium)	Damaging	Damaging	6	Turkmen (0.005)	Persian Gulf Islander (0)
c.506G>A	1	25.9	Damaging	Benign	Damaging	Predicted functional (Medium)	Damaging	Damaging	5	Arab (0.005)	Turkmen (0)
c.281T>G	1	21.9	Damaging	Benign	Damaging	Predicted functional (Medium)	Damaging	Damaging	5	Arab (0.005)	Turkmen (0)
c.280A>G	1	7.262	Tolerated	Benign	Damaging	Predicted non-functional (Neutral)	Damaging	Damaging	3	Turkmen (0.005)	Persian Gulf Islander (0)
c.169G>A	3	22.8	Tolerated	Benign	Damaging	Predicted non-functional (Low)	Damaging	Damaging	3	Lur (0.01)	Turkmen (0)
c.165T>G	3	24.5	Damaging	Probably damaging	Damaging	Predicted functional (Medium)	Damaging	Damaging	6	Persian (0.015)	Turkmen (0)
c.143T>C	1	27.8	Damaging	Probably damaging	Damaging	Predicted functional (High)	Damaging	Damaging	6	Persian (0.005)	Turkmen (0)
c.86G>A	1	8.002	Damaging	Benign	Tolerated	Predicted non-functional (Neutral)	Damaging	Tolerated	2	Lur (0.005)	Turkmen (0)
c.25A>G	1	14.07	Damaging	Benign	Tolerated	Predicted non-functional (Neutral)	Damaging	Damaging	3	Baloch (0.005)	Turkmen (0)
c.34G>T	1	21.3	Damaging	Benign	Tolerated	Predicted non-functional (Neutral)	Damaging	Tolerated	2	Lur (0.005)	Turkmen (0)
c.51G>T	1	13.91	Damaging	Benign	Tolerated	Predicted non-functional (Neutral)	Damaging	Damaging	3	Arab (0.005)	Turkmen (0)
c.121G>T	5	13.92	Damaging	Benign	Tolerated	Predicted non-functional (Neutral)	Tolerated	Damaging	2	Baloch (0.01099)	Persian Gulf Islander (0)

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Supplementary 1 Article:10-127-11

| Post date: 2025/12/29 |

Supplementary 1. Mutation spectrum of PAH gene in Iranian patients with PKU along with type of marriage, number of patients, and genetic test

c.variant	p.variant	Number of patients	Type of marriage	Genetic test	Study
c.168+5G>A	IVS2+5G>A	39	NA	PCR-sequencing	(Biglari et al., 2015)
c.168+5G>C	IVS2+5G>C
c.143T>C	p.L48S
c.526C>T	p.R176X
c.632delC	p.P211>Hfs
c.838G>A	p.E280K
c.782G>A	p.R261Q
c.842C>T	p.P281L
c.781C>T	p.R261X
c.755G>A	p.R252Q
c.728G>A	p.R243Q
c.848T>A	p.I283N
c.969+1G>A	VS9+1G>A
c.969+5G>A	IVS9 +5G>A
c.1199+1G>C	IVS11+1G>C
c.1069T>C	p.C357R
c.1066-11G>A	IVS10-11G>A	40	77.50%	PCR-sequencing	(Ajami et al., 2013)
c.1068C>A	Y356X
c.691T>C	S231P
c.727C>T	R243X
c.526C>T	R176X
c.672T>C	I224T
c.592_613del22	p.Y198_E205>Sfs
c.754C>T	R252W
c.782G>A	R261Q
c.1199+1G>C	IVS11+1G>C
c.1200-2A>G	VS11-2A>G
c.1124A>G	Q375R
c.1162G>A	V388M
c.1066-11G > A	IVS10-11G > A	122	70%	PCR-sequencing	(Jafarzadeh-Esfehani et al., 2020)
c.143T > C	p.Leu48Ser
c.1197A > T	p.Val399Val
c.526C > T	p.Arg176Ter
c.727C > T	p.Arg243Ter
c.671T > C	p.Ile224Thr
c.842C > T	p.Pro281Leu
c.926C > A	p.Ala309Asp
c.782G > A	p.Arg261Gln
c.1169A > G	p.Glu390Gly
c.122 G > A	p.Gly46Asp
c.696A > G	p.Cys237Trp
c.168 + 5 G > C	IVS2 + 5G > A
c.45_46delCT	p.Ser16Ter
c.691 T > C	p.Ser231Pro
c.115_117delTTC	p.Phe39del
c.721C > T	p.Arg241Cys
c.10G > A	p.Ala4Thr
c.1208C > T	p.Ala403Val
c.1155C > G	p.Leu385 =
c.1089_1089delG	p.Lys363AsnfsTer37
c.506 G > C	p.Arg169Pro
c.650G > T	p.Cys217Phe
c.838 G > A	p.Glu280Lys
c.898 G > T	p.Ala300Ser
c.998T > C	p.Leu333Pro
c.1313 A > T	p.Asn438Ile
c.479A > C	p.Gln160Pro

Supplementary 1 (Continued)

c.1066-11G>A	IVS10-11G>A	40	NA	RFLP	(Zamanfar et al., 2017)
c.782G>A	p. R261Q
c.754C>T	p. R252W
c.781C>T	p. R261X
c.1199+1G>C	IVS11+1G>C
c.782G>A	p .R261Q	30	53%	PCR-sequencing	(Moghadam et al., 2018)
c.781C>T	p .R261X
c.838G>A	p .E280K
c.842C>T	p .P281L
c.721C>T	p .R241C
c.727C>T	p .R243X
c.1197A>T	p .V399V
c.1199+1G>C	IVS11+1G>C
c.696A>G	p .Q232Q
c.735G>A	p .V245V
c.1155G>C	p .L385L
c.706+36T>G	IVS6+36 T>G
c.706+44T>G	VS6+44T>G
c.1066-15A>C	IVS10-15A>C
c.335dup A	p.(Asp112Glufs *2)	1	Consanguineous	Sanger sequencing and genotyping	(Alavinejad et al., 2017)
c.727C>T	p.Arg243Ter	1	NA	PCR-sequencing	(Razipour et al., 2017)
c.1223G>Tb	p.Arg408Leub	1	NA	PCR-sequencing	(Razipour et al., 2017)
c.781C>T	R261X	25	92%	PCR-sequencing	(Moradi et al., 2012)
c.526C>T	R176X
c.728G>A	R243Q
c.727C>T	R243X
c.782G>A	R261Q
c.1066-11G>A	IVS10-11	40	47.50%	PCR-sequencing and RFLP	(Bagheri et al., 2015)
c.199T>C	S67P
c.782G>A	R261Q
c.754 C>T	R252W
c.1223G>A	R408Q
c.696A>G	Q232Q
c.728G>A	R243Q
c.997C>T	L333F
c.194T>C	I65T
c.1222C>T	R408W
c.754 C>T	R252W	20	NA	PCR and VNTR allele analysis	(Bagheri et al., 2014)
c.782G>A	R261Q
c.754 C>T	R252W
c.199T>C	S67P
c.842C>T	p.P281L	25	NA	PCR-sequencing	(Khazaei Koohpar et al., 2020)
c.727C>T	p.R243X
c.754 C>T	p. R252W
c.782G>A	p.R261Q
c.781C>T	p.R261X
c.838G>A	p. E280K
c.441+5G>T	IVS4+5G>T	25	NA	PCR-sequencing	(Pourvatan and Khazaei-Koohpar, 2018)
c.473G>A	R158Q	25	NA	PCR-sequencing	(Zarinkoob and Koohpar, 2022)
c.1066-11G>A	IVS10-11G>A	40	NA	PCR-RFLP	(Mahdavi et al., 2016)
c.782G>A	R261Q
c.754 C>T	R252W
c.781C>T	R261X
c.1199+1G>C	IVS11+1G>C
NA	G > C IVS2 + 5	2	NA	PCR-sequencing	(Zade and Moradzadegan, 2023)
c.1066-11G>A	IVS10-11 G > A	2	NA	PCR-sequencing	(Zade and Moradzadegan, 2023)
EX3del4765	NA	1	Consanguineous	PCR-sequencing	(Soltani et al., 2016)
c.581T>G	L194R	1	Consanguineous	PCR-RFLP

(Zare et al., 2008)

Supplementary 1 (Continued)

c.1066-11G>A	IVS10-11g>a	150	NA	PCR-RFLP	(Zare et al., 2009)
c.754 C>T	R252W
c.781C>T	R261X
c.782G>A	R261Q
c.1222C>T	R408W
c.997C>T	L333F
c.199T>C	S67P
c.1223G>A	R408Q
c.696A>G	Q232Q	25	NA	PCR-sequencing	(Madadi et al., 2019)
c.526C>T	R176X	25	NA	PCR-sequencing	(Madadi et al., 2019)
c.1066-11G>A	IVS10-11	33	NA	PCR-sequencing	(Hosseini et al., 2022)
c.727C>T	p.Arg243X
c.898G>T	p.Ala300Ser
c.601C>T	p.His201Tyr
c.722delG	p.Arg241fs
c.842C>T	p.Pro281Leu
c.1066-11G>A	p.Gln355_Tyr356insGlyLeuGln / IVS10–11G>A	NA	NA	NA	(Alibakhshi et al., 2021)
c.782G>A	p.Arg261Gln (p.R261Q
c.842C>T	p.Pro281Leu (p.P281L)
c.168+5G>C	p. IVS2+5G>C
c.727C>T	p.Arg243Ter (p.R243*)
c.969+5G>A	p.IVS9+5G>A
c.526C>T	p.Arg176Ter (p.R176*)
c.1089delG	p.Lys363AsnfsTer37 (p.K363Nfs*37)
c.1199+1G>C	p. IVS11+1G>C
c.143 T>C	p.Leu48Ser (p.L48S)
c.754C>T	p.Arg252Trp (p.R252W)
c.441+5G>T	p.IVS4+5G>T
c.781C>T	p.Arg261Ter (p.R261*
c.898G>T	p.Ala300Ser (p.A300S)
c.838G>A	p.Glu280Lys (p.E280K)
c.113_115delTCT	p.Phe39del (p.F39del)
c.691 T>C	p.Ser231Pro (p.S231P)
c.843-5 T>C	p.IVS7-5 T>C
c.1222C>T	p.Arg408Trp (p.R408W)
c.473G>A	p.Arg158Gln (p.R158Q)
c.728G>A	p.Arg243Gln (p.R243Q)
c.1208C>T	p.Ala403Val (p.A403V)
c.199 T>C	.Ser67Pro (p.S67P)
c.1169A>G	p.Glu390Gly (p.E390G)
c.671 T>C	p.Ile224Thr (p.I224T)
c.1197A>T	p.Val399Val (p.V399V)
c.926C>A	.Ala309Asp (p.A309D)
c.441+1G>A	p.IVS4+1G>A
c.592_613Del22	p.Tyr198SerfsTer136 (p.Y198Sfs*136)
c.688G>A	p.Val230Ile (p.V230I)
c.721C>T	p.Arg241Cys (p.R241C)
c.535 T>C	p.Tyr179His (p.Y179H)
c.1114A>T	p.Thr372Ser (p.T372S)
c.(168+73_169–201)_(352+33_370)de	NA
c.755G>A	p.Arg252Gln (p.R252Q)
c.1223G>A	p.Arg408Gln (p.R408Q)
c.165delT	p.Phe55LeufsTer6 (p.F55Lfs*6)
c.740G>A	p.Gly247Asp (p.G247D)
c.1068C>A	p.Tyr356Ter (p.Y356*)
c.510-1G>A	p. IVS5-1G>A
c.2 T>C	p.(Met1Thr) (p.M1T)
c.970-1G>T	p. IVS9-1G>T

Supplementary 1 (Continued)

c.1068C>G	p.Tyr356Ter (p.Y356*)	NA	NA	NA	(Alibakhshi et al., 2021)
c.1049C>A	p.Ser350Tyr (p.S350Y)
c.842C>G	p.Pro281Arg (p.P281R)
c.913-7A>G	p. IVS8-7A>G
c.1092_1094delTCT	p.Leu365del (p.L365del)
c.590_612del23	p.Ser196_Leu197insTer
c.441+1G>C	p. IVS4+1G>C
c.169-13 T>G	p. IVS2-13 T>G
c.803A>G	p.Tyr268Cys (p.Y268C)
c.632DelC	p.Pro211HisfsTer130 (p.P211Hfs*130)
c.997C>T	p.Leu333Phe (p.L333F)
c.334G>C	p.Asp112His (p.D112H)
c.969+5G>C	p.IVS9+5G>C
c.1028A>G	p.Tyr343Cys (p.Y343C)
c.1250A>G	p.Tyr417Cys (p.Y417C)
c.848 T>A	p.Ile283Asn (p.I283N)
c.1200-2A>G	p.IVS11-2A>G
c.47_48delCT	p.Ser16Ter (p.S16*)
c.169-1G>A	p.IVS2-1G>A
c.533A>G	p.Glu178Gly (p.E178G)
c.722G>A	p.Arg241His (p.R241H)
c.1139C>T	p.Thr380Met (p.T380M)
c.305 T>C	p.Ile102Thr (p.I102T)
c.650G>T	p.Cys217Phe (p.C217F
c.331C>T	p.Arg111Ter (p.R111*)
c.707-96A>G	p.IVS6-96A>G
c.1066-2A>G	p.IVS10-2A>G
c.158G>A	p.Arg53His (p.R53H)
c.194 T>C	p.Ile65Thr (p.I65T)
c.311C>A	p.Ala104Asp (p.A104D)
c.353-1G>A	p.IVS3-1G>A
c.464G>A	p.Arg155His (p.R155H)
c.558_559delAT	p.Trp187GlyfsTer12 (p.W187Gfs*12)
c.603 T>G	p.His201Gln (p.H201Q)
c.638 T>C	p.Leu213Pro (p.L213P)
c.689 T>C	p.Val230Ala (p.V230A)
c.926C>T	p.Ala309Val (p.A309V)
c.1066-14C>G	p.IVS10-14C>G
c.1069 T>C	p.Cys357Arg (p.C357R)
c.1106_1107insAGCT	p.Glu370AlafsTer25 (p.E370Afs*25)
c.1162G>A	p.Val388Met (p.V388M)
c.1238G>C	p.Arg413Pro (p.R413P)
c.1245delC	p.Pro416HisfsTer36 (p.P416Hfs*36
c.1315+1G>A	p.IVS12+1G>A
c.250G>T	p.Asp84Tyr (p.D84Y)
c.581 T>G	p.Leu194Arg (p.L194R)
c.581 T>C	p.Leu194Pro (p.L194P)
c.916A>G	p.Ile306Val (p.I306V)
c.206dupC	p.Ser70PhefsTer7 (p.S70Pfs*7)
c.842+1G>A	p. IVS7+1G>A
c.506G>C	p.Lys115ThrfsTer79 (p.L115Tfs*79)
c.344_347delAAGA	p.Lys115ThrfsTer79
c.611A>G	p.Tyr204Cys (p.Y204C)
c.335dupA	p.Asp112GlufsTer2 (p.D112Efs*2)
c.168+5G>A	p.IVS2+5G>A
c.1147C>T	p.Gln383Ter (p.Q383*)
c.169_352del184	p.Ex3del4765

Supplementary 1 (Continued)

c.998 T>C	p.Leu333Pro (p.L333P)	NA	NA	NA	(Alibakhshi et al., 2021)
c.(1-1393_1–405)_(352 +33_370)del	p. Ex1_3del
c.165 T>G	p.Phe55Leu (p.F55L)
c.329C>T	p.Ser110Leu (p.S110L)
c.452A>G	p.Asp151Gly (p.D151G)
c.506delG	p.Arg169ProfsTer26 (p.R169Pfs*26)
c.592 T>G	p.Tyr198Asp (p.Y198D)
c.602A>G	p.His201Arg (p.H201R)
c.631C>A	p.Pro211Thr (p.P211T)
c.692C>T	p.Ser231Phe (p.S231F)
c.707-1G>C	p.IVS6-1G>C
c.773 T>G	p.Leu258Arg (p.L258R)
c.801G>T	p.Gln267His (p.Q267H)
c.1066-3C>T	p.IVS10-3C>T
c.1157A>G	p.Tyr386Cys (p.Y386C)
c.1177_1178InsT	p.Asn393IlefsTer2 (p.N393Ifs*2)
c.1218A>G	p.Ile406Met (p.I406M)
c.1243G>A	p.Asp415Asn (p.D415N)
c.1253C>A	p.Thr418Asn (p.T418N)
c.208 T>C	p.Ser70Pro (p.S70P)
c.1124A>G	p.Gln375Arg (p.Q375R)
c.355C>T	p.Pro119Ser (p.P119S)
c.441+4A>G	p.IVS4+4A>G
c.163_165delTTT	p.Phe55del (p.F55del)
c.995G>A	p.Gly332Glu (p.G332E)
c.1223G>T	p.Arg408Leu (p.R408L)
c.969+1G>A	p. IVS9+1G>A
c.809G>A	p.Arg270Lys (p.R270K)
c.479A>C	p.Gln160Pro (p.Q160P)
c.1313A>T	p.Asp438Ile (p.D438I)

Ajami N, Kazeminezhad SR, Foroughmand AM, Hasanpour M, Aminzadeh M. A preliminary mutation analysis of phenylketonuria in southwest Iran. Genet Mol Res. 2013;12(4):4958-66.
Alavinejad E, Sajedi SZ, Razipour M, Entezam M, Mohajer N, Setoodeh A, Talebi S, Keramatipour M. A Novel Variant in the PAH Gene Causing Phenylketonuria in an Iranian Pedigree. Avicenna J Med Biotechnol. 2017;9(3):146-9.
Alibakhshi R, Mohammadi A, Salari N, Khamooshian S, Kazeminia M, Moradi K. Spectrum of PAH gene mutations in 1547 phenylketonuria patients from Iran: a comprehensive systematic review. Metab Brain Dis. 2021;36(5):767-80.
Bagheri M, Rad IA, Jazani NH, Zarrin R, Ghazavi A. Association Between PAH Mutations and VNTR Alleles in the West Azerbaijani PKU Patients. Maedica (Bucur). 2014;9(3):242-7.
Bagheri M, Rad IA, Jazani NH, Zarrin R, Ghazavi A. Mutation analysis of the phenylalanine hydroxylase gene in Azerbaijani population, a report from West Azerbaijan province of Iran. Iran J Basic Med Sci. 2015;18(7):649-53.
Biglari A, Saffari F, Rashvand Z, Alizadeh S, Najafipour R, Sahmani M. Mutations of the phenylalanine hydroxylase gene in Iranian patients with phenylketonuria. Springerplus. 2015;4:542.
Hosseini E, Mousavi SS, Zamanfar D, Hashemi-Soteh SMB. Frequency of PAH Mutations Among Classic Phenylketon Urea Patients in Mazandaran and Golestan Provinces, North of Iran. Clin Lab. 2022;68(1).
Jafarzadeh-Esfehani R, Vojdani S, Hashemian S, Mirinezhad M, Pourafshar M, Forouzanfar N, Zargari S, Jaripour ME, Sadr-Nabavi A. Genetic variants of the phenylalanine hydroxylase gene in patients with phenylketonuria in the northeast of Iran. J Pediatr Endocrinol Metab. 2020;33(3):355-9.
Khazaei Koohpar Z, Ranji N, Safaei Asl A, Shabani S. Investigation of six common mutations on phenylalanine hydroxylase gene IN phenylketonuria patients IN GUILAN province. Studies in Medical Sciences. 2020;31(1):24-33.
Madadi N, Khazaei Koohpar Z, Ranji N. Molecular analysis of exon 6 mutations of phenylalanine hydroxylase gene in phenylketonuria patients from Guilan province. Razi J Med Sci. 2019;26(1):32-9.
Mahdavi MR, Zamanfar D, Jalali H. Investigation of IVS10-11G> A, R261Q, R252W, R261X, and IVS11+ 1G> C Mutations on PAH Gene of PKU Patients from Mazandaran and Golestan Districts of Iran.
Rastegar Moghadam M, Shojaei A, Babaei V, Rohani F, Ghazi F. Mutation analysis of Phenylalanine hydroxylase gene in Iranian patients with Phenylketonuria. Med J Islam Repub Iran. 2018;32:21.
Moradi K, Alibakhshi R, Ghadiri K, Khatami SR, Galehdari H. Molecular analysis of exons 6 and 7 of phenylalanine hydroxylase gene mutations in Phenylketonuria patients in Western Iran. Indian J Hum Genet. 2012;18(3):290-3.
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Razipour M, Kooshavar D, Alavinejad E, Sajedi SZ, Mohajer N, Setoodeh A, Talebi S, Keramatipour M. Identification of a Novel Mutation in the PAH Gene in an Iranian Phenylketonuria Family: A Case Report. Iran J Public Health. 2017;46(4):560-4.
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Zare KS, Hosseini MS, Javadi G, Zeinali S. Identification of new mutation of L194r in phenylalanine hydroxylase gene (PAH) in Iranian population.
Zare KS, Hosseini MS, Koochmeshgi J, Morteza SS, Zeinali S, Javadi G. Molecular analysis of most common mutations in phenylalanine hydroxylase gene in Iranian population.
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Supplementary Table 2 Article: 127-10

| Post date: 2025/12/29 |

Supplementary Table 2. Conservation scores (ConSurf) of G6PD variants. Based on the scores obtained from this tool, 28 variants received the highest score of 9, followed by 12 variants with a score of 8 while no variant received the lowest scores of 1 or 2.

Variant	Protein	Consurf	Variant	Protein	Consurf
c.130G>A	p.Ala44Thr	8	c.921G>C	p.Gln307His	9
c.148C>T	p.Pro50Ser	9	c.962G>T	p.Gly321Val	6
c.152C>T	p.Thr51Ile	8	c.962G>A	p.Gly321Glu	6
c179T>C	p.Leu60Pro	4	c.1006A>G	p.Thr336Ala	9
c.185C>A	p.Pro62His	5	c.1052G>T	p.Gly351Val	7
C.224T>C	p.Leu75Pro	3	c.1057C>T	p.Pro353Ser	9
c.404A>C	p.Asn135Thr	7	c.1081G>A	p.Ala361Thr	7
c.409C>T	p.Leu137Phe	5	c.1138A>G	p.Ile380Val	6
c.473G>A	p.Cys158Tyr	4	c.1139T>C	p.Ile380Thr	6
c.488G>A	p.Gly163Asp	3	c.1141T>C	p.Phe381Leu	8
c.497G>A	p.Arg166His	9	c.1159C>T	p.Arg387Cys	5
c.514C>T	p.Pro172Ser	9	c.1160G>A	p.Arg387His	4
c.517T>C	p.Phe173Leu	8	c.1166A>G	p.Glu389Gly	5
c.527A>G	p.Asp176Gly	9	c.1175T>C	p.Ile392Thr	7
c.536G>A	p.Ser179Asn	8	c.1177C>G	p.Arg393Gly	7
c.592C>T	p.Arg198Cys	9	c.1178G>A	p.Arg393His	7
c.592C>A	p.Arg198Ser	9	c.1186C>G	p.Pro396Ala	9
c.593G>C	p.Arg198Pro	9	c.1187C>G	p.Pro396Arg	9
c.593G>A	p.Arg198His	9	c.1192G>A	p.Glu398Lys	9
c.679C>T	p.Arg227Trp	6	c.1220A>C	p.Lys407Thr	9
c.737G>T	p.Arg246Leu	9	c.1225C>T	p.Pro409Ser	8
c.769C>G	p.Arg257Gly	9	c.1226C>A	p.Pro409Gln	8
c.770G>T	p.Arg257Leu	9	c.1229G>A	p.Gly410Asp	8
c.806G>A	p.Cys269Tyr	6	c.1316G>C	p.Arg439Pro	7
c.820G>A	p.Glu274Lys	9	c.1318C>T	p.Leu440phe	9
c.825G>C	p.Lys275Asn	7	c.1339G>A	p.Gly447Arg	9
c.826C>T	p.Pro276Ser	9	c.1340G>T	p.Gly447Val	9
c.844G>C	p.Asp282His	5	c.1358T>A	p.Val453Glu	7
c.844G>T	p.Asp282Tyr	5	c.1361G>A	p.Arg454His	9
c.848A>G	p.Asp283Gly	5	c.1366G>C	p.Asp456His	9
c.851T>C	p.Val284Ala	7	c.1367A>T	p.Asp456Val	8
c.853C>T	p.Arg285Cys	9	c.1381G>A	p.Ala461Thr	8
c.910G>T	p.Val304Phe	8	c.1387C>T	p.Arg463Cys	3
c.920A>C	p.Gln307Pro	9	c.1463G>T	p.Gly488Val	8

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Supplementary Table 1 Article: 127-10

| Post date: 2025/12/29 |

Supplementary Table 1. Bioinformatic filters applied on G6PD variants. Initially, 215 missense variants were identified. Based on the first filter (ACMG), 115 variants were classified as pathogenic. Among these, 108 variants had a CADD score greater than 20 and were chosen for further investigations. In the next step, PANTHER, SIFT, FATHMM, and PolyOhen-2 were used, according to which 82 variants were retained as harmful or probably harmful. Finally, based on predictions from I-Mutant and MUpro, 69 variants were predicted to decrease protein stability.

Variant	Protein	ACMG	Panther	CADD	FATHM	SIFT	I-Mutant 2.0	Mupro	Poly Phen 2
c.130G>A	p.Ala44Thr	Pathogenic	Probably damaging 0.95	26.7	Damaging (-5.07)	Damaging	Decrease (DDG=-0.55)	Decrease (DDG=-1.07)	Probably damaging (0.999)
c.148C>T	p.Pro50Ser	Pathogenic	Probably damaging 0.95	26.7	Damaging (-5.97)	Damaging	Decrease (DDG=-0.85)	Decrease (DDG=-0.84)	Probably damaging (1.000)
c.152C>T	p.Thr51Ile	Pathogenic	Probably damaging 0.85	26.1	Damaging (-4.86)	Damaging	Decrease (DDG=-1.52)	Decrease (DDG=-0.25)	Probably damaging (0.998)
c179T>C	p.Leu60Pro	Pathogenic	Probably damaging 0.85	26.5	Damaging (-6.06)	Damaging	Decrease (DDG=-2.25)	Decrease (DDG=-2.33)	Probably damaging (1.000)
c.185C>A	p.Pro62His	Pathogenic	Probably damaging 0.95	24.7	Damaging (-6.30)	Damaging	Decrease (DDG=-1.90)	Decrease (DDG=-0.69)	Probably damaging (1.000)
C.224T>C	p.Leu75Pro	Pathogenic	Probably damaging 0.74	27	Damaging (-4.98)	Damaging	Decrease (DDG=-1.66)	Decrease (DDG=-2.31)	Probably damaging (1.000)
c.404A>C	p.Asn135Thr	Pathogenic	Probably damaging 0.95	23.7	Damaging (-6.76)	Damaging	Decrease (DDG=-2.18)	Decrease (DDG=-1.43)	Probably damaging (0.987)
c.409C>T	p.Leu137Phe	Pathogenic	Probably damaging 0.85	25.7	Damaging (-6.32)	Damaging	Decrease (DDG=-1.22)	Decrease (DDG=-1.56)	Probably damaging (0.981)
c.473G>A	p.Cys158Tyr	Pathogenic	Probably damaging 0.95	25.1	Damaging (-6.17)	Damaging	Decrease (DDG=-0.55)	Decrease (DDG=-0.87)	Probably damaging(1.000)
c.488G>A	p.Gly163Asp	Pathogenic	Probably damaging 0.95	28.5	Damaging (-6.62)	Damaging	Decrease (DDG=-0.46)	Decrease (DDG=-0.68)	Probably damaging (0.993)
c.497G>A	p.Arg166His	Pathogenic	Probably damaging 0.95	26.3	Damaging (-6.73)	Damaging	Decrease (DDG=-1.25)	Decrease (DDG=-0.89)	Probably damaging (1.000)
c.514C>T	p.Pro172Ser	Pathogenic	Probably damaging 0.95	27.2	Damaging (-7.09)	Damaging	Decrease (DDG=-1.36)	Decrease (DDG=-0.65)	Probably damaging (1.000)
c.517T>C	p.Phe173Leu	Pathogenic	Probably damaging 0.95	25.7	Damaging (-6.67)	Damaging	Decrease (DDG=-2.26)	Decrease (DDG=-0.59)	Probably damaging (1.000)
c.527A>G	p.Asp176Gly	Pathogenic	Probably damaging 0.95	27.3	Damaging (-5.31)	Damaging	Decrease (DDG=-2.55)	Decrease (DDG=-1.76)	Probably damaging (0.999)
c.536G>A	p.Ser179Asn	Pathogenic	Probably damaging 0.95	24.9	Damaging (-5.46)	Damaging	Decrease (DDG=-1.32)	Decrease (DDG=-0.3)	Probably damaging (0.838)
c.592C>T	p.Arg198Cys	Pathogenic	Probably damaging 0.95	31	Damaging (-5.84)	Damaging	Decrease (DDG=-1.15)	Decrease (DDG=-0.82)	Probably damaging (1.000)
c.592C>A	p.Arg198Ser	Pathogenic	Probably damaging 0.95	28.6	Damaging (-5.81)	Damaging	Decrease (DDG=-2.44)	Decrease (DDG=-1.19)	Probably damaging (1.000)
c.593G>C	p.Arg198Pro	Pathogenic	Probably damaging 0.95	26.9	Damaging (-5.83)	Damaging	Decrease (DDG=-1.77)	Decrease (DDG=-1.44)	Probably damaging (1.000)
c.593G>A	p.Arg198His	Pathogenic	Probably damaging 0.95	25.8	Damaging (-5.81)	Damaging	Decrease (DDG=-1.97)	Decrease (DDG=-1.3)	Probably damaging (1.000)
c.679C>T	p.Arg227Trp	Pathogenic	Probably damaging 0.86	29.6	Damaging (-7.13)	Damaging	Decrease (DDG=-1.29)	Decrease (DDG=-1.39)	Probably damaging (1.000)
c.737G>T	p.Arg246Leu	Pathogenic	Probably damaging 0.95	25.9	Damaging (-5.93)	Damaging	Decrease (DDG=-0.13)	Decrease (DDG=-0.27)	Probably damaging (1.000)
c.769C>G	p.Arg257Gly	Pathogenic	Probably damaging 0.95	27.8	Damaging (-5.55)	Damaging	Decrease (DDG=-0.99)	Decrease (DDG=-1.6)	Probably damaging (0.999)
c.770G>T	p.Arg257Leu	Pathogenic	Probably damaging 0.95	35	Damaging (-5.51)	Damaging	Decrease (DDG=-1.25)	Decrease (DDG=-0.51)	Probably damaging (1.000)
c.806G>A	p.Cys269Tyr	Pathogenic	Probably damaging 0.85	26.9	Damaging (-6.94)	Damaging	Decrease (DDG=-0.24)	Decrease (DDG=-1.6)	Probably damaging (0.988)
c.820G>A	p.Glu274Lys	Pathogenic	Probably damaging 0.95	28.1	Damaging (-5.29)	Damaging	Decrease (DDG=-0.57)	Decrease (DDG=-1.28)	Probably damaging (0.992)
c.825G>C	p.Lys275Asn	Pathogenic	Probably damaging 0.85	22.3	Damaging (-7.01)	Damaging	Decrease (DDG=-0.76)	Decrease (DDG=-0.55)	Probably damaging (1.000)
c.826C>T	p.Pro276Ser	Pathogenic	Probably damaging 0.95	26.9	Damaging (-6.67)	Damaging	Decrease (DDG=-1.53)	Decrease (DDG=-0.51)	Probably Damaging (1.000)
c.844G>C	p.Asp282His	Pathogenic	Probably damaging 0.74	23.5	Damaging (-7.06)	Damaging	Decrease (DDG=-1.28)	Decrease (DDG=-1.6)	Probably damaging (0.995)
c.844G>T	p.Asp282Tyr	Pathogenic	Probably damaging 0.74	23.8	Damaging (-7.07)	Damaging	Decrease (DDG=-0.63)	Decrease (DDG=-1.24)	Probably damaging (0.999)

Supplementary Table 1 (Continued)

c.848A>G	p.Asp283Gly	Pathogenic	Probably damaging 0.89	24.4	Damaging (-7.02)	Damaging	Decrease (DDG=-1.99)	Decrease (DDG=-1.61)	Probably damaging (1.000)
c.851T>C	p.Val284Ala	Pathogenic	Probably damaging 0.57	24.9	Damaging (-5.15)	Damaging	Decrease (DDG=-2.36)	Decrease (DDG=-2.64)	Probably Damaging (0.995)
c.853C>T	p.Arg285Cys	Pathogenic	Probably damaging 0.95	27.5	Damaging (-7.88)	Damaging	Decrease (DDG=-1.17)	Decrease (DDG=-0.71)	Probably damaging(1.000)
c.910G>T	p.Val304Phe	Pathogenic	Probably damaging 0.86	23.8	Damaging (-7.44)	Damaging	Decrease (DDG=-1.86)	Decrease (DDG=-0.89)	Probably damaging (0.995)
c.920A>C	p.Gln307Pro	Pathogenic	Probably damaging 0.95	24.6	Damaging (-7.61)	Damaging	Decrease (DDG=-1.74)	Decrease (DDG=-1.26)	Probably damaging (0.995)
c.921G>C	p.Gln307His	Pathogenic	Probably damaging 0.95	22.1	Damaging (-7.61)	Damaging	Decrease (DDG=-1.28)	Decrease (DDG=-1.1)	Probably damaging (1.000)
c.962G>T	p.Gly321Val	Pathogenic	-	24.8	Damaging (-7.23)	Damaging	Decrease (DDG=-1.77)	Decrease (DDG=0.32)	Probably damaging (1.000)
c.962G>A	p.Gly321Glu	Pathogenic	Probably damaging 0.95	24.8	Damaging (-7.21)	Damaging	Decrease (DDG=-0.72)	Decrease (DDG=-0.60)	Probably damaging (1.000)
c.1006A>G	p.Thr336Ala	Pathogenic	Probably damaging 0.95	23.8	Damaging (-5.90)	Damaging	Decrease (DDG=-0.38)	Decrease (DDG=-0.69)	Probably damaging (1.000)
c.1052G>T	p.Gly351Val	Pathogenic	Probably damaging 0.95	27.7	Damaging (-8.32)	Damaging	Decrease (DDG=-1.24)	Decrease (DDG=-0.64)	Probably damaging (1.000)
c.1057C>T	p.Pro353Ser	Pathogenic	Probably damaging 0.95	23.6	Damaging (-6.47)	Damaging	Decrease (DDG=-1.48)	Decrease (DDG=-0.36)	Probably damaging (0.999)
c.1081G>A	p.Ala361Thr	Pathogenic	Probably damaging 0.95	23.9	Damaging (-7.08)	Damaging	Decrease (DDG=-0.68)	Decrease (DDG=-0.79)	Probably damaging (1.000)
c.1138A>G	p.Ile380Val	Pathogenic	Probably damaging 0.86	23.5	Damaging (-6.94)	Damaging	Decrease (DDG=-1.49)	Decrease (DDG=-0.53)	Probably damaging (0.972)
c.1139T>C	p.Ile380Thr	Pathogenic	Probably damaging 0.86	23.5	Damaging (-7.17)	Damaging	Decrease (DDG=-3.21)	Decrease (DDG=-1.33)	Probably damaging (1.000)
c.1141T>C	p.Phe381Leu	Pathogenic	Probably damaging 0.95	25.9	Damaging (-7.34)	Damaging	Decrease (DDG=-2.23)	Decrease (DDG=-0.70)	Probably damaging (1.000)
c.1159C>T	p.Arg387Cys	Pathogenic	Probably damaging 0.95	26.8	Damaging (-7.04)	Damaging	Decrease (DDG=-0.77)	Decrease (DDG=-0.53)	Probably damaging (1.000)
c.1160G>A	p.Arg387His	Pathogenic	Probably damaging 0.95	27.5	Damaging (-7.01)	Damaging	Decrease (DDG=-1.91)	Decrease (DDG=-0.95)	Probably damaging (1.000)
c.1166A>G	p.Glu389Gly	Pathogenic	Probably damaging 0.95	28.7	Damaging (-7.07)	Damaging	Decrease (DDG=-0.89)	Decrease (DDG=-2.02)	Probably damaging (1.000)
c.1175T>C	p.Ile392Thr	Pathogenic	Probably damaging 0.57	25.9	Damaging (-7.63)	Damaging	Decrease (DDG=-3.98)	Decrease (DDG=-2.09)	Probably damaging (1.000)
c.1177C>G	p.Arg393Gly	Pathogenic	Probably damaging 0.95	24.6	Damaging (-7.12)	Damaging	Decrease (DDG=-1.84)	Decrease (DDG=-1.77)	Probably damaging (1.000)
c.1178G>A	p.Arg393His	Pathogenic	Probably damaging 0.95	24.3	Damaging (-7.12)	Damaging	Decrease (DDG=-2.09)	Decrease (DDG=-1.36)	Probably damaging (1.000)
c.1186C>G	p.Pro396Ala	Pathogenic	Probably damaging 0.95	24.8	Damaging (-8.18)	Damaging	Decrease (DDG=-1.83)	Decrease (DDG=-1.14)	Probably damaging (0.998)
c.1187C>G	p.Pro396Arg	Pathogenic	Probably damaging 0.95	26.9	Damaging (-8.21)	Damaging	Decrease (DDG=-0.72)	Decrease (DDG=-0.62)	Probably damaging (0.999)
c.1192G>A	p.Glu398Lys	Pathogenic	Probably damaging 0.95	25.6	Damaging (-7.21)	Damaging	Decrease (DDG=-0.55)	Decrease (DDG=-1.45)	Probably damaging (1.000)
c.1220A>C	p.Lys407Thr	Pathogenic	Probably damaging 0.95	24.9	Damaging (-7.72)	Damaging	Decrease (DDG=-0.48)	Decrease (DDG=-1.1)	Probably damaging (0.999)
c.1225C>T	p.Pro409Ser	Pathogenic	Probably damaging 0.95	24.3	Damaging (-7.22)	Damaging	Decrease (DDG=-0.48)	Decrease (DDG=-0.83)	Probably damaging (1.000)
c.1226C>A	p.Pro409Gln	Pathogenic	Probably damaging 0.95	25.7	Damaging (-7.27)	Damaging	Decrease (DDG=-0.4)	Decrease (DDG=-0.55)	Probably damaging (1.000)
c.1229G>A	p.Gly410Asp	Pathogenic	Probably damaging 0.95	23.7	Damaging (-7.30)	Damaging	Decrease (DDG=-0.84)	Decrease (DDG=-0.38)	Probably damaging (0.997)
c.1316G>C	p.Arg439Pro	Pathogenic	Probably damaging 0.95	26.9	Damaging (-7.16)	Damaging	Decrease (DDG=-1.71)	Decrease (DDG=-1.17)	Probably damaging (1.000)
c.1318C>T	p.Leu440phe	Pathogenic	Probably damaging 0.95	27	Damaging (-5.91)	Damaging	Decrease (DDG=-0.59)	Decrease (DDG=-1.74)	Probably damaging (0.999)
c.1339G>A	p.Gly447Arg	Pathogenic	Probably damaging 0.95	27.2	Damaging (-8.32)	Damaging	Decrease (DDG=-1.00)	Decrease (DDG=-0.32)	Probably damaging (1.000)

Supplementary Table 1 (Continued)

c.1340G>T	p.Gly447Val	Pathogenic	Probably damaging 0.95	26.5	Damaging (-8.32)	Damaging	Decrease (DDG=-1.09)	Decrease (DDG=-0.07)	Probably damaging (1.000)
c.1358T>A	p.Val453Glu	Pathogenic	Probably damaging 0.95	24.6	Damaging (-7.38)	Damaging	Decrease (DDG=-1.49)	Decrease (DDG=-1.21)	Probably damaging (1.000)
c.1361G>A	p.Arg454His	Pathogenic	Probably damaging 0.95	26.5	Damaging (-7.27)	Damaging	Decrease (DDG=-1.99)	Decrease (DDG=-1.07)	Probably damaging (1.000)
c.1366G>C	p.Asp456His	Pathogenic	Probably damaging 0.95	25.2	Damaging (-7.44)	Damaging	Decrease (DDG=-1.39)	Decrease (DDG=-0.70)	Probably damaging (0.967)
c.1367A>T	p.Asp456Val	Pathogenic	Probably damaging 0.95	23.8	Damaging (-7.45)	Damaging	Decrease (DDG=-1.04)	Decrease (DDG=-0.09)	Probably damaging (0.998)
c.1381G>A	p.Ala461Thr	Pathogenic	Probably damaging 0.95	25.7	Damaging (-7.14)	Damaging	Decrease (DDG=-0.82)	Decrease (DDG=-1.52)	Probably damaging (0.986)
c.1387C>T	p.Arg463Cys	Pathogenic	Probably damaging 0.85	24.2	Damaging (-7.01)	Damaging	Decrease (DDG=-0.66)	Decrease (DDG=-0.55)	Probably damaging (1.000)
c.1463G>T	p.Gly488Val	Pathogenic	Probably damaging 0.95	24.8	Damaging (-8.32)	Damaging	Decrease (DDG=-1.08)	Decrease (DDG=-0.60)	Probably damaging (1.000)
c.1465C>T	p.Pro489Ser	Pathogenic	Probably damaging 0.95	24.4	Damaging (-6.20)	Damaging	Decrease (DDG=-1.72)	Decrease (DDG=-1.04)	Probably damaging (1.000)

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