Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.

c.dna	Variant	SGM Consensus	Domain	ClinVar			gnomAD			ESM1b		AlphaMissense			REVEL		FoldX			Rosetta		Foldetta		PremPS		PROVEAN		PolyPhen-2 HumDiv		PolyPhen-2 HumVar		FATHMM		SIFT				PAM		Physical		SASA		Normalized B-factor backbone		Normalized B-factor sidechain		SynGAP Structural Annotation									DOI
				Clinical Status	Review	Subm.	ID	Allele count	Allele freq.	LLR score	Prediction	Pathogenicity	Class	Optimized	Score	Prediction	Average ΔΔG	Prediction	StdDev	ΔΔG	Prediction	ΔΔG	Prediction	ΔΔG	Prediction	Score	Prediction	pph2_prob	Prediction	pph2_prob	Prediction	Nervous System Score	Prediction	Prediction	Status	Conservation	Sequences	PAM250	PAM120	Hydropathy Δ	MW Δ	Average	Δ	Δ	StdDev	Δ	StdDev	Secondary	Tertiary bonds	Inside out	GAP-Ras interface	At membrane	No effect	MD Alert	Verdict	Description
c.467T>G	F156C	Likely Pathogenic		Uncertain		1				-13.658	Likely Pathogenic	0.988	Likely Pathogenic	Likely Pathogenic	0.297	Likely Benign										-3.54	Deleterious	0.999	Probably Damaging	0.990	Probably Damaging	3.92	Benign	0.00	Affected			-4	-2	-0.3	-44.04
c.2719A>T	S907C	Likely Benign		Likely Benign		1				-6.685	Likely Benign	0.298	Likely Benign	Likely Benign	0.113	Likely Benign										-2.34	Neutral	0.999	Probably Damaging	0.988	Probably Damaging	2.60	Benign	0.02	Affected	3.77	5	0	-1	3.3	16.06
c.401G>A	S134N	Likely Benign		Uncertain		1				-5.534	Likely Benign	0.813	Likely Pathogenic	Ambiguous	0.075	Likely Benign										-1.62	Neutral	0.001	Benign	0.002	Benign	3.90	Benign	0.00	Affected	3.61	5	1	1	-2.7	27.03
c.2291A>G	N764S	Likely Benign		Benign		1				-3.149	Likely Benign	0.159	Likely Benign	Likely Benign	0.058	Likely Benign										-0.84	Neutral	0.992	Probably Damaging	0.846	Possibly Damaging	2.65	Benign	0.61	Tolerated	3.64	6	1	1	2.7	-27.03
c.2294G>A	S765N	Likely Benign		Uncertain		1				-5.098	Likely Benign	0.378	Ambiguous	Likely Benign	0.094	Likely Benign										-0.94	Neutral	0.985	Probably Damaging	0.950	Probably Damaging	4.11	Benign	0.06	Tolerated	3.64	6	1	1	-2.7	27.03
c.2299A>G	I767V	Likely Benign		Uncertain		1				-2.791	Likely Benign	0.064	Likely Benign	Likely Benign	0.096	Likely Benign										0.10	Neutral	0.072	Benign	0.029	Benign	4.21	Benign	1.00	Tolerated	3.64	6	4	3	-0.3	-14.03
c.2300T>C	I767T	Likely Benign		Uncertain		1				-3.749	Likely Benign	0.252	Likely Benign	Likely Benign	0.138	Likely Benign										-0.78	Neutral	0.625	Possibly Damaging	0.249	Benign	4.12	Benign	0.46	Tolerated	3.64	6	0	-1	-5.2	-12.05
c.4008G>C	E1336D	Likely Benign		Likely Benign		1				-3.344	Likely Benign	0.596	Likely Pathogenic	Likely Benign	0.062	Likely Benign										-1.92	Neutral	0.001	Benign	0.003	Benign	3.30	Benign	0.00	Affected	3.77	5	2	3	0.0	-14.03
c.3G>A	M1I	Likely Benign		Conflicting		3				-5.397	Likely Benign				0.227	Likely Benign										-0.17	Neutral	0.001	Benign	0.000	Benign	4.25	Benign	0.00	Affected	4.32	1	2	1	2.6	-18.03
c.2305C>T	L769F	Likely Benign		Uncertain		1				-5.044	Likely Benign	0.146	Likely Benign	Likely Benign	0.060	Likely Benign										-0.89	Neutral	0.925	Possibly Damaging	0.510	Possibly Damaging	3.94	Benign	0.02	Affected			2	0	-1.0	34.02
c.3977C>T	P1326L	Likely Benign		Uncertain		1				-5.541	Likely Benign	0.115	Likely Benign	Likely Benign	0.117	Likely Benign										-1.06	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	3.62	Benign	0.00	Affected	3.77	5	-3	-3	5.4	16.04
c.406C>T	R136W	Likely Pathogenic		Uncertain		2				-10.453	Likely Pathogenic	0.989	Likely Pathogenic	Likely Pathogenic	0.237	Likely Benign										-4.71	Deleterious	0.965	Probably Damaging	0.416	Benign	3.45	Benign	0.00	Affected	3.61	5	2	-3	3.6	30.03
c.2270G>C	G757A	Likely Benign		Uncertain		1				-2.626	Likely Benign	0.091	Likely Benign	Likely Benign	0.066	Likely Benign										-0.45	Neutral	0.267	Benign	0.127	Benign	2.73	Benign	0.35	Tolerated			1	0	2.2	14.03
c.2210A>C	Q737P	Likely Benign		Uncertain		1				-2.407	Likely Benign	0.054	Likely Benign	Likely Benign	0.154	Likely Benign										-1.22	Neutral	0.005	Benign	0.013	Benign	2.78	Benign	0.04	Affected	4.07	3	-1	0	1.9	-31.01
c.458C>A	T153N	Likely Benign		Conflicting		3				-0.739	Likely Benign	0.226	Likely Benign	Likely Benign	0.161	Likely Benign										0.88	Neutral	0.888	Possibly Damaging	0.537	Possibly Damaging	4.23	Benign	0.81	Tolerated	3.61	5	0	0	-2.8	13.00
c.2215G>C	E739Q	Likely Benign		Uncertain		1				-2.846	Likely Benign	0.161	Likely Benign	Likely Benign	0.071	Likely Benign										-1.06	Neutral	0.801	Possibly Damaging	0.339	Benign	2.57	Benign	0.00	Affected	4.32	2	2	2	0.0	-0.98
c.2216A>T	E739V	Likely Benign		Uncertain		1				-3.136	Likely Benign	0.274	Likely Benign	Likely Benign	0.085	Likely Benign										-1.86	Neutral	0.891	Possibly Damaging	0.575	Possibly Damaging	2.47	Pathogenic	0.00	Affected	4.32	2	-2	-2	7.7	-29.98
c.2217G>C	E739D	Likely Benign		Uncertain		1				-3.369	Likely Benign	0.062	Likely Benign	Likely Benign	0.097	Likely Benign										-0.49	Neutral	0.002	Benign	0.005	Benign	2.59	Benign	0.00	Affected			3	2	0.0	-14.03
c.453C>A	D151E	Likely Benign		Uncertain		1				-5.662	Likely Benign	0.886	Likely Pathogenic	Ambiguous	0.142	Likely Benign										-2.02	Neutral	0.984	Probably Damaging	0.967	Probably Damaging	3.99	Benign	0.11	Tolerated	3.61	5	3	2	0.0	14.03
c.43G>C	A15P	Likely Benign		Uncertain		1				-3.436	Likely Benign	0.097	Likely Benign	Likely Benign	0.146	Likely Benign										-0.23	Neutral	0.880	Possibly Damaging	0.123	Benign	4.09	Benign	0.00	Affected			1	-1	-3.4	26.04
c.223G>A	E75K	Likely Benign		Benign/Likely benign		2				-4.020	Likely Benign	0.358	Ambiguous	Likely Benign	0.134	Likely Benign										-1.12	Neutral	0.748	Possibly Damaging	0.017	Benign	4.07	Benign	0.00	Affected			0	1	-0.4	-0.94
c.407G>C	R136P	Likely Pathogenic		Uncertain		1				-11.952	Likely Pathogenic	0.981	Likely Pathogenic	Likely Pathogenic	0.277	Likely Benign										-3.72	Deleterious	0.910	Possibly Damaging	0.578	Possibly Damaging	3.47	Benign	0.00	Affected	3.61	5	0	-2	2.9	-59.07
c.2249G>A	G750E			Uncertain		1				-2.618	Likely Benign	0.413	Ambiguous	Likely Benign	0.146	Likely Benign										-2.27	Neutral	1.000	Probably Damaging	0.982	Probably Damaging	2.49	Pathogenic	0.01	Affected	3.99	5	0	-2	-3.1	72.06
c.2324G>C	R775P	Likely Benign		Benign		1				-5.072	Likely Benign	0.452	Ambiguous	Likely Benign	0.168	Likely Benign										-0.79	Neutral	0.971	Probably Damaging	0.944	Probably Damaging	4.13	Benign	0.07	Tolerated	3.64	6	-2	0	2.9	-59.07
c.3977C>G	P1326R	Likely Benign		Uncertain		1				-5.097	Likely Benign	0.240	Likely Benign	Likely Benign	0.133	Likely Benign										-0.82	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	3.62	Benign	0.00	Affected	3.77	5	0	-2	-2.9	59.07
c.233G>T	R78L	Likely Benign		Uncertain		1				-3.389	Likely Benign	0.635	Likely Pathogenic	Likely Benign	0.062	Likely Benign										-1.59	Neutral	0.385	Benign	0.021	Benign	3.84	Benign	0.00	Affected			-3	-2	8.3	-43.03
c.2408A>G	K803R	Likely Benign	SH3-binding motif	Uncertain		1				-2.281	Likely Benign	0.097	Likely Benign	Likely Benign	0.018	Likely Benign										-1.52	Neutral	0.103	Benign	0.038	Benign	2.38	Pathogenic	0.00	Affected	3.77	5	3	2	-0.6	28.01
c.2414T>C	L805P		SH3-binding motif	Uncertain		1				-4.661	Likely Benign	0.444	Ambiguous	Likely Benign	0.272	Likely Benign										-3.40	Deleterious	0.975	Probably Damaging	0.767	Possibly Damaging	2.36	Pathogenic	0.00	Affected	3.77	5	-3	-3	-5.4	-16.04
c.3773A>G	Q1258R	Likely Pathogenic	Coiled-coil	Uncertain		1				-10.971	Likely Pathogenic	0.931	Likely Pathogenic	Ambiguous	0.316	Likely Benign										-3.19	Deleterious	0.994	Probably Damaging	0.988	Probably Damaging	2.00	Pathogenic	0.00	Affected			1	1	-1.0	28.06
c.2420A>T	Y807F	Likely Benign	SH3-binding motif	Uncertain		1				-3.667	Likely Benign	0.073	Likely Benign	Likely Benign	0.057	Likely Benign										0.14	Neutral	0.012	Benign	0.022	Benign	2.92	Benign	0.98	Tolerated	3.77	5	7	3	4.1	-16.00
c.373C>T	P125S	Likely Benign		Uncertain		1				-3.769	Likely Benign	0.238	Likely Benign	Likely Benign	0.121	Likely Benign										-3.57	Deleterious	0.580	Possibly Damaging	0.140	Benign	2.86	Benign	0.02	Affected	3.61	5	1	-1	0.8	-10.04
c.3731G>A	S1244N	Likely Pathogenic	Coiled-coil	Uncertain		1				-9.008	Likely Pathogenic	0.751	Likely Pathogenic	Likely Benign	0.154	Likely Benign										-1.87	Neutral	0.997	Probably Damaging	0.992	Probably Damaging	2.10	Pathogenic	0.15	Tolerated	3.77	5	1	1	-2.7	27.03
c.2443C>A	R815S		SH3-binding motif	Benign		1				-7.324	In-Between	0.950	Likely Pathogenic	Ambiguous	0.138	Likely Benign										-1.86	Neutral	0.999	Probably Damaging	0.997	Probably Damaging	2.67	Benign	0.02	Affected			0	-1	3.7	-69.11
c.2443C>G	R815G		SH3-binding motif	Uncertain		1				-7.983	In-Between	0.854	Likely Pathogenic	Ambiguous	0.146	Likely Benign										-3.22	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	2.62	Benign	0.02	Affected	4.32	4	-3	-2	4.1	-99.14
c.3721C>A	L1241M		Coiled-coil	Uncertain		1				-5.881	Likely Benign	0.782	Likely Pathogenic	Likely Benign	0.167	Likely Benign										-1.43	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.65	Pathogenic	0.00	Affected			4	2	-1.9	18.03
c.2444G>T	R815L	Likely Pathogenic	SH3-binding motif	Uncertain		1				-8.546	Likely Pathogenic	0.865	Likely Pathogenic	Ambiguous	0.175	Likely Benign										-3.06	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	2.63	Benign	0.03	Affected	4.32	4	-2	-3	8.3	-43.03
c.3794G>C	R1265T	Likely Pathogenic	Coiled-coil	Likely Pathogenic		1				-10.129	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.529	Likely Pathogenic										-4.97	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	2.29	Pathogenic	0.00	Affected	3.77	5	-1	-1	3.8	-55.08
c.2401G>A	G801S	Likely Benign	SH3-binding motif	Uncertain		1				-3.665	Likely Benign	0.087	Likely Benign	Likely Benign	0.039	Likely Benign										-0.41	Neutral	0.009	Benign	0.019	Benign	2.76	Benign	0.48	Tolerated	4.32	2	0	1	-0.4	30.03
c.2343G>A	M781I	Likely Benign		Benign		1				-2.484	Likely Benign	0.323	Likely Benign	Likely Benign	0.101	Likely Benign										0.05	Neutral	0.000	Benign	0.001	Benign	2.89	Benign	1.00	Tolerated	3.64	6	1	2	2.6	-18.03
c.3943T>C	W1315R	Likely Benign		Uncertain		1				0.205	Likely Benign	0.660	Likely Pathogenic	Likely Benign	0.114	Likely Benign										1.31	Neutral	0.000	Benign	0.001	Benign	4.37	Benign	0.91	Tolerated	3.77	5	2	-3	-3.6	-30.03
c.2350G>A	A784T	Likely Benign		Benign		1				-3.579	Likely Benign	0.089	Likely Benign	Likely Benign	0.046	Likely Benign										1.23	Neutral	0.001	Benign	0.006	Benign	2.92	Benign	1.00	Tolerated	3.64	6	1	0	-2.5	30.03
c.391G>C	G131R			Uncertain		1				-6.564	Likely Benign	0.983	Likely Pathogenic	Likely Pathogenic	0.099	Likely Benign										-3.82	Deleterious	0.983	Probably Damaging	0.656	Possibly Damaging	3.92	Benign	0.00	Affected	3.61	5	-2	-3	-4.1	99.14
c.3907G>A	G1303S	Likely Benign		Uncertain		1				-2.271	Likely Benign	0.125	Likely Benign	Likely Benign	0.155	Likely Benign										-0.19	Neutral	0.649	Possibly Damaging	0.433	Benign	2.84	Benign	0.18	Tolerated			1	0	-0.4	30.03
c.3906G>C	L1302F			Uncertain		1				-5.674	Likely Benign	0.148	Likely Benign	Likely Benign	0.211	Likely Benign										-2.70	Deleterious	0.960	Probably Damaging	0.657	Possibly Damaging	1.53	Pathogenic	0.00	Affected			2	0	-1.0	34.02
c.3806T>A	V1269E	Likely Pathogenic	Coiled-coil	Uncertain		1				-11.418	Likely Pathogenic	0.989	Likely Pathogenic	Likely Pathogenic	0.403	Likely Benign										-5.05	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	2.09	Pathogenic	0.00	Affected	3.77	5	-2	-2	-7.7	29.98
c.2369C>G	T790S	Likely Benign	SH3-binding motif	Uncertain		1				-3.914	Likely Benign	0.123	Likely Benign	Likely Benign	0.134	Likely Benign										-1.83	Neutral	0.997	Probably Damaging	0.989	Probably Damaging	2.39	Pathogenic	0.33	Tolerated	3.64	6	1	1	-0.1	-14.03
c.37A>G	I13V	Likely Benign		Uncertain		1				-2.497	Likely Benign	0.105	Likely Benign	Likely Benign	0.110	Likely Benign										0.01	Neutral	0.000	Benign	0.000	Benign	4.25	Benign	0.00	Affected			4	3	-0.3	-14.03
c.379C>T	R127W			Uncertain		1				-4.776	Likely Benign	0.806	Likely Pathogenic	Ambiguous	0.118	Likely Benign										-2.98	Deleterious	0.989	Probably Damaging	0.420	Benign	3.88	Benign	0.00	Affected			2	-3	3.6	30.03
c.2458T>A	Y820N			Uncertain		1				-9.032	Likely Pathogenic	0.842	Likely Pathogenic	Ambiguous	0.143	Likely Benign										-1.53	Neutral	0.999	Probably Damaging	0.977	Probably Damaging	2.74	Benign	0.20	Tolerated			-2	-2	-2.2	-49.07
c.484C>G	R162G	Likely Benign		Uncertain		1				-6.985	Likely Benign	0.664	Likely Pathogenic	Likely Benign	0.190	Likely Benign										-0.73	Neutral	0.487	Possibly Damaging	0.272	Benign	4.09	Benign	0.78	Tolerated	3.74	4	-2	-3	4.1	-99.14
c.1851G>T	E617D (3D Viewer)	Likely Benign	GAP	Uncertain		1				-1.349	Likely Benign	0.241	Likely Benign	Likely Benign	0.322	Likely Benign	0.12	Likely Benign	0.1	0.80	Ambiguous	0.46	Likely Benign	0.07	Likely Benign	-0.01	Neutral	0.994	Probably Damaging	0.979	Probably Damaging	-1.35	Pathogenic	0.88	Tolerated	3.37	35	2	3	0.0	-14.03
c.1964T>A	L655Q (3D Viewer)	Likely Benign	GAP	Uncertain		1				-5.278	Likely Benign	0.144	Likely Benign	Likely Benign	0.139	Likely Benign	-0.01	Likely Benign	0.0	0.69	Ambiguous	0.34	Likely Benign	-0.15	Likely Benign	0.61	Neutral	0.955	Possibly Damaging	0.602	Possibly Damaging	3.59	Benign	0.65	Tolerated	3.39	24	-2	-2	-7.3	14.97	229.9	-8.6	0.0	0.0	0.4	0.0						X		Potentially Benign	The iso-butyl side chain of Leu655, located on the surface of an α helix (res. Ser641-Glu666), is not involved in any interactions in the WT simulations. In the variant simulations, the carboxamide side chain of Gln655 dynamically interacts with neighboring residues (e.g., Glu651, Glu656, Arg544) on the protein surface, with no negative structural effects.
c.59C>T	P20L	Likely Benign		Uncertain		3				-3.289	Likely Benign	0.464	Ambiguous	Likely Benign	0.100	Likely Benign										-0.44	Neutral	0.909	Possibly Damaging	0.713	Possibly Damaging	4.27	Benign	0.00	Affected	4.32	1	-3	-3	5.4	16.04
c.196C>G	P66A	Likely Benign		Uncertain		1				-2.845	Likely Benign	0.891	Likely Pathogenic	Ambiguous	0.091	Likely Benign										-1.56	Neutral	0.805	Possibly Damaging	0.539	Possibly Damaging	4.04	Benign	0.00	Affected	4.32	1	1	-1	3.4	-26.04
c.3250C>G	P1084A	Likely Benign		Uncertain		1				-3.928	Likely Benign	0.066	Likely Benign	Likely Benign	0.114	Likely Benign										-2.54	Deleterious	0.649	Possibly Damaging	0.157	Benign	4.05	Benign	0.35	Tolerated	3.77	5	-1	1	3.4	-26.04
c.1970G>T	W657L (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-14.411	Likely Pathogenic	0.960	Likely Pathogenic	Likely Pathogenic	0.213	Likely Benign	0.14	Likely Benign	0.1	0.73	Ambiguous	0.44	Likely Benign	0.87	Ambiguous	-10.86	Deleterious	0.277	Benign	0.078	Benign	3.52	Benign	0.14	Tolerated	3.39	24	-2	-2	4.7	-73.05
c.1971G>C	W657C	Likely Pathogenic	GAP	Uncertain		1				-12.035	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.463	Likely Benign	2.74	Destabilizing	0.3	1.69	Ambiguous	2.22	Destabilizing	1.30	Destabilizing	-11.06	Deleterious	1.000	Probably Damaging	0.982	Probably Damaging	3.43	Benign	0.03	Affected			-8	-2	3.4	-83.07
c.59C>G	P20R	Likely Benign		Uncertain		1				-3.548	Likely Benign	0.434	Ambiguous	Likely Benign	0.146	Likely Benign										-0.15	Neutral	0.972	Probably Damaging	0.804	Possibly Damaging	4.33	Benign	0.00	Affected	4.32	1	0	-2	-2.9	59.07
c.1976C>T	S659F (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-10.925	Likely Pathogenic	0.662	Likely Pathogenic	Likely Benign	0.194	Likely Benign	-0.81	Ambiguous	0.1	-0.25	Likely Benign	-0.53	Ambiguous	0.32	Likely Benign	-4.59	Deleterious	0.806	Possibly Damaging	0.171	Benign	3.39	Benign	0.05	Affected	3.38	28	-3	-2	3.6	60.10	221.3	-61.2	0.0	0.0	0.6	0.4						X		Potentially Benign	In the WT simulations, the hydroxyl group of Ser659, located in a kink in the middle of the long α-helix (res. Ser641-Glu666), forms a hydrogen bond with the carboxylate group of Glu656. However, the phenol ring of the Phe659 side chain cannot form a similar hydrogen bond. Instead, it interacts with the hydrophobic isopropyl side chain of Val555 from the opposing α-helix (res. Ala533-Val560). This residue swap may therefore cause issues during protein folding.
c.597C>A	N199K (3D Viewer)		PH	Uncertain		1				-8.198	Likely Pathogenic	0.686	Likely Pathogenic	Likely Benign	0.024	Likely Benign	-0.19	Likely Benign	0.1	0.03	Likely Benign	-0.08	Likely Benign	0.33	Likely Benign	-1.48	Neutral	0.276	Benign	0.083	Benign	4.27	Benign	0.13	Tolerated	3.47	9	1	0	-0.4	14.07	207.8	21.5	-0.1	1.5	0.1	0.0						X		Uncertain	Asn199, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by a positively charged lysine. On the protein surface, both the carboxamide group of Asn199 and the amino group of Lys199 side chains can form hydrogen bonds with the backbone carbonyl groups of residues (e.g., Ala249) at the end of an α helix (res. Ala236-Lys251). However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.583G>C	A195P	Likely Pathogenic		Likely Pathogenic		1				-9.715	Likely Pathogenic	0.978	Likely Pathogenic	Likely Pathogenic	0.152	Likely Benign										-3.03	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	4.00	Benign	0.04	Affected	3.54	6	1	-1	-3.4	26.04
c.1957C>G	L653V	Likely Benign	GAP	Uncertain		1				-7.050	In-Between	0.301	Likely Benign	Likely Benign	0.146	Likely Benign	3.28	Destabilizing	0.3	2.18	Destabilizing	2.73	Destabilizing	1.32	Destabilizing	-2.25	Neutral	0.227	Benign	0.039	Benign	3.28	Benign	0.08	Tolerated			2	1	0.4	-14.03
c.1947G>C	M649I (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-9.361	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	0.449	Likely Benign	2.42	Destabilizing	0.2	1.96	Ambiguous	2.19	Destabilizing	1.01	Destabilizing	-3.99	Deleterious	0.672	Possibly Damaging	0.093	Benign	3.40	Benign	0.02	Affected	3.38	27	2	1	2.6	-18.03	243.7	21.5	0.0	0.1	0.0	0.1							X	Potentially Benign	The thioether side chain of Met649, located on an α helix (res. Ser641-Glu666), bridges Phe652, Phe648, and Phe639 in an inter-helix hydrophobic cavity in the WT simulations. In the variant simulations, the sec-butyl side chain of Ile649 maintains hydrophobic interactions with nearby residues, with no significant effects on the protein structure.However, methionine is known as a bridging motif for aromatic residues, and these Met-aromatic interactions are lost in the variant. Indeed, in the second variant simulation,the bridging of Phe652, Phe648 and Phe639 is completely lost. In reality, the effect could be more severe on the structure during the protein folding.
c.1855A>T	T619S (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-8.608	Likely Pathogenic	0.677	Likely Pathogenic	Likely Benign	0.602	Likely Pathogenic	1.09	Ambiguous	0.2	1.35	Ambiguous	1.22	Ambiguous	0.85	Ambiguous	-3.42	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	-1.30	Pathogenic	0.05	Affected	3.37	35	1	1	-0.1	-14.03
c.1873C>G	L625V	Likely Pathogenic	GAP	Uncertain		1				-11.319	Likely Pathogenic	0.833	Likely Pathogenic	Ambiguous	0.480	Likely Benign	1.80	Ambiguous	0.7	1.69	Ambiguous	1.75	Ambiguous	1.42	Destabilizing	-2.96	Deleterious	0.998	Probably Damaging	0.992	Probably Damaging	3.07	Benign	0.01	Affected			2	1	0.4	-14.03
c.1877T>C	I626T	Likely Pathogenic	GAP	Uncertain		1				-10.420	Likely Pathogenic	0.946	Likely Pathogenic	Ambiguous	0.640	Likely Pathogenic	2.94	Destabilizing	0.1	2.70	Destabilizing	2.82	Destabilizing	2.23	Destabilizing	-4.18	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	3.04	Benign	0.00	Affected			0	-1	-5.2	-12.05
c.187G>A	E63K	Likely Benign		Uncertain		1				-4.976	Likely Benign	0.894	Likely Pathogenic	Ambiguous	0.103	Likely Benign										-0.70	Neutral	0.458	Possibly Damaging	0.678	Possibly Damaging	3.98	Benign	0.00	Affected	4.32	1	1	0	-0.4	-0.94
c.187G>C	E63Q	Likely Benign		Uncertain		1				-4.038	Likely Benign	0.687	Likely Pathogenic	Likely Benign	0.078	Likely Benign										-0.85	Neutral	0.659	Possibly Damaging	0.775	Possibly Damaging	3.90	Benign	0.00	Affected	4.32	1	2	2	0.0	-0.98
c.603T>A	D201E (3D Viewer)	Likely Benign	PH	Benign		1				-2.640	Likely Benign	0.406	Ambiguous	Likely Benign	0.165	Likely Benign	0.42	Likely Benign	0.2	1.99	Ambiguous	1.21	Ambiguous	0.23	Likely Benign	-0.69	Neutral	0.633	Possibly Damaging	0.108	Benign	4.30	Benign	1.00	Tolerated	3.46	9	3	2	0.0	14.03	258.7	-24.8	0.9	0.1	-0.3	0.2						X		Uncertain	Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.1898T>C	L633P (3D Viewer)	Likely Pathogenic	GAP	Pathogenic/Likely path.		2				-15.669	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.693	Likely Pathogenic	6.60	Destabilizing	0.2	10.15	Destabilizing	8.38	Destabilizing	2.42	Destabilizing	-6.97	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.70	Benign	0.00	Affected	3.37	34	-3	-3	-5.4	-16.04	193.2	65.1	0.0	0.0	0.1	0.0	X							Potentially Pathogenic	The iso-butyl side chain of Leu633, located in the middle of an α helix (res. Glu617-Asn635), packs hydrophobically with nearby residues (e.g., Leu653, Val629, Leu551) in the WT simulations.In the variant simulations, the pyrrolidine side chain of Pro633 is not as optimal for hydrophobic packing as Leu633 in the WT. Additionally, proline lacks a free backbone amide group, so Pro633 cannot form a hydrogen bond with the backbone carbonyl group of Val629, which disrupts the continuity of the secondary structure element.
c.1913A>G	K638R (3D Viewer)	Likely Benign	GAP	Uncertain		1				-2.700	Likely Benign	0.110	Likely Benign	Likely Benign	0.216	Likely Benign	0.09	Likely Benign	0.1	-0.04	Likely Benign	0.03	Likely Benign	0.53	Ambiguous	-2.55	Deleterious	0.649	Possibly Damaging	0.240	Benign	3.41	Benign	0.13	Tolerated	3.37	31	2	3	-0.6	28.01
c.1925A>C	K642T (3D Viewer)	Likely Pathogenic	GAP	Likely Pathogenic		1				-12.823	Likely Pathogenic	0.948	Likely Pathogenic	Ambiguous	0.484	Likely Benign	0.53	Ambiguous	0.1	0.30	Likely Benign	0.42	Likely Benign	0.28	Likely Benign	-5.88	Deleterious	0.872	Possibly Damaging	0.839	Possibly Damaging	2.86	Benign	0.00	Affected	3.37	31	0	-1	3.2	-27.07	213.5	-8.7	-0.3	0.4	0.3	0.2				X				Uncertain	The amino side chain of Lys642, located on the surface of an α helix (res. Ser641-Glu666), is not involved in any interactions in the WT simulations. In the variant simulations, the shorter side chain of Thr642 forms hydrogen bonds with Glu643 and Thr640 on the same α helix.Regardless, Lys642 is positioned directly at the GAP-Ras interface, and in the SynGAP-Ras WT simulations, its amino side chain forms salt bridges with the carboxylate groups of Ras residues Asp33 and Asp38. The shorter Thr642 is more likely to prefer hydrogen bonding with Glu643 and Thr640 on the same α helix, even in the Ras complex. Thus, the effect of the residue swap on the complex formation with the GTPase cannot be explored using solvent-only simulations.
c.1942T>C	F648L	Likely Pathogenic	GAP	Uncertain		1				-9.296	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.468	Likely Benign	2.71	Destabilizing	0.8	2.08	Destabilizing	2.40	Destabilizing	1.04	Destabilizing	-5.98	Deleterious	0.999	Probably Damaging	0.976	Probably Damaging	3.45	Benign	0.08	Tolerated			2	0	1.0	-34.02
c.1998G>C	E666D (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-8.820	Likely Pathogenic	0.704	Likely Pathogenic	Likely Benign	0.197	Likely Benign	0.88	Ambiguous	0.0	0.37	Likely Benign	0.63	Ambiguous	1.05	Destabilizing	-2.69	Deleterious	0.992	Probably Damaging	0.603	Possibly Damaging	3.43	Benign	0.06	Tolerated	3.38	28	3	2	0.0	-14.03	237.2	16.5	0.0	0.0	-0.3	0.1		X						Potentially Pathogenic	The carboxylate group of Glu666, located on the α-helix (res. Ser641-Glu666), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), such as Lys566, Thr672, and Asn669, in the WT simulations. In the variant simulations, the shorter side chain of Asp666 cannot maintain these interactions as efficiently as Glu666 in the WT, resulting in a less coordinated hydrogen-bond network.
c.2003C>T	S668F (3D Viewer)	Likely Pathogenic	GAP	Likely Pathogenic		1				-15.047	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.643	Likely Pathogenic	16.72	Destabilizing	5.0	11.07	Destabilizing	13.90	Destabilizing	0.00	Likely Benign	-5.98	Deleterious	0.999	Probably Damaging	0.935	Probably Damaging	3.18	Benign	0.00	Affected	3.38	28	-3	-2	3.6	60.10	250.9	-59.6	-0.1	0.1	0.0	0.1		X	X				X	Potentially Pathogenic	In the WT simulations, the hydroxyl side chain of Ser668, located on an α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), forms hydrogen bonds with the backbone carbonyl groups of Leu664, Tyr665, and Glu666, as well as the guanidinium group of Arg573 on a nearby α-helix (res. Arg563-Glu578). In the variant simulations, the side chain of Phe668 cannot maintain the same hydrogen-bond network. Due to its larger size, it moves away to avoid steric hindrance. In the WT simulations, a network of hydrogen bonds between several residues (e.g., Asn669, Lys566, and Glu666) keeps both α-helices and the proceeding loop (res. Asn669-Asp684) tightly connected, but this setup is not present in the variant simulations. Additionally, in the variant simulations, the side chain of Arg573 shifts to form a more stable salt bridge with the carboxylate group of Glu582 instead of hydrogen bonding with Ser668 as in the WT simulations.
c.558G>C	L186F	Likely Pathogenic		Uncertain		1				-11.861	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.132	Likely Benign										-3.03	Deleterious	0.009	Benign	0.012	Benign	3.50	Benign	0.00	Affected			2	0	-1.0	34.02
c.2105A>G	Q702R (3D Viewer)		GAP	Uncertain		1				-7.894	In-Between	0.348	Ambiguous	Likely Benign	0.294	Likely Benign	-0.31	Likely Benign	0.1	0.63	Ambiguous	0.16	Likely Benign	0.13	Likely Benign	-3.14	Deleterious	0.909	Possibly Damaging	0.889	Possibly Damaging	3.43	Benign	0.02	Affected	3.47	10	1	1	-1.0	28.06	270.3	-52.9	0.0	0.0	0.0	0.1		X						Potentially Pathogenic	The carboxamide side chain of Gln702 is located at the end and outer surface of an α-helix (res. Leu685-Gln702), where it does not directly form hydrogen bonds with any residues in the WT simulations. In the variant simulations, the positively charged guanidinium group of Arg702 forms a salt bridge with the negatively charged carboxylate group of Glu698 on the same helix and/or hydrogen bonds with the backbone carbonyl group of Ala438 on an opposite α-helix (res. Tyr428-Glu436). Consequently, the residue swap could strengthen the tertiary structure assembly, which could have either positive or negative effects on its function.
c.2111G>C	S704T (3D Viewer)	Likely Benign	GAP	Uncertain		1				-4.930	Likely Benign	0.265	Likely Benign	Likely Benign	0.071	Likely Benign	0.80	Ambiguous	0.0	0.15	Likely Benign	0.48	Likely Benign	0.29	Likely Benign	-1.72	Neutral	0.525	Possibly Damaging	0.107	Benign	3.45	Benign	0.07	Tolerated	3.47	10	1	1	0.1	14.03	201.7	-18.0	0.0	0.0	-0.2	0.7						X		Potentially Benign	Ser704 is located at the end and outer surface of an α-helix (res. Thr704-Gly712), which is connected via a tight turn or loop to another α-helix (res. Asp684-Gln702). The hydroxyl side chain of Ser704 occasionally forms a hydrogen bond with the amide group of Ala707. Similarly, in the variant simulations, the hydroxyl side chain of Thr704 forms hydrogen bonds with the amide groups of Ala707 and Leu708. Thus, the residue swap does not cause any apparent structural change.
c.509G>A	R170Q			Pathogenic/Likely path.		6				-9.021	Likely Pathogenic	0.798	Likely Pathogenic	Ambiguous	0.221	Likely Benign										-2.31	Neutral	0.947	Possibly Damaging	0.342	Benign	3.91	Benign	0.00	Affected	3.74	4	1	1	1.0	-28.06																10.1016/j.ajhg.2020.11.011
c.2115G>C	K705N (3D Viewer)	Likely Pathogenic	GAP	Likely Pathogenic		1				-9.767	Likely Pathogenic	0.925	Likely Pathogenic	Ambiguous	0.183	Likely Benign	0.74	Ambiguous	0.0	0.37	Likely Benign	0.56	Ambiguous	0.44	Likely Benign	-3.12	Deleterious	0.996	Probably Damaging	0.876	Possibly Damaging	3.37	Benign	0.02	Affected	3.47	10	1	0	0.4	-14.07	221.4	-20.2	0.0	0.0	0.0	0.1						X		Uncertain	The amino side chain of Lys705, located at the end and outer surface of an α-helix (res. Thr704-Gly712), does not form any interactions in the WT simulations. In the variant simulations, the carboxamide side chain of Asn705 briefly forms a salt bridge with Glu706. However, there is no apparent difference between the systems. Due to the model ending abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations.
c.2116G>A	E706K (3D Viewer)		GAP	Uncertain		1				-10.519	Likely Pathogenic	0.833	Likely Pathogenic	Ambiguous	0.080	Likely Benign	1.17	Ambiguous	0.1	0.51	Ambiguous	0.84	Ambiguous	0.08	Likely Benign	-1.51	Neutral	0.345	Benign	0.028	Benign	4.15	Benign	0.52	Tolerated	3.47	10	0	1	-0.4	-0.94	187.1	49.2	0.0	0.0	0.4	0.1						X		Uncertain	The carboxylate side chain of Glu706, located at the end and outer surface of an α-helix (res. Thr704-Gly712), forms a salt bridge with Lys710 and a hydrogen bond with its own backbone amino group at the helix end in the WT simulations. Although Lys706 is unable to make these transient interactions in the variant simulations, there is no apparent negative effect on the protein structure due to the residue swap. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations.
c.508C>T	R170W	Likely Pathogenic		Uncertain		2				-11.660	Likely Pathogenic	0.978	Likely Pathogenic	Likely Pathogenic	0.241	Likely Benign										-4.28	Deleterious	0.999	Probably Damaging	0.849	Possibly Damaging	3.84	Benign	0.00	Affected	3.74	4	2	-3	3.6	30.03
c.505G>A	D169N			Uncertain		1				-10.713	Likely Pathogenic	0.761	Likely Pathogenic	Likely Benign	0.110	Likely Benign										-2.04	Neutral	0.079	Benign	0.052	Benign	4.07	Benign	0.01	Affected	3.74	4	2	1	0.0	-0.98
c.2162T>G	I721S (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-14.032	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.466	Likely Benign	3.91	Destabilizing	0.1	3.96	Destabilizing	3.94	Destabilizing	2.28	Destabilizing	-5.26	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.21	Pathogenic	0.00	Affected	3.50	9	-1	-2	-5.3	-26.08	203.3	49.3	-0.1	0.0	-1.1	0.0							X	Uncertain	The sec-butyl side chain of Ile721, located on an α-helix (res. Leu714-Arg726), engages in hydrophobic packing with other residues in the hydrophobic inter-helix space, such as Phe420, Tyr417, His693, and Leu717. In the variant simulations, the hydroxyl side chain of Ser721 forms hydrogen bonds with nearby residues, such as Leu717 and His693. Although no major structural changes are observed during the variant simulations, the hydrophilic residue Ser721 could disrupt the hydrophobic packing during folding. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations.
c.2186A>G	N729S (3D Viewer)	Likely Benign	GAP	Uncertain		1				-1.578	Likely Benign	0.066	Likely Benign	Likely Benign	0.063	Likely Benign	0.14	Likely Benign	0.1	1.34	Ambiguous	0.74	Ambiguous	-0.36	Likely Benign	-0.42	Neutral	0.221	Benign	0.027	Benign	3.38	Benign	0.93	Tolerated	3.59	7	1	1	2.7	-27.03
c.484C>T	R162C			Pathogenic		2				-8.157	Likely Pathogenic	0.787	Likely Pathogenic	Ambiguous	0.150	Likely Benign										-2.05	Neutral	0.988	Probably Damaging	0.513	Possibly Damaging	4.00	Benign	0.11	Tolerated	3.74	4	-4	-3	7.0	-53.05
c.526A>C	S176R	Likely Benign		Uncertain		1				-6.492	Likely Benign	0.987	Likely Pathogenic	Likely Pathogenic	0.247	Likely Benign										0.94	Neutral	0.718	Possibly Damaging	0.168	Benign	4.16	Benign	0.87	Tolerated			0	-1	-3.7	69.11
c.2087T>C	L696P (3D Viewer)	Likely Pathogenic	GAP	Likely Pathogenic		1				-16.926	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.678	Likely Pathogenic	6.66	Destabilizing	0.2	10.84	Destabilizing	8.75	Destabilizing	2.13	Destabilizing	-6.58	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	3.00	Benign	0.00	Affected	3.46	13	-3	-3	-5.4	-16.04	180.6	65.9	0.1	0.0	-0.6	0.1	X							Potentially Pathogenic	The isobutyl side chain of Leu696, located in the middle of an α-helix (res. Leu685-Gln702), engages in hydrophobic packing with nearby residues (e.g., Leu441, Leu431, Leu692, Leu714) in the inter-helix space. Prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Leu692 in the same manner as Leu696 in the WT. Consequently, the residue swap with proline disrupts the continuity of the secondary structure element in the variant simulations. Additionally, the side chain of Pro696 is not as optimal as Leu696 for hydrophobic packing in the inter-helix space.
c.2015C>A	T672K (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-12.192	Likely Pathogenic	0.698	Likely Pathogenic	Likely Benign	0.065	Likely Benign	0.20	Likely Benign	0.5	1.21	Ambiguous	0.71	Ambiguous	0.72	Ambiguous	-4.31	Deleterious	0.745	Possibly Damaging	0.051	Benign	3.40	Benign	0.07	Tolerated	3.40	25	0	-1	-3.2	27.07	195.1	7.0	0.4	0.7	0.4	0.1		X				X		Potentially Pathogenic	The hydroxyl group of Thr672, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop itself, such as Lys566, Glu666, and Asn669. In the variant simulations, Lys672 can only form a hydrogen bond with the amino group of the Lys566 side chain via its backbone carbonyl group. Consequently, it cannot maintain the Lys566-Glu666 salt bridge through hydrogen bonding. However, the amino group of Lys periodically forms a salt bridge with the carboxylate group of Glu666, which prevents a drastic disruption of the hydrogen-bond network that keeps the loop close to the helices.
c.2029A>T	S677C (3D Viewer)	Likely Benign	GAP	Benign		1				-8.496	Likely Pathogenic	0.076	Likely Benign	Likely Benign	0.153	Likely Benign	-0.51	Ambiguous	0.3	-0.30	Likely Benign	-0.41	Likely Benign	0.15	Likely Benign	-2.41	Neutral	0.932	Possibly Damaging	0.222	Benign	3.25	Benign	0.04	Affected	3.41	23	-1	0	3.3	16.06
c.2050G>A	D684N (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-13.155	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	0.382	Likely Benign	1.47	Ambiguous	0.8	1.76	Ambiguous	1.62	Ambiguous	0.37	Likely Benign	-4.99	Deleterious	0.999	Probably Damaging	0.746	Possibly Damaging	3.39	Benign	0.01	Affected			2	1	0.0	-0.98
c.2050G>C	D684H (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-14.194	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.613	Likely Pathogenic	3.36	Destabilizing	1.0	2.95	Destabilizing	3.16	Destabilizing	0.55	Ambiguous	-6.98	Deleterious	1.000	Probably Damaging	0.972	Probably Damaging	3.36	Benign	0.00	Affected	3.42	17	-1	1	0.3	22.05
c.2060G>A	R687Q (3D Viewer)	Likely Pathogenic	GAP	Likely Benign		1				-10.002	Likely Pathogenic	0.575	Likely Pathogenic	Likely Benign	0.401	Likely Benign	0.92	Ambiguous	0.1	-0.37	Likely Benign	0.28	Likely Benign	1.55	Destabilizing	-3.37	Deleterious	1.000	Probably Damaging	0.844	Possibly Damaging	3.91	Benign	0.03	Affected	3.42	17	1	1	1.0	-28.06
c.2068T>C	S690P (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-14.568	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.431	Likely Benign	4.84	Destabilizing	0.3	4.40	Destabilizing	4.62	Destabilizing	1.42	Destabilizing	-4.77	Deleterious	0.998	Probably Damaging	0.790	Possibly Damaging	3.44	Benign	0.01	Affected	3.42	17	1	-1	-0.8	10.04	207.5	15.1	0.1	0.0	-0.1	0.2	X	X						Potentially Pathogenic	The hydroxyl side chain of Ser690, located in an α-helix (res. Leu696-Leu685), forms a hydrogen bond with the backbone carbonyl group of Ser410 in an anti-parallel β-sheet of the C2 domain (res. Ile411-Ala399). In the variant simulations, the pyrrolidine side chain of Pro690 cannot form hydrogen bonds with the C2 domain residue, resulting in the loss of this inter-domain connection. Additionally, prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Gly686, introducing a slight bend in the α-helix and compromising its integrity.
c.2071A>C	T691P (3D Viewer)	Likely Pathogenic	GAP	Likely Pathogenic		1				-13.801	Likely Pathogenic	0.905	Likely Pathogenic	Ambiguous	0.214	Likely Benign	5.04	Destabilizing	0.4	6.09	Destabilizing	5.57	Destabilizing	1.27	Destabilizing	-3.43	Deleterious	1.000	Probably Damaging	0.952	Probably Damaging	3.43	Benign	0.06	Tolerated	3.43	14	0	-1	-0.9	-3.99	188.9	33.0	0.1	0.0	-0.6	0.0	X	X						Potentially Pathogenic	The hydroxyl side chain of Thr691, located in an α-helix (res. Leu696-Leu685), can form hydrogen bonds with the backbone carbonyl and the side chain guanidinium group of Arg687. This interaction facilitates the simultaneous formation of salt bridges between Arg687 and Glu688 on the same α-helix. Additionally, Thr691 occasionally interacts with the thioether side chain of Met409 in an anti-parallel β-sheet of the C2 domain (res. Ile411-Ala399), although this interaction is not consistently maintained throughout the WT simulations. In the variant simulations, the pyrrolidine side chain of Pro691 lacks hydrogen bond donors, making a similar setup impossible. Moreover, proline lacks a free amide group necessary for hydrogen bonding with the carbonyl group of Arg687, introducing a slight bend in the α-helix and compromising its integrity.
c.2075T>A	L692Q (3D Viewer)	Likely Pathogenic	GAP	Pathogenic		1				-13.873	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.596	Likely Pathogenic	3.24	Destabilizing	0.1	3.27	Destabilizing	3.26	Destabilizing	2.76	Destabilizing	-5.98	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	3.06	Benign	0.00	Affected	3.42	17	-2	-2	-7.3	14.97
c.2075T>C	L692P (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-16.447	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.668	Likely Pathogenic	9.19	Destabilizing	0.1	13.20	Destabilizing	11.20	Destabilizing	1.69	Destabilizing	-6.98	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	3.06	Benign	0.00	Affected	3.42	17	-3	-3	-5.4	-16.04	186.2	62.8	-0.2	0.1	-0.7	0.3	X							Potentially Pathogenic	The isobutyl side chain of Leu692, located in the middle of an α-helix (res. Leu685-Gln702), engages in hydrophobic packing with nearby residues (e.g., Leu441, Leu431, Leu696) in the inter-helix space. Prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Glu688 in the same manner as Leu692 in the WT. Consequently, the residue swap with proline disrupts the continuity of the secondary structure element in the variant simulations. Additionally, the side chain of Pro692 is not as optimal as Leu692 for hydrophobic packing in the inter-helix space.
c.2086C>G	L696V (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-11.909	Likely Pathogenic	0.745	Likely Pathogenic	Likely Benign	0.351	Likely Benign	2.35	Destabilizing	0.1	1.85	Ambiguous	2.10	Destabilizing	1.46	Destabilizing	-2.79	Deleterious	0.992	Probably Damaging	0.970	Probably Damaging	3.16	Benign	0.00	Affected	3.46	13	1	2	0.4	-14.03
c.2195G>C	R732T			Uncertain		1				-8.545	Likely Pathogenic	0.434	Ambiguous	Likely Benign	0.075	Likely Benign										-1.96	Neutral	0.999	Probably Damaging	0.892	Possibly Damaging	2.59	Benign	0.12	Tolerated	3.59	7	-1	-1	3.8	-55.08
c.2459A>G	Y820C	Likely Pathogenic		Uncertain		1				-8.797	Likely Pathogenic	0.744	Likely Pathogenic	Likely Benign	0.113	Likely Benign										-3.16	Deleterious	1.000	Probably Damaging	0.983	Probably Damaging	2.68	Benign	0.06	Tolerated	3.77	5	0	-2	3.8	-60.04
c.3287A>C	E1096A	Likely Benign		Uncertain		1				-4.504	Likely Benign	0.510	Ambiguous	Likely Benign	0.164	Likely Benign										-1.37	Neutral	0.626	Possibly Damaging	0.184	Benign	2.77	Benign	0.16	Tolerated	3.77	5	-1	0	5.3	-58.04
c.3209_3210delinsCA	R1070T	Likely Benign		Uncertain		1				-5.093	Likely Benign	0.860	Likely Pathogenic	Ambiguous												-2.35	Neutral	0.948	Possibly Damaging	0.507	Possibly Damaging	3.78	Benign	0.01	Affected	3.77	5	-1	-1	3.8	-55.08
c.3209G>A	R1070K	Likely Benign		Conflicting		2				-5.093	Likely Benign	0.326	Likely Benign	Likely Benign	0.104	Likely Benign										-1.42	Neutral	0.049	Benign	0.048	Benign	3.86	Benign	0.09	Tolerated	3.77	5	3	2	0.6	-28.01
c.2822C>T	P941L	Likely Benign		Uncertain		2				-5.692	Likely Benign	0.066	Likely Benign	Likely Benign	0.054	Likely Benign										-0.44	Neutral	0.144	Benign	0.039	Benign	2.76	Benign	0.01	Affected			-3	-3	5.4	16.04
c.3196C>T	P1066S	Likely Benign		Likely Pathogenic		1				-4.746	Likely Benign	0.070	Likely Benign	Likely Benign	0.145	Likely Benign										-2.47	Neutral	0.972	Probably Damaging	0.850	Possibly Damaging	2.74	Benign	0.00	Affected	4.32	2	1	-1	0.8	-10.04
c.3192G>C	Q1064H	Likely Benign		Uncertain		1				-4.576	Likely Benign	0.162	Likely Benign	Likely Benign	0.063	Likely Benign										-0.66	Neutral	0.938	Possibly Damaging	0.596	Possibly Damaging	4.15	Benign	0.05	Affected			3	0	0.3	9.01
c.3181G>A	G1061S	Likely Benign		Uncertain		1				-4.891	Likely Benign	0.079	Likely Benign	Likely Benign	0.283	Likely Benign										-0.68	Neutral	0.004	Benign	0.004	Benign	4.00	Benign	0.00	Affected			1	0	-0.4	30.03
c.3170G>A	S1057N	Likely Benign		Uncertain		1				-6.386	Likely Benign	0.117	Likely Benign	Likely Benign	0.218	Likely Benign										-0.41	Neutral	0.451	Benign	0.129	Benign	5.25	Benign	0.28	Tolerated			1	1	-2.7	27.03
c.3161G>A	G1054D			Uncertain		1				-10.385	Likely Pathogenic	0.351	Ambiguous	Likely Benign	0.279	Likely Benign										-0.26	Neutral	0.818	Possibly Damaging	0.266	Benign	4.07	Benign	0.37	Tolerated	3.77	5	1	-1	-3.1	58.04
c.3154G>A	G1052R			Uncertain		1				-9.050	Likely Pathogenic	0.383	Ambiguous	Likely Benign	0.497	Likely Benign										-0.41	Neutral	0.990	Probably Damaging	0.798	Possibly Damaging	3.90	Benign	0.10	Tolerated	3.77	5	-2	-3	-4.1	99.14
c.2852A>G	H951R	Likely Benign		Likely Pathogenic		1				-4.964	Likely Benign	0.125	Likely Benign	Likely Benign	0.185	Likely Benign										-1.08	Neutral	0.048	Benign	0.029	Benign	5.46	Benign	0.24	Tolerated	3.77	5	2	0	-1.3	19.05
c.2812G>A	G938R	Likely Benign		Uncertain		1				-5.271	Likely Benign	0.732	Likely Pathogenic	Likely Benign	0.141	Likely Benign										-1.11	Neutral	0.999	Probably Damaging	0.985	Probably Damaging	2.74	Benign	0.36	Tolerated	3.77	5	-3	-2	-4.1	99.14
c.2809G>C	D937H	Likely Benign		Uncertain		1				-0.733	Likely Benign	0.677	Likely Pathogenic	Likely Benign	0.150	Likely Benign										-1.74	Neutral	1.000	Probably Damaging	0.975	Probably Damaging	2.68	Benign	0.13	Tolerated	3.77	5	-1	1	0.3	22.05
c.3262A>G	S1088G	Likely Benign		Uncertain		1				-5.034	Likely Benign	0.285	Likely Benign	Likely Benign	0.163	Likely Benign										-1.83	Neutral	0.979	Probably Damaging	0.973	Probably Damaging	2.63	Benign	0.03	Affected	3.77	5	0	1	0.4	-30.03
c.3260C>T	S1087F			Uncertain		1				-3.843	Likely Benign	0.497	Ambiguous	Likely Benign	0.105	Likely Benign										-2.75	Deleterious	0.990	Probably Damaging	0.796	Possibly Damaging	2.56	Benign	0.03	Affected	3.77	5	-2	-3	3.6	60.10
c.272A>G	E91G	Likely Benign		Likely Benign		1				-3.226	Likely Benign	0.783	Likely Pathogenic	Likely Benign	0.110	Likely Benign										-2.18	Neutral	0.947	Possibly Damaging	0.727	Possibly Damaging	3.86	Benign	0.00	Affected	4.32	1	0	-2	3.1	-72.06
c.2735C>A	T912N	Likely Benign		Uncertain		1				-4.260	Likely Benign	0.190	Likely Benign	Likely Benign	0.116	Likely Benign										-1.15	Neutral	0.999	Probably Damaging	0.977	Probably Damaging	3.96	Benign	0.00	Affected	3.77	5	0	0	-2.8	13.00
c.2741A>T	D914V	Likely Benign		Uncertain		1				-4.260	Likely Benign	0.723	Likely Pathogenic	Likely Benign	0.187	Likely Benign										-2.24	Neutral	0.999	Probably Damaging	0.986	Probably Damaging	2.64	Benign	0.01	Affected	3.77	5	-3	-2	7.7	-15.96
c.3237C>G	S1079R	Likely Benign		Benign		1				-4.579	Likely Benign	0.955	Likely Pathogenic	Ambiguous	0.124	Likely Benign										-1.81	Neutral	0.177	Benign	0.075	Benign	3.86	Benign	0.00	Affected	3.77	5	0	-1	-3.7	69.11
c.3233T>A	V1078D	Likely Benign		Uncertain		1				-5.155	Likely Benign	0.979	Likely Pathogenic	Likely Pathogenic	0.158	Likely Benign										-1.45	Neutral	0.003	Benign	0.008	Benign	3.84	Benign	0.00	Affected	3.77	5	-3	-2	-7.7	15.96
c.3223C>A	Q1075K	Likely Benign		Uncertain		1				-5.135	Likely Benign	0.728	Likely Pathogenic	Likely Benign	0.134	Likely Benign										-0.67	Neutral	0.963	Probably Damaging	0.959	Probably Damaging	2.75	Benign	1.00	Tolerated	3.77	5	1	1	-0.4	0.04
c.2768T>A	I923N	Likely Benign		Uncertain		1				-0.733	Likely Benign	0.712	Likely Pathogenic	Likely Benign	0.108	Likely Benign										-1.16	Neutral	0.991	Probably Damaging	0.793	Possibly Damaging	2.70	Benign	0.13	Tolerated	3.77	5	-2	-3	-8.0	0.94
c.277C>G	R93G	Likely Benign		Uncertain		1				-2.674	Likely Benign	0.400	Ambiguous	Likely Benign	0.093	Likely Benign										-1.69	Neutral	0.103	Benign	0.019	Benign	3.99	Benign	0.00	Affected	4.32	1	-2	-3	4.1	-99.14
c.3151G>T	G1051C			Likely Pathogenic		1				-9.050	Likely Pathogenic	0.122	Likely Benign	Likely Benign	0.497	Likely Benign										-0.90	Neutral	0.971	Probably Damaging	0.750	Possibly Damaging	-0.74	Pathogenic	0.10	Tolerated	3.77	5	-3	-3	2.9	46.09
c.2855G>T	G952V	Likely Benign		Uncertain		1				-7.074	In-Between	0.078	Likely Benign	Likely Benign	0.231	Likely Benign										-0.33	Neutral	0.000	Benign	0.000	Benign	3.20	Benign	0.02	Affected	3.77	5	-1	-3	4.6	42.08
c.2858C>A	P953Q	Likely Benign		Uncertain		1				-6.038	Likely Benign	0.079	Likely Benign	Likely Benign	0.086	Likely Benign										-0.78	Neutral	0.058	Benign	0.015	Benign	2.78	Benign	0.29	Tolerated	3.77	5	0	-1	-1.9	31.01
c.2932C>T	P978S	Likely Benign		Uncertain		1				-3.913	Likely Benign	0.151	Likely Benign	Likely Benign	0.085	Likely Benign										-1.07	Neutral	0.481	Possibly Damaging	0.220	Benign	4.22	Benign	0.48	Tolerated			1	-1	0.8	-10.04
c.2935T>C	F979L	Likely Benign		Uncertain		1				-2.341	Likely Benign	0.870	Likely Pathogenic	Ambiguous	0.228	Likely Benign										-1.00	Neutral	0.625	Possibly Damaging	0.430	Benign	4.22	Benign	0.73	Tolerated	4.32	2	2	0	1.0	-34.02
c.3020G>A	S1007N	Likely Benign		Benign		1				-5.113	Likely Benign	0.803	Likely Pathogenic	Ambiguous	0.075	Likely Benign										-1.54	Neutral	0.997	Probably Damaging	0.992	Probably Damaging	2.65	Benign	0.01	Affected	3.77	5	1	1	-2.7	27.03
c.3009C>G	S1003R			Uncertain		1				-5.113	Likely Benign	0.991	Likely Pathogenic	Likely Pathogenic	0.141	Likely Benign										-1.88	Neutral	0.999	Probably Damaging	0.996	Probably Damaging	2.48	Pathogenic	0.00	Affected	3.77	5	0	-1	-3.7	69.11
c.2954G>A	S985N	Likely Benign		Uncertain		1				-6.979	Likely Benign	0.845	Likely Pathogenic	Ambiguous	0.088	Likely Benign										-1.68	Neutral	0.991	Probably Damaging	0.988	Probably Damaging	2.65	Benign	0.00	Affected	4.32	1	1	1	-2.7	27.03
c.2960A>G	D987G	Likely Pathogenic		Uncertain		1				-4.782	Likely Benign	0.849	Likely Pathogenic	Ambiguous	0.234	Likely Benign										-2.79	Deleterious	0.943	Possibly Damaging	0.808	Possibly Damaging	2.45	Pathogenic	0.07	Tolerated	4.32	2	1	-1	3.1	-58.04
c.3002T>C	L1001P	Likely Benign		Uncertain		1				-3.071	Likely Benign	0.209	Likely Benign	Likely Benign	0.113	Likely Benign										-1.02	Neutral	0.966	Probably Damaging	0.690	Possibly Damaging	2.65	Benign	0.00	Affected	4.32	4	-3	-3	-5.4	-16.04
c.2983C>T	P995S	Likely Benign		Uncertain		1				-4.457	Likely Benign	0.071	Likely Benign	Likely Benign	0.042	Likely Benign										-1.03	Neutral	0.011	Benign	0.015	Benign	4.24	Benign	0.00	Affected	4.32	1	1	-1	0.8	-10.04
c.2987C>G	P996R	Likely Benign		Benign		1				-4.457	Likely Benign	0.141	Likely Benign	Likely Benign	0.040	Likely Benign										-1.04	Neutral	0.144	Benign	0.085	Benign	4.26	Benign	0.01	Affected	4.32	4	-2	0	-2.9	59.07
c.2989G>A	A997T	Likely Benign		Uncertain		1				-4.102	Likely Benign	0.071	Likely Benign	Likely Benign	0.085	Likely Benign										-0.62	Neutral	0.224	Benign	0.120	Benign	4.17	Benign	0.00	Affected	4.32	4	1	0	-2.5	30.03
c.2928T>G	F976L	Likely Benign		Uncertain		1				-2.432	Likely Benign	0.825	Likely Pathogenic	Ambiguous	0.212	Likely Benign										-0.87	Neutral	0.264	Benign	0.102	Benign	4.20	Benign	0.53	Tolerated	4.32	2	2	0	1.0	-34.02
c.3026A>C	E1009A	Likely Pathogenic		Uncertain		1				-3.118	Likely Benign	0.679	Likely Pathogenic	Likely Benign	0.109	Likely Benign										-3.06	Deleterious	0.980	Probably Damaging	0.630	Possibly Damaging	2.39	Pathogenic	0.01	Affected	3.77	5	0	-1	5.3	-58.04
c.3142G>C	G1048R	Likely Benign		Uncertain		1				-4.305	Likely Benign	0.435	Ambiguous	Likely Benign	0.503	Likely Pathogenic										-0.54	Neutral	0.919	Possibly Damaging	0.728	Possibly Damaging	2.54	Benign	0.10	Tolerated	3.77	5	-2	-3	-4.1	99.14
c.313T>C	S105P	Likely Benign		Uncertain		1				-3.631	Likely Benign	0.166	Likely Benign	Likely Benign	0.204	Likely Benign										0.03	Neutral	0.808	Possibly Damaging	0.212	Benign	4.00	Benign	0.00	Affected	4.32	1	-1	1	-0.8	10.04
c.3103C>A	P1035T	Likely Benign		Uncertain		1				-4.447	Likely Benign	0.426	Ambiguous	Likely Benign	0.087	Likely Benign										-0.96	Neutral	0.901	Possibly Damaging	0.537	Possibly Damaging	2.72	Benign	0.23	Tolerated	3.77	5	0	-1	0.9	3.99
c.3100C>G	P1034A	Likely Benign		Benign		1				-4.174	Likely Benign	0.178	Likely Benign	Likely Benign	0.060	Likely Benign										-2.44	Neutral	0.059	Benign	0.061	Benign	2.47	Pathogenic	0.06	Tolerated	3.77	5	1	-1	3.4	-26.04
c.3059G>T	R1020L			Uncertain		1				-6.031	Likely Benign	0.907	Likely Pathogenic	Ambiguous	0.216	Likely Benign										-4.03	Deleterious	0.990	Probably Damaging	0.921	Probably Damaging	2.50	Benign	0.00	Affected	3.77	5	-3	-2	8.3	-43.03
c.3059G>C	R1020P	Likely Pathogenic		Uncertain		1				-3.491	Likely Benign	0.902	Likely Pathogenic	Ambiguous	0.205	Likely Benign										-3.50	Deleterious	0.999	Probably Damaging	0.977	Probably Damaging	2.46	Pathogenic	0.00	Affected			0	-2	2.9	-59.07
c.2909A>G	E970G	Likely Benign		Benign		1				-0.167	Likely Benign	0.139	Likely Benign	Likely Benign	0.139	Likely Benign										-0.93	Neutral	0.144	Benign	0.058	Benign	4.09	Benign	0.10	Tolerated	4.32	2	0	-2	3.1	-72.06
c.3049T>C	F1017L	Likely Benign		Benign		1				-2.048	Likely Benign	0.934	Likely Pathogenic	Ambiguous	0.157	Likely Benign										-2.38	Neutral	0.798	Possibly Damaging	0.373	Benign	2.65	Benign	0.72	Tolerated	3.77	5	0	2	1.0	-34.02
c.3041G>T	G1014V	Likely Benign		Uncertain		1				-4.612	Likely Benign	0.181	Likely Benign	Likely Benign	0.053	Likely Benign										-2.47	Neutral	0.818	Possibly Damaging	0.377	Benign	2.72	Benign	0.06	Tolerated	3.77	5	-1	-3	4.6	42.08
c.2924C>G	T975S	Likely Benign		Uncertain		1				-2.743	Likely Benign	0.068	Likely Benign	Likely Benign	0.109	Likely Benign										-0.57	Neutral	0.059	Benign	0.061	Benign	4.16	Benign	0.20	Tolerated			1	1	-0.1	-14.03
c.2998A>G	I1000V	Likely Benign		Uncertain		2				-4.102	Likely Benign	0.098	Likely Benign	Likely Benign	0.086	Likely Benign										-0.20	Neutral	0.437	Benign	0.170	Benign	2.76	Benign	0.81	Tolerated	4.32	4	3	4	-0.3	-14.03
c.3290C>T	P1097L	Likely Benign		Benign		1				-4.410	Likely Benign	0.145	Likely Benign	Likely Benign	0.131	Likely Benign										-2.07	Neutral	0.611	Possibly Damaging	0.198	Benign	2.64	Benign	0.05	Affected	3.77	5	-3	-3	5.4	16.04
c.3705G>A	M1235I	Likely Benign	Coiled-coil	Uncertain		1				-4.312	Likely Benign	0.310	Likely Benign	Likely Benign	0.027	Likely Benign										-1.44	Neutral	0.139	Benign	0.056	Benign	2.69	Benign	0.04	Affected	3.77	5	1	2	2.6	-18.03
c.2557G>C	G853R	Likely Benign		Uncertain		1				-4.749	Likely Benign	0.366	Ambiguous	Likely Benign	0.091	Likely Benign										-1.27	Neutral	0.846	Possibly Damaging	0.624	Possibly Damaging	4.18	Benign	0.00	Affected			-3	-2	-4.1	99.14
c.3635C>T	S1212F	Likely Pathogenic	Coiled-coil	Conflicting		2				-14.445	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.271	Likely Benign										-4.52	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	2.03	Pathogenic	0.00	Affected	3.77	5	-3	-2	3.6	60.10
c.502C>T	H168Y	Likely Benign		Benign		1				-8.914	Likely Pathogenic	0.264	Likely Benign	Likely Benign	0.065	Likely Benign										-1.53	Neutral	0.192	Benign	0.062	Benign	4.18	Benign	0.01	Affected	4.32	3	0	2	1.9	26.03
c.3632T>A	M1211K	Likely Pathogenic	Coiled-coil	Likely Benign		1				-9.013	Likely Pathogenic	0.662	Likely Pathogenic	Likely Benign	0.595	Likely Pathogenic										-2.95	Deleterious	0.987	Probably Damaging	0.979	Probably Damaging	5.59	Benign	0.01	Affected	3.77	5	0	-1	-5.8	-3.02
c.256G>A	V86I	Likely Benign		Uncertain		1				-4.726	Likely Benign	0.338	Likely Benign	Likely Benign	0.076	Likely Benign										-0.31	Neutral	0.267	Benign	0.097	Benign	3.94	Benign	0.00	Affected	4.32	1	4	3	0.3	14.03
c.3614T>C	L1205P	Likely Pathogenic	Coiled-coil	Uncertain		1				-16.878	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.536	Likely Pathogenic										-5.91	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.45	Pathogenic	0.00	Affected			-3	-3	-5.4	-16.04
c.3607C>G	H1203D	Likely Benign	Coiled-coil	Uncertain		1				-6.729	Likely Benign	0.525	Ambiguous	Likely Benign	0.403	Likely Benign										-1.89	Neutral	0.473	Possibly Damaging	0.265	Benign	5.51	Benign	0.24	Tolerated	3.77	5	1	-1	-0.3	-22.05
c.3574C>G	L1192V	Likely Benign	Coiled-coil	Uncertain		1				-4.132	Likely Benign	0.471	Ambiguous	Likely Benign	0.041	Likely Benign										-0.89	Neutral	0.779	Possibly Damaging	0.527	Possibly Damaging	2.69	Benign	0.16	Tolerated			2	1	0.4	-14.03
c.3529G>A	E1177K	Likely Benign	Coiled-coil	Uncertain		1				-3.413	Likely Benign	0.944	Likely Pathogenic	Ambiguous	0.560	Likely Pathogenic										-1.75	Neutral	0.905	Possibly Damaging	0.637	Possibly Damaging	5.44	Benign	0.11	Tolerated	4.32	2	0	1	-0.4	-0.94
c.3511_3512delinsTG	A1171C	Likely Benign	Coiled-coil	Uncertain		1				-5.363	Likely Benign	0.496	Ambiguous	Likely Benign												-1.16	Neutral	0.978	Probably Damaging	0.825	Possibly Damaging	5.32	Benign	0.02	Affected	4.32	4	-2	0	0.7	32.06
c.2548G>A	G850R	Likely Benign		Uncertain		1				-5.082	Likely Benign	0.398	Ambiguous	Likely Benign	0.194	Likely Benign										-0.07	Neutral	0.010	Benign	0.010	Benign	4.30	Benign	0.01	Affected	3.77	5	-3	-2	-4.1	99.14
c.2525C>A	S842Y	Likely Pathogenic		Likely Pathogenic		1				-16.124	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	0.191	Likely Benign										-4.28	Deleterious	0.944	Possibly Damaging	0.676	Possibly Damaging	1.97	Pathogenic	0.00	Affected	3.77	5	-3	-2	-0.5	76.10
c.2485G>A	E829K	Likely Pathogenic		Pathogenic		1				-7.527	In-Between	0.807	Likely Pathogenic	Ambiguous	0.194	Likely Benign										-2.65	Deleterious	0.994	Probably Damaging	0.900	Possibly Damaging	2.27	Pathogenic	0.00	Affected	3.77	5	0	1	-0.4	-0.94
c.249A>T	R83S	Likely Benign		Uncertain		1				-2.550	Likely Benign	0.999	Likely Pathogenic	Likely Pathogenic	0.094	Likely Benign										-1.87	Neutral	0.909	Possibly Damaging	0.587	Possibly Damaging	3.19	Benign	0.00	Affected	4.32	1	0	-1	3.7	-69.11
c.2502G>C	M834I	Likely Benign		Uncertain		1				-3.377	Likely Benign	0.291	Likely Benign	Likely Benign	0.055	Likely Benign										-1.21	Neutral	0.026	Benign	0.009	Benign	2.56	Benign	0.00	Affected	4.32	4	1	2	2.6	-18.03
c.2503C>A	L835M	Likely Benign		Benign		1				-4.153	Likely Benign	0.121	Likely Benign	Likely Benign	0.068	Likely Benign										-0.45	Neutral	0.999	Probably Damaging	0.977	Probably Damaging	2.67	Benign	0.12	Tolerated	3.77	5	2	4	-1.9	18.03
c.3686A>C	Q1229P	Likely Pathogenic	Coiled-coil	Uncertain		1				-10.397	Likely Pathogenic	0.980	Likely Pathogenic	Likely Pathogenic	0.422	Likely Benign										-3.69	Deleterious	0.998	Probably Damaging	0.995	Probably Damaging	1.75	Pathogenic	0.12	Tolerated	3.77	5	0	-1	1.9	-31.01
c.250C>G	R84G			Uncertain		1				-6.627	Likely Benign	0.989	Likely Pathogenic	Likely Pathogenic	0.139	Likely Benign										-2.64	Deleterious	0.962	Probably Damaging	0.726	Possibly Damaging	3.68	Benign	0.00	Affected	4.32	1	-3	-2	4.1	-99.14
c.2514C>A	N838K	Likely Pathogenic		Uncertain		2				-8.470	Likely Pathogenic	0.862	Likely Pathogenic	Ambiguous	0.097	Likely Benign										-2.78	Deleterious	0.997	Probably Damaging	0.995	Probably Damaging	2.69	Benign	0.16	Tolerated	3.77	5	1	0	-0.4	14.07
c.2518A>T	S840C	Likely Pathogenic		Uncertain		1				-8.799	Likely Pathogenic	0.904	Likely Pathogenic	Ambiguous	0.376	Likely Benign										-3.96	Deleterious	0.999	Probably Damaging	0.975	Probably Damaging	1.50	Pathogenic	0.00	Affected	3.77	5	0	-1	3.3	16.06
c.3655T>C	Y1219H	Likely Pathogenic	Coiled-coil	Uncertain		1				-9.511	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.363	Likely Benign										-3.62	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.15	Pathogenic	0.00	Affected	3.77	5	0	2	-1.9	-26.03
c.3653A>T	E1218V	Likely Pathogenic	Coiled-coil	Uncertain		2				-5.647	Likely Benign	0.936	Likely Pathogenic	Ambiguous	0.418	Likely Benign										-5.68	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	2.21	Pathogenic	0.00	Affected	3.77	5	-2	-2	7.7	-29.98
c.3511G>A	A1171T	Likely Benign	Coiled-coil	Uncertain		1				-3.658	Likely Benign	0.149	Likely Benign	Likely Benign	0.201	Likely Benign										-0.48	Neutral	0.245	Benign	0.138	Benign	5.45	Benign	0.07	Tolerated	4.32	4	1	0	-2.5	30.03
c.2608C>G	L870V	Likely Benign		Uncertain		1				-4.123	Likely Benign	0.300	Likely Benign	Likely Benign	0.111	Likely Benign										-1.19	Neutral	0.997	Probably Damaging	0.992	Probably Damaging	2.64	Benign	0.12	Tolerated	3.88	3	2	1	0.4	-14.03
c.3508A>G	S1170G	Likely Benign	Coiled-coil	Uncertain		1				-4.288	Likely Benign	0.221	Likely Benign	Likely Benign	0.349	Likely Benign										-0.81	Neutral	0.241	Benign	0.229	Benign	5.31	Benign	0.54	Tolerated	4.32	4	1	0	0.4	-30.03
c.266C>T	P89L			Uncertain		2				-6.775	Likely Benign	0.982	Likely Pathogenic	Likely Pathogenic	0.119	Likely Benign										-3.29	Deleterious	0.889	Possibly Damaging	0.058	Benign	3.73	Benign	0.00	Affected	4.32	1	-3	-3	5.4	16.04
c.3386T>C	L1129P	Likely Benign		Uncertain		2				-2.991	Likely Benign	0.154	Likely Benign	Likely Benign	0.432	Likely Benign										0.27	Neutral	0.971	Probably Damaging	0.773	Possibly Damaging	5.44	Benign	0.00	Affected	4.32	4	-3	-3	-5.4	-16.04
c.2684G>A	S895N	Likely Benign		Uncertain		1				-6.399	Likely Benign	0.604	Likely Pathogenic	Likely Benign	0.118	Likely Benign										-0.85	Neutral	0.991	Probably Damaging	0.988	Probably Damaging	2.64	Benign	0.30	Tolerated	4.32	4	1	1	-2.7	27.03
c.2690C>T	S897L	Likely Benign		Uncertain		1				-4.034	Likely Benign	0.299	Likely Benign	Likely Benign	0.028	Likely Benign										-1.71	Neutral	0.901	Possibly Damaging	0.636	Possibly Damaging	2.66	Benign	0.01	Affected			-3	-2	4.6	26.08
c.3377G>A	G1126D			Uncertain		1				-8.888	Likely Pathogenic	0.432	Ambiguous	Likely Benign	0.376	Likely Benign										-0.65	Neutral	0.906	Possibly Damaging	0.473	Possibly Damaging	4.82	Benign	0.02	Affected	3.77	5	1	-1	-3.1	58.04
c.269T>A	V90E	Likely Benign		Uncertain		1				-4.079	Likely Benign	0.703	Likely Pathogenic	Likely Benign	0.108	Likely Benign										-0.38	Neutral	0.001	Benign	0.000	Benign	4.00	Benign	0.00	Affected	4.32	1	-2	-2	-7.7	29.98
c.3354C>A	S1118R	Likely Benign		Uncertain		1				-2.670	Likely Benign	0.553	Ambiguous	Likely Benign	0.166	Likely Benign										-0.74	Neutral	0.034	Benign	0.023	Benign	5.17	Benign	0.05	Affected	4.32	2	-1	0	-3.7	69.11
c.3328A>G	S1110G	Likely Benign		Likely Benign		1				-4.674	Likely Benign	0.079	Likely Benign	Likely Benign	0.035	Likely Benign										-2.26	Neutral	0.036	Benign	0.026	Benign	2.19	Pathogenic	0.08	Tolerated	4.32	2	1	0	0.4	-30.03
c.3326T>C	L1109P	Likely Benign		Conflicting		2				-5.313	Likely Benign	0.120	Likely Benign	Likely Benign	0.151	Likely Benign										-0.52	Neutral	0.002	Benign	0.003	Benign	2.65	Benign	0.07	Tolerated	4.32	2	-3	-3	-5.4	-16.04
c.2711T>C	M904T	Likely Benign		Uncertain		1				-2.721	Likely Benign	0.668	Likely Pathogenic	Likely Benign	0.042	Likely Benign										-1.15	Neutral	0.277	Benign	0.103	Benign	2.78	Benign	0.18	Tolerated	3.77	5	-1	-1	-2.6	-30.09
c.3395C>A	S1132Y	Likely Benign		Likely Benign		1				-5.894	Likely Benign	0.392	Ambiguous	Likely Benign	0.401	Likely Benign										-1.76	Neutral	0.500	Possibly Damaging	0.208	Benign	5.40	Benign	0.09	Tolerated	4.32	4	-3	-2	-0.5	76.10
c.3405G>C	K1135N	Likely Benign		Uncertain		1				-5.715	Likely Benign	0.960	Likely Pathogenic	Likely Pathogenic	0.166	Likely Benign										-0.97	Neutral	0.411	Benign	0.321	Benign	5.43	Benign	0.07	Tolerated	4.32	2	1	0	0.4	-14.07
c.3502A>G	I1168V	Likely Benign		Uncertain		1				-3.263	Likely Benign	0.524	Ambiguous	Likely Benign	0.363	Likely Benign										-0.14	Neutral	0.876	Possibly Damaging	0.643	Possibly Damaging	5.47	Benign	0.84	Tolerated	3.88	3	4	3	-0.3	-14.03
c.2627C>T	S876L			Uncertain		2				-5.856	Likely Benign	0.489	Ambiguous	Likely Benign	0.249	Likely Benign										-3.56	Deleterious	0.998	Probably Damaging	0.992	Probably Damaging	2.57	Benign	0.05	Affected	3.77	5	-2	-3	4.6	26.08
c.2632A>G	T878A	Likely Benign		Uncertain		1				-2.154	Likely Benign	0.081	Likely Benign	Likely Benign	0.088	Likely Benign										-0.67	Neutral	0.003	Benign	0.006	Benign	2.73	Benign	0.18	Tolerated	3.77	5	1	0	2.5	-30.03
c.2635_2636delinsAA	A879K	Likely Benign		Likely Benign		1				-5.877	Likely Benign	0.757	Likely Pathogenic	Likely Benign												-0.71	Neutral	0.969	Probably Damaging	0.593	Possibly Damaging	2.69	Benign	0.21	Tolerated	3.77	5	-1	-1	-5.7	57.10
c.263T>C	V88A	Likely Benign		Uncertain		1				-5.860	Likely Benign	0.993	Likely Pathogenic	Likely Pathogenic	0.050	Likely Benign										-1.22	Neutral	0.053	Benign	0.008	Benign	3.75	Benign	0.00	Affected	4.32	1	0	0	-2.4	-28.05
c.3494C>T	S1165L	Likely Benign		Conflicting		2				-2.984	Likely Benign	0.793	Likely Pathogenic	Ambiguous	0.166	Likely Benign										-2.01	Neutral	0.998	Probably Damaging	0.992	Probably Damaging	2.60	Benign	0.33	Tolerated	3.88	3	-3	-2	4.6	26.08																10.1016/j.ajhg.2020.11.011
c.3487C>G	H1163D			Uncertain		1				-2.107	Likely Benign	0.949	Likely Pathogenic	Ambiguous	0.476	Likely Benign										-2.60	Deleterious	0.991	Probably Damaging	0.991	Probably Damaging	5.44	Benign	0.31	Tolerated	3.88	3	1	-1	-0.3	-22.05
c.3484C>T	P1162S	Likely Benign		Uncertain		1				-2.118	Likely Benign	0.913	Likely Pathogenic	Ambiguous	0.215	Likely Benign										-1.93	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	2.73	Benign	0.55	Tolerated	3.88	3	1	-1	0.8	-10.04
c.265C>G	P89A	Likely Benign		Uncertain		2				-5.778	Likely Benign	0.920	Likely Pathogenic	Ambiguous	0.095	Likely Benign										-2.47	Neutral	0.225	Benign	0.020	Benign	3.77	Benign	0.00	Affected	4.32	1	1	-1	3.4	-26.04
c.3442A>T	M1148L	Likely Benign		Uncertain		1				-1.777	Likely Benign	0.093	Likely Benign	Likely Benign	0.068	Likely Benign										-1.13	Neutral	0.016	Benign	0.016	Benign	2.62	Benign	0.00	Affected	4.32	2	4	2	1.9	-18.03
c.3304G>C	A1102P	Likely Benign		Uncertain		1				-5.120	Likely Benign	0.077	Likely Benign	Likely Benign	0.118	Likely Benign										-0.97	Neutral	0.000	Benign	0.002	Benign	2.26	Pathogenic	0.13	Tolerated	3.77	5	-1	1	-3.4	26.04
c.1367A>C	Q456P (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-15.250	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.469	Likely Benign	3.68	Destabilizing	0.2	8.43	Destabilizing	6.06	Destabilizing	0.82	Ambiguous	-5.66	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	3.34	Benign	0.07	Tolerated	3.37	34	-1	0	1.9	-31.01