Data | SynGAP Server

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
c.dna	Variant	SGM Consensus	Domain	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	DOI
c.2825C>T	P942L	Likely Benign		Uncertain		1	6-33443377-C-T	4	2.48e-6	-5.063	Likely Benign	0.086	Likely Benign	Likely Benign	0.048	Likely Benign										-2.00	Neutral	0.411	Benign	0.239	Benign	2.37	Pathogenic	0.00	Affected	4.32	4	-3	-3	5.4	16.04													MD Alert	Verdict	Description
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.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.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.3056G>A	R1019H	Likely Benign		Conflicting		2	6-33443608-G-A	67	4.15e-5	-4.610	Likely Benign	0.258	Likely Benign	Likely Benign	0.122	Likely Benign										-1.95	Neutral	0.995	Probably Damaging	0.845	Possibly Damaging	2.39	Pathogenic	0.01	Affected	3.77	5	2	0	1.3	-19.05
c.3136C>G	P1046A	Likely Benign		Uncertain		1	6-33443688-C-G	1	6.20e-7	-3.246	Likely Benign	0.048	Likely Benign	Likely Benign	0.041	Likely Benign										-1.67	Neutral	0.001	Benign	0.008	Benign	2.39	Pathogenic	0.29	Tolerated	3.77	5	-1	1	3.4	-26.04
c.3056G>T	R1019L	Likely Pathogenic		Uncertain		1	6-33443608-G-T	2	1.24e-6	-5.194	Likely Benign	0.752	Likely Pathogenic	Likely Benign	0.110	Likely Benign										-3.57	Deleterious	0.800	Possibly Damaging	0.573	Possibly Damaging	2.40	Pathogenic	0.01	Affected	3.77	5	-2	-3	8.3	-43.03
c.1786C>T	R596C (3D Viewer)	Likely Pathogenic	GAP	Conflicting		2	6-33440838-C-T	6	3.72e-6	-10.805	Likely Pathogenic	0.972	Likely Pathogenic	Likely Pathogenic	0.633	Likely Pathogenic	2.94	Destabilizing	0.0	1.49	Ambiguous	2.22	Destabilizing	-0.03	Likely Benign	-7.96	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.41	Pathogenic	0.00	Affected	3.37	35	-4	-3	7.0	-53.05	230.7	97.9	-0.1	0.0	-0.3	0.4		X		X				Potentially Pathogenic	The guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).In the variant simulations, the thiol group of the Cys596 side chain is unable to form salt bridges or any of the hydrogen bonds that the Arg596 side chain can. Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation.
c.3307C>T	R1103C			Uncertain		1	6-33443859-C-T	6	3.92e-6	-2.440	Likely Benign	0.246	Likely Benign	Likely Benign	0.140	Likely Benign										-3.01	Deleterious	0.996	Probably Damaging	0.787	Possibly Damaging	2.41	Pathogenic	0.01	Affected	3.77	5	-3	-4	7.0	-53.05
c.2420A>G	Y807C		SH3-binding motif	Uncertain		1	6-33442972-A-G	1	6.20e-7	-7.228	In-Between	0.204	Likely Benign	Likely Benign	0.243	Likely Benign										-3.89	Deleterious	0.997	Probably Damaging	0.934	Probably Damaging	2.42	Pathogenic	0.01	Affected	3.77	5	0	-2	3.8	-60.04
c.3313C>T	R1105W			Uncertain		1	6-33443865-C-T	6	3.93e-6	-6.911	Likely Benign	0.488	Ambiguous	Likely Benign	0.133	Likely Benign										-4.34	Deleterious	0.999	Probably Damaging	0.696	Possibly Damaging	2.42	Pathogenic	0.02	Affected	3.77	5	-3	2	3.6	30.03
c.1352T>C	L451P (3D Viewer)	Likely Pathogenic	GAP	Likely Pathogenic		1				-14.549	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.750	Likely Pathogenic	6.92	Destabilizing	0.2	8.57	Destabilizing	7.75	Destabilizing	2.58	Destabilizing	-6.81	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.43	Pathogenic	0.00	Affected	3.37	34	-3	-3	-5.4	-16.04
c.1787G>A	R596H (3D Viewer)	Likely Pathogenic	GAP	Likely Benign		1	6-33440839-G-A	15	9.29e-6	-11.128	Likely Pathogenic	0.950	Likely Pathogenic	Ambiguous	0.717	Likely Pathogenic	3.00	Destabilizing	0.9	0.43	Likely Benign	1.72	Ambiguous	1.35	Destabilizing	-4.97	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.43	Pathogenic	0.00	Affected	3.37	35	2	0	1.3	-19.05	223.5	80.5	-0.1	0.0	-0.1	0.3		X		X				Potentially Pathogenic	The guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).In the variant simulations, the imidazole ring of His596 can form hydrogen bonds with the same residues as arginine; however, these interactions are not as coordinated or strong in comparison. Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation.
c.1393C>G	L465V (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-9.893	Likely Pathogenic	0.838	Likely Pathogenic	Ambiguous	0.276	Likely Benign	2.46	Destabilizing	0.1	2.66	Destabilizing	2.56	Destabilizing	1.21	Destabilizing	-2.98	Deleterious	0.996	Probably Damaging	0.992	Probably Damaging	2.44	Pathogenic	0.10	Tolerated	3.37	34	2	1	0.4	-14.03	204.3	30.9	0.0	0.0	-0.4	0.6						X		Potentially Benign	The iso-butyl side chain of Leu465, located in the middle of an α helix (res. Ala461–Phe476), packs with hydrophobic residues (e.g., Phe464, Met468, Tyr497, Ile494) in an inter-helix space formed with two other α helices (res. Ala461–Phe476 and res. Thr488-Gly502). In the variant simulations, the iso-propyl side chain of Val465 is equally sized and similarly hydrophobic as the original side chain of Leu465. Hence, the mutation does not exert any negative effects on the protein structure based on the variant simulations.
c.3308G>T	R1103L	Likely Benign		Uncertain		1	6-33443860-G-T			-2.330	Likely Benign	0.205	Likely Benign	Likely Benign	0.173	Likely Benign										-2.35	Neutral	0.002	Benign	0.005	Benign	2.44	Pathogenic	0.02	Affected	3.77	5	-3	-2	8.3	-43.03
c.3323G>T	S1108I			Uncertain		1	6-33443875-G-T			-3.666	Likely Benign	0.292	Likely Benign	Likely Benign	0.145	Likely Benign										-3.73	Deleterious	0.971	Probably Damaging	0.604	Possibly Damaging	2.44	Pathogenic	0.10	Tolerated	3.77	5	-2	-1	5.3	26.08
c.1787G>T	R596L (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-13.197	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	0.756	Likely Pathogenic	1.51	Ambiguous	0.3	-0.58	Ambiguous	0.47	Likely Benign	-0.02	Likely Benign	-6.97	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.45	Pathogenic	0.00	Affected	3.37	35	-3	-2	8.3	-43.03	234.2	63.4	-0.1	0.0	-0.5	0.6		X		X				Potentially Pathogenic	The guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).However, in the variant simulations, the branched hydrocarbon side chain of Leu596 cannot form any of the hydrogen bonds or salt bridges maintained by the considerably bulkier and positively charged Arg596 side chain. Instead, Leu596 packs hydrophobically with the phenyl ring of Phe484 in the linker loop or residues from the opposing helix (e.g., Ile494, Thr491).Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation.	10.1016/j.ajhg.2020.11.011
c.2591C>T	A864V	Likely Benign		Uncertain		2	6-33443143-C-T	6	3.72e-6	-4.749	Likely Benign	0.126	Likely Benign	Likely Benign	0.038	Likely Benign										-1.35	Neutral	0.767	Possibly Damaging	0.119	Benign	2.45	Pathogenic	0.30	Tolerated	3.82	4	0	0	2.4	28.05
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.3640C>T	R1214W	Likely Pathogenic	Coiled-coil	Uncertain		1	6-33446632-C-T	2	1.24e-6	-8.799	Likely Pathogenic	0.710	Likely Pathogenic	Likely Benign	0.143	Likely Benign										-4.95	Deleterious	1.000	Probably Damaging	0.983	Probably Damaging	2.45	Pathogenic	0.00	Affected	3.77	5	2	-3	3.6	30.03
c.2359C>A	P787T	Likely Pathogenic	SH3-binding motif	Likely Benign		1	6-33442911-C-A	17	1.05e-5	-4.813	Likely Benign	0.603	Likely Pathogenic	Likely Benign	0.258	Likely Benign										-4.40	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.46	Pathogenic	0.01	Affected	3.64	6	0	-1	0.9	3.99
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.3820C>T	R1274C			Uncertain		1	6-33447868-C-T			-6.467	Likely Benign	0.439	Ambiguous	Likely Benign	0.170	Likely Benign										-5.22	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	2.46	Pathogenic	0.00	Affected	3.77	5	-4	-3	7.0	-53.05
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.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.2206C>T	R736C			Conflicting		3	6-33441671-C-T	8	4.96e-6	-7.113	In-Between	0.120	Likely Benign	Likely Benign	0.190	Likely Benign										-2.06	Neutral	0.999	Probably Damaging	0.825	Possibly Damaging	2.48	Pathogenic	0.00	Affected	4.07	3	-4	-3	7.0	-53.05
c.2359C>T	P787S		SH3-binding motif	Uncertain		1	6-33442911-C-T	3	1.86e-6	-4.203	Likely Benign	0.564	Ambiguous	Likely Benign	0.221	Likely Benign										-3.81	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.48	Pathogenic	0.02	Affected	3.64	6	-1	1	0.8	-10.04
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.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.3308G>A	R1103H	Likely Benign		Benign/Likely benign		3	6-33443860-G-A	31	2.03e-5	-3.622	Likely Benign	0.156	Likely Benign	Likely Benign	0.116	Likely Benign										-1.97	Neutral	0.996	Probably Damaging	0.733	Possibly Damaging	2.49	Pathogenic	0.01	Affected	3.77	5	2	0	1.3	-19.05
c.3821G>A	R1274H			Likely Benign		1	6-33447869-G-A	4	2.58e-6	-5.259	Likely Benign	0.256	Likely Benign	Likely Benign	0.149	Likely Benign										-3.20	Deleterious	1.000	Probably Damaging	0.995	Probably Damaging	2.49	Pathogenic	0.01	Affected	3.77	5	0	2	1.3	-19.05
c.2207G>A	R736H	Likely Benign		Uncertain		1	6-33441672-G-A	6	3.72e-6	-5.409	Likely Benign	0.067	Likely Benign	Likely Benign	0.029	Likely Benign										-0.12	Neutral	0.004	Benign	0.001	Benign	2.50	Benign	0.00	Affected	4.07	3	2	0	1.3	-19.05
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.3314G>A	R1105Q	Likely Benign		Uncertain		2	6-33443866-G-A	3	1.96e-6	-3.666	Likely Benign	0.216	Likely Benign	Likely Benign	0.104	Likely Benign										-1.21	Neutral	0.958	Probably Damaging	0.194	Benign	2.50	Benign	0.16	Tolerated	3.77	5	1	1	1.0	-28.06
c.3661C>T	R1221W	Likely Pathogenic	Coiled-coil	Conflicting		3	6-33446653-C-T	1	6.20e-7	-10.938	Likely Pathogenic	0.651	Likely Pathogenic	Likely Benign	0.174	Likely Benign										-4.57	Deleterious	1.000	Probably Damaging	0.987	Probably Damaging	2.50	Benign	0.01	Affected	3.77	5	2	-3	3.6	30.03
c.2218C>T	R740W			Uncertain		2	6-33441683-C-T	6	3.72e-6	-8.561	Likely Pathogenic	0.168	Likely Benign	Likely Benign	0.180	Likely Benign										-3.09	Deleterious	1.000	Probably Damaging	0.938	Probably Damaging	2.52	Benign	0.01	Affected	4.32	2	2	-3	3.6	30.03
c.3595G>A	E1199K		Coiled-coil	Uncertain		1	6-33446587-G-A	1	6.20e-7	-10.853	Likely Pathogenic	0.954	Likely Pathogenic	Ambiguous	0.171	Likely Benign										-2.26	Neutral	1.000	Probably Damaging	0.995	Probably Damaging	2.52	Benign	0.00	Affected	3.77	5	0	1	-0.4	-0.94
c.3175G>A	G1059R			Uncertain		1	6-33443727-G-A	68	4.23e-5	-8.452	Likely Pathogenic	0.376	Ambiguous	Likely Benign	0.333	Likely Benign										-0.55	Neutral	0.001	Benign	0.001	Benign	2.53	Benign	0.00	Affected	4.32	2	-3	-2	-4.1	99.14
c.1802C>A	A601E (3D Viewer)	Likely Pathogenic	GAP	Conflicting		2				-16.752	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	0.588	Likely Pathogenic	6.68	Destabilizing	0.8	5.76	Destabilizing	6.22	Destabilizing	1.24	Destabilizing	-4.98	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.54	Benign	0.00	Affected	3.37	35	0	-1	-5.3	58.04	240.0	-82.3	0.0	0.0	0.7	0.1		X	X				X	Potentially Pathogenic	The methyl side chain of Ala601, located on an α helix (res. Glu582-Met603), packs hydrophobically against other hydrophobic residues in the inter-helix space (e.g., Phe597, Leu598, Leu506, Phe608).In the variant simulations, the carboxylate group of Glu601 faces the inter-helix space and is forced to shift slightly away from the hydrophobic niche. Additionally, in two of the simulations, Glu601 forms a salt bridge with Arg499, causing the otherwise stable salt bridge between Arg499 and Glu496 at the outer surface of an α helix (res. Leu489-Glu519) to break due to the residue swap.These effects suggest that the protein folding process could be seriously affected. Moreover, due to its location at the GAP-Ras interface, it could also impact the complex formation with the GTPase.
c.2506A>G	S836G	Likely Benign		Uncertain		1	6-33443058-A-G	4	2.48e-6	-4.749	Likely Benign	0.112	Likely Benign	Likely Benign	0.066	Likely Benign										-1.65	Neutral	0.006	Benign	0.019	Benign	2.54	Benign	0.39	Tolerated	3.77	5	1	0	0.4	-30.03
c.2521G>A	V841M			Uncertain		1	6-33443073-G-A	3	1.86e-6	-7.000	In-Between	0.651	Likely Pathogenic	Likely Benign	0.119	Likely Benign										-0.74	Neutral	0.999	Probably Damaging	0.998	Probably Damaging	2.54	Benign	0.02	Affected	3.77	5	1	2	-2.3	32.06
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.3824G>T	R1275L			Likely Benign		1	6-33447872-G-T	1	6.45e-7	-6.052	Likely Benign	0.446	Ambiguous	Likely Benign	0.117	Likely Benign										-4.04	Deleterious	0.800	Possibly Damaging	0.277	Benign	2.55	Benign	0.01	Affected	3.77	5	-3	-2	8.3	-43.03
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.2650C>T	R884W	Likely Benign		Uncertain		1	6-33443202-C-T	5	3.10e-6	-3.785	Likely Benign	0.332	Likely Benign	Likely Benign	0.151	Likely Benign										0.26	Neutral	0.995	Probably Damaging	0.812	Possibly Damaging	2.56	Benign	0.05	Affected	4.32	4	-3	2	3.6	30.03
c.3176G>C	G1059A	Likely Benign		Uncertain		1	6-33443728-G-C	4	2.49e-6	-6.754	Likely Benign	0.081	Likely Benign	Likely Benign	0.329	Likely Benign										-0.17	Neutral	0.001	Benign	0.002	Benign	2.56	Benign	0.00	Affected	4.32	2	1	0	2.2	14.03
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.3662G>A	R1221Q	Likely Benign	Coiled-coil	Conflicting		2	6-33446654-G-A	4	2.48e-6	-5.491	Likely Benign	0.115	Likely Benign	Likely Benign	0.078	Likely Benign										-1.46	Neutral	0.836	Possibly Damaging	0.153	Benign	2.56	Benign	0.12	Tolerated	3.77	5	1	1	1.0	-28.06
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.2522T>C	V841A			Uncertain		1	6-33443074-T-C	3	1.86e-6	-8.152	Likely Pathogenic	0.901	Likely Pathogenic	Ambiguous	0.183	Likely Benign										-2.13	Neutral	0.992	Probably Damaging	0.989	Probably Damaging	2.57	Benign	0.02	Affected	3.77	5	0	0	-2.4	-28.05
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.2713C>T	R905C			Conflicting		2	6-33443265-C-T	15	9.31e-6	-5.578	Likely Benign	0.723	Likely Pathogenic	Likely Benign	0.194	Likely Benign										-3.14	Deleterious	1.000	Probably Damaging	0.980	Probably Damaging	2.57	Benign	0.01	Affected	3.77	5	-4	-3	7.0	-53.05
c.2765G>A	R922Q	Likely Benign		Benign		1	6-33443317-G-A	7	4.34e-6	-3.295	Likely Benign	0.189	Likely Benign	Likely Benign	0.085	Likely Benign										-0.27	Neutral	0.992	Probably Damaging	0.736	Possibly Damaging	2.57	Benign	0.20	Tolerated	3.77	5	1	1	1.0	-28.06
c.2724G>C	Q908H	Likely Benign		Conflicting		4	6-33443276-G-C	1	6.20e-7	-4.658	Likely Benign	0.311	Likely Benign	Likely Benign	0.112	Likely Benign										-0.74	Neutral	0.996	Probably Damaging	0.995	Probably Damaging	2.58	Benign	0.05	Affected	3.77	5	3	0	0.3	9.01
c.3338G>A	G1113D	Likely Benign		Uncertain		1	6-33443890-G-A			-4.638	Likely Benign	0.354	Ambiguous	Likely Benign	0.061	Likely Benign										-0.72	Neutral	0.029	Benign	0.017	Benign	2.58	Benign	0.34	Tolerated	4.32	2	-1	1	-3.1	58.04
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.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.2245C>T	R749W			Likely Benign		1	6-33441710-C-T	3	1.86e-6	-7.647	In-Between	0.338	Likely Benign	Likely Benign	0.173	Likely Benign										-2.62	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	2.59	Benign	0.00	Affected	4.32	2	2	-3	3.6	30.03
c.2339C>G	S780C	Likely Benign		Uncertain		4	6-33442891-C-G	16	9.94e-6	-7.603	In-Between	0.278	Likely Benign	Likely Benign	0.078	Likely Benign										-1.41	Neutral	0.065	Benign	0.043	Benign	2.59	Benign	0.10	Tolerated	3.64	6	-1	0	3.3	16.06
c.2443C>T	R815C	Likely Pathogenic	SH3-binding motif	Uncertain		1	6-33442995-C-T	5	3.10e-6	-9.373	Likely Pathogenic	0.828	Likely Pathogenic	Ambiguous	0.174	Likely Benign										-3.89	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	2.59	Benign	0.00	Affected	4.32	4	-4	-3	7.0	-53.05
c.2714G>A	R905H	Likely Benign		Uncertain		1	6-33443266-G-A	8	4.96e-6	-4.182	Likely Benign	0.457	Ambiguous	Likely Benign	0.192	Likely Benign										-1.11	Neutral	1.000	Probably Damaging	0.991	Probably Damaging	2.59	Benign	0.09	Tolerated	3.77	5	2	0	1.3	-19.05
c.3824G>A	R1275Q	Likely Benign		Uncertain		1	6-33447872-G-A	2	1.29e-6	-4.928	Likely Benign	0.121	Likely Benign	Likely Benign	0.103	Likely Benign										-1.72	Neutral	0.898	Possibly Damaging	0.147	Benign	2.59	Benign	0.03	Affected	3.77	5	1	1	1.0	-28.06
c.1513T>G	Y505D (3D Viewer)	Likely Pathogenic	GAP	Likely Pathogenic		1				-14.078	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.718	Likely Pathogenic	4.98	Destabilizing	0.1	4.72	Destabilizing	4.85	Destabilizing	2.49	Destabilizing	-9.95	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.60	Benign	0.00	Affected	3.37	35	-3	-4	-2.2	-48.09
c.2219G>A	R740Q	Likely Benign		Uncertain		1	6-33441684-G-A	4	2.48e-6	-5.195	Likely Benign	0.078	Likely Benign	Likely Benign	0.102	Likely Benign										-0.67	Neutral	0.999	Probably Damaging	0.881	Possibly Damaging	2.60	Benign	0.08	Tolerated	4.32	2	1	1	1.0	-28.06
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.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.2444G>A	R815H		SH3-binding motif	Likely Benign		2	6-33442996-G-A	24	1.49e-5	-7.474	In-Between	0.553	Ambiguous	Likely Benign	0.157	Likely Benign										-1.81	Neutral	1.000	Probably Damaging	0.998	Probably Damaging	2.61	Benign	0.02	Affected	4.32	4	2	0	1.3	-19.05																10.1016/j.ajhg.2020.11.011
c.2704G>A	A902T	Likely Benign		Likely Benign		1	6-33443256-G-A	36	2.23e-5	-4.966	Likely Benign	0.116	Likely Benign	Likely Benign	0.075	Likely Benign										-1.11	Neutral	0.951	Possibly Damaging	0.617	Possibly Damaging	2.61	Benign	0.01	Affected	3.77	5	1	0	-2.5	30.03
c.2753C>T	A918V	Likely Benign		Uncertain		3	6-33443305-C-T	2	1.24e-6	-3.684	Likely Benign	0.112	Likely Benign	Likely Benign	0.119	Likely Benign										-1.61	Neutral	0.980	Probably Damaging	0.782	Possibly Damaging	2.61	Benign	0.03	Affected	4.32	4	0	0	2.4	28.05
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.2651G>A	R884Q	Likely Benign		Uncertain		2	6-33443203-G-A	5	3.10e-6	-3.785	Likely Benign	0.128	Likely Benign	Likely Benign	0.055	Likely Benign										-0.42	Neutral	0.012	Benign	0.004	Benign	2.62	Benign	0.36	Tolerated	4.32	4	1	1	1.0	-28.06
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.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.3179G>T	G1060V	Likely Benign		Benign		1	6-33443731-G-T	1	6.22e-7	-6.966	Likely Benign	0.103	Likely Benign	Likely Benign	0.369	Likely Benign										-0.73	Neutral	0.986	Probably Damaging	0.728	Possibly Damaging	2.63	Benign	0.33	Tolerated	4.32	2	-1	-3	4.6	42.08
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.1513T>C	Y505H (3D Viewer)	Likely Pathogenic	GAP	Likely Pathogenic		1				-11.383	Likely Pathogenic	0.982	Likely Pathogenic	Likely Pathogenic	0.646	Likely Pathogenic	2.91	Destabilizing	0.1	2.88	Destabilizing	2.90	Destabilizing	1.60	Destabilizing	-4.97	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.64	Benign	0.00	Affected	3.37	35	2	0	-1.9	-26.03
c.2246G>A	R749Q	Likely Benign		Likely Benign		1	6-33441711-G-A	4	2.48e-6	-3.069	Likely Benign	0.212	Likely Benign	Likely Benign	0.152	Likely Benign										-1.00	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	2.64	Benign	0.03	Affected	4.32	2	1	1	1.0	-28.06
c.2493G>C	E831D	Likely Benign		Uncertain		1	6-33443045-G-C	1	6.19e-7	-3.055	Likely Benign	0.063	Likely Benign	Likely Benign	0.073	Likely Benign										1.23	Neutral	0.002	Benign	0.002	Benign	2.64	Benign	0.77	Tolerated	3.77	5	3	2	0.0	-14.03
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.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.2702C>T	A901V	Likely Benign		Uncertain		2	6-33443254-C-T	2	1.24e-6	-5.043	Likely Benign	0.219	Likely Benign	Likely Benign	0.029	Likely Benign										-1.83	Neutral	0.106	Benign	0.009	Benign	2.64	Benign	0.17	Tolerated	3.77	5	0	0	2.4	28.05
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.2752G>A	A918T	Likely Benign		Uncertain		1	6-33443304-G-A	1	6.20e-7	-4.139	Likely Benign	0.083	Likely Benign	Likely Benign	0.065	Likely Benign										-1.09	Neutral	0.980	Probably Damaging	0.721	Possibly Damaging	2.64	Benign	0.03	Affected	4.32	4	0	1	-2.5	30.03
c.3038C>G	S1013C	Likely Benign		Uncertain		1	6-33443590-C-G	4	2.48e-6	-6.745	Likely Benign	0.110	Likely Benign	Likely Benign	0.058	Likely Benign										-2.06	Neutral	0.898	Possibly Damaging	0.579	Possibly Damaging	2.64	Benign	0.05	Affected	3.77	5	0	-1	3.3	16.06
c.3048C>A	D1016E	Likely Benign		Likely Benign		1	6-33443600-C-A	2	1.24e-6	-3.422	Likely Benign	0.216	Likely Benign	Likely Benign	0.017	Likely Benign										-0.37	Neutral	0.008	Benign	0.028	Benign	2.64	Benign	0.65	Tolerated	3.77	5	2	3	0.0	14.03
c.3134C>G	A1045G	Likely Benign		Benign/Likely benign		7	6-33443686-C-G	1407	8.72e-4	-3.246	Likely Benign	0.075	Likely Benign	Likely Benign	0.024	Likely Benign										-1.21	Neutral	0.224	Benign	0.066	Benign	2.64	Benign	0.33	Tolerated	3.77	5	1	0	-2.2	-14.03																10.1016/j.ajhg.2020.11.011
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.3424T>C	S1142P	Likely Benign		Likely Benign		1	6-33444459-T-C	1	6.20e-7	-2.713	Likely Benign	0.222	Likely Benign	Likely Benign	0.107	Likely Benign										-2.19	Neutral	0.918	Possibly Damaging	0.761	Possibly Damaging	2.64	Benign	0.00	Affected	4.32	4	-1	1	-0.8	10.04
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.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.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.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.3023A>G	D1008G			Uncertain		1	6-33443575-A-G	1	6.20e-7	-3.213	Likely Benign	0.742	Likely Pathogenic	Likely Benign	0.203	Likely Benign										-2.84	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	2.65	Benign	0.01	Affected	3.77	5	-1	1	3.1	-58.04
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.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.3557C>T	S1186L		Coiled-coil	Uncertain		1	6-33444592-C-T			-4.829	Likely Benign	0.923	Likely Pathogenic	Ambiguous	0.177	Likely Benign										-2.58	Deleterious	0.998	Probably Damaging	0.992	Probably Damaging	2.65	Benign	0.04	Affected	3.82	4	-3	-2	4.6	26.08
c.2224C>T	R742W	Likely Benign		Uncertain		1	6-33441689-C-T	6	3.72e-6	-7.725	In-Between	0.133	Likely Benign	Likely Benign	0.079	Likely Benign										-1.71	Neutral	0.992	Probably Damaging	0.684	Possibly Damaging	2.66	Benign	0.01	Affected	4.32	2	-3	2	3.6	30.03
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.2239G>C	V747L	Likely Benign		Uncertain		1	6-33441704-G-C	2	1.24e-6	-2.790	Likely Benign	0.096	Likely Benign	Likely Benign	0.047	Likely Benign										-0.52	Neutral	0.065	Benign	0.033	Benign	2.67	Benign	0.00	Affected	4.32	2	2	1	-0.4	14.03
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.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.2619C>G	S873R			Uncertain		1	6-33443171-C-G	1	6.20e-7	-5.856	Likely Benign	0.976	Likely Pathogenic	Likely Pathogenic	0.192	Likely Benign										-2.74	Deleterious	0.997	Probably Damaging	0.995	Probably Damaging	2.67	Benign	0.06	Tolerated	3.77	5	0	-1	-3.7	69.11
c.3092T>C	M1031T	Likely Benign		Uncertain		1	6-33443644-T-C	2	1.24e-6	-1.863	Likely Benign	0.540	Ambiguous	Likely Benign	0.085	Likely Benign										-0.24	Neutral	0.002	Benign	0.005	Benign	2.67	Benign	1.00	Tolerated	3.77	5	-1	-1	-2.6	-30.09
c.2435C>A	P812H		SH3-binding motif	Uncertain		2	6-33442987-C-A	3	1.86e-6	-7.470	In-Between	0.698	Likely Pathogenic	Likely Benign	0.272	Likely Benign										-2.81	Deleterious	1.000	Probably Damaging	0.995	Probably Damaging	2.68	Benign	0.00	Affected	4.32	4	0	-2	-1.6	40.02
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.2681G>A	G894E	Likely Benign		Uncertain		1	6-33443233-G-A	6	3.72e-6	-5.377	Likely Benign	0.859	Likely Pathogenic	Ambiguous	0.180	Likely Benign										-2.07	Neutral	1.000	Probably Damaging	1.000	Probably Damaging	2.68	Benign	0.01	Affected	4.32	4	0	-2	-3.1	72.06
c.2750C>G	P917R	Likely Benign		Uncertain		1	6-33443302-C-G	5	3.10e-6	-4.475	Likely Benign	0.363	Ambiguous	Likely Benign	0.142	Likely Benign										-1.70	Neutral	0.642	Possibly Damaging	0.316	Benign	2.68	Benign	0.00	Affected	3.77	5	-2	0	-2.9	59.07
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.3572G>A	R1191Q	Likely Benign	Coiled-coil	Uncertain		2	6-33444607-G-A	9	5.58e-6	-1.069	Likely Benign	0.943	Likely Pathogenic	Ambiguous	0.343	Likely Benign										-1.41	Neutral	0.998	Probably Damaging	0.992	Probably Damaging	2.68	Benign	0.08	Tolerated	3.82	4	1	1	1.0	-28.06
c.2195G>A	R732K	Likely Benign		Conflicting		2	6-33441660-G-A	4	2.48e-6	-5.278	Likely Benign	0.240	Likely Benign	Likely Benign	0.045	Likely Benign										-0.82	Neutral	0.973	Probably Damaging	0.943	Probably Damaging	2.69	Benign	0.21	Tolerated	3.59	7	3	2	0.6	-28.01
c.2214T>G	S738R	Likely Benign		Benign		1	6-33441679-T-G	1	6.20e-7	-4.241	Likely Benign	0.570	Likely Pathogenic	Likely Benign	0.068	Likely Benign										-1.55	Neutral	0.473	Possibly Damaging	0.193	Benign	2.69	Benign	0.01	Affected	4.32	2	0	-1	-3.7	69.11
c.2282G>C	R761P	Likely Benign		Uncertain		3	6-33441747-G-C	1	6.20e-7	-5.091	Likely Benign	0.640	Likely Pathogenic	Likely Benign	0.201	Likely Benign										-1.89	Neutral	0.999	Probably Damaging	0.968	Probably Damaging	2.69	Benign	0.38	Tolerated	3.99	5	0	-2	2.9	-59.07
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.2596G>A	V866I	Likely Benign		Conflicting		3	6-33443148-G-A	5	3.10e-6	-4.652	Likely Benign	0.118	Likely Benign	Likely Benign	0.059	Likely Benign										-0.39	Neutral	0.957	Probably Damaging	0.541	Possibly Damaging	2.69	Benign	0.27	Tolerated	3.82	4	4	3	0.3	14.03
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.2962C>T	L988F	Likely Benign		Uncertain		1	6-33443514-C-T	1	6.20e-7	-4.368	Likely Benign	0.356	Ambiguous	Likely Benign	0.135	Likely Benign										-1.70	Neutral	0.977	Probably Damaging	0.900	Possibly Damaging	2.69	Benign	0.00	Affected	4.32	2	2	0	-1.0	34.02
c.3178G>A	G1060S	Likely Benign		Uncertain		1	6-33443730-G-A			-4.759	Likely Benign	0.082	Likely Benign	Likely Benign	0.376	Likely Benign										-0.08	Neutral	0.271	Benign	0.054	Benign	2.69	Benign	0.49	Tolerated	4.32	2	1	0	-0.4	30.03
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.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.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.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.3253C>T	R1085W			Uncertain		1	6-33443805-C-T	2	1.26e-6	-6.339	Likely Benign	0.821	Likely Pathogenic	Ambiguous	0.202	Likely Benign										-3.15	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	2.70	Benign	0.00	Affected	3.77	5	-3	2	3.6	30.03
c.3846G>C	E1282D	Likely Benign		Uncertain		1	6-33447894-G-C	1	6.44e-7	-3.879	Likely Benign	0.074	Likely Benign	Likely Benign	0.104	Likely Benign										-1.26	Neutral	0.112	Benign	0.036	Benign	2.70	Benign	0.39	Tolerated	3.77	5	3	2	0.0	-14.03
c.2596G>T	V866L	Likely Benign		Uncertain		1	6-33443148-G-T	1	6.20e-7	-3.352	Likely Benign	0.148	Likely Benign	Likely Benign	0.046	Likely Benign										-0.97	Neutral	0.217	Benign	0.229	Benign	2.71	Benign	0.21	Tolerated	3.82	4	2	1	-0.4	14.03
c.3835G>A	A1279T	Likely Benign		Uncertain		2	6-33447883-G-A	2	1.29e-6	-4.871	Likely Benign	0.071	Likely Benign	Likely Benign	0.178	Likely Benign										-0.30	Neutral	0.001	Benign	0.000	Benign	2.71	Benign	0.09	Tolerated	3.77	5	1	0	-2.5	30.03
c.1784T>C	L595P (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-11.856	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.747	Likely Pathogenic	2.09	Destabilizing	0.8	5.88	Destabilizing	3.99	Destabilizing	1.78	Destabilizing	-6.97	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.72	Benign	0.00	Affected	3.37	35	-3	-3	-5.4	-16.04
c.2405G>A	G802D	Likely Benign	SH3-binding motif	Uncertain		1	6-33442957-G-A	1	6.20e-7	-5.083	Likely Benign	0.476	Ambiguous	Likely Benign	0.153	Likely Benign										-0.38	Neutral	0.126	Benign	0.138	Benign	2.72	Benign	0.09	Tolerated	3.77	5	1	-1	-3.1	58.04
c.2623G>A	A875T	Likely Benign		Uncertain		1	6-33443175-G-A	1	6.20e-7	-3.793	Likely Benign	0.179	Likely Benign	Likely Benign	0.110	Likely Benign										-1.56	Neutral	0.972	Probably Damaging	0.864	Possibly Damaging	2.72	Benign	0.26	Tolerated	3.77	5	0	1	-2.5	30.03
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.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.3197C>T	P1066L	Likely Benign		Likely Benign		1	6-33443749-C-T	14	8.71e-6	-5.478	Likely Benign	0.092	Likely Benign	Likely Benign	0.173	Likely Benign										-3.68	Deleterious	0.996	Probably Damaging	0.903	Possibly Damaging	2.72	Benign	0.00	Affected	4.32	2	-3	-3	5.4	16.04
c.3932T>C	L1311P	Likely Benign		Likely Benign		1	6-33451806-T-C	1	6.21e-7	-1.831	Likely Benign	0.079	Likely Benign	Likely Benign	0.123	Likely Benign										-0.52	Neutral	0.579	Possibly Damaging	0.335	Benign	2.72	Benign	0.18	Tolerated	3.77	5	-3	-3	-5.4	-16.04
c.2225G>A	R742Q	Likely Benign		Uncertain		2	6-33441690-G-A	24	1.49e-5	-4.090	Likely Benign	0.068	Likely Benign	Likely Benign	0.054	Likely Benign										-0.19	Neutral	0.032	Benign	0.007	Benign	2.73	Benign	0.07	Tolerated	4.32	2	1	1	1.0	-28.06
c.2243T>G	L748R	Likely Benign		Conflicting		2	6-33441708-T-G	3	1.86e-6	-3.331	Likely Benign	0.245	Likely Benign	Likely Benign	0.055	Likely Benign										-0.67	Neutral	0.912	Possibly Damaging	0.448	Possibly Damaging	2.73	Benign	0.02	Affected	4.32	2	-3	-2	-8.3	43.03
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.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.2743G>A	G915S	Likely Benign		Benign		1	6-33443295-G-A	9	5.58e-6	-3.557	Likely Benign	0.083	Likely Benign	Likely Benign	0.050	Likely Benign										-0.88	Neutral	0.801	Possibly Damaging	0.201	Benign	2.73	Benign	0.31	Tolerated	3.77	5	1	0	-0.4	30.03
c.2818G>C	G940R	Likely Benign		Benign		1	6-33443370-G-C	5	3.10e-6	-6.169	Likely Benign	0.480	Ambiguous	Likely Benign	0.060	Likely Benign										0.02	Neutral	0.922	Possibly Damaging	0.543	Possibly Damaging	2.73	Benign	0.15	Tolerated	3.77	5	-3	-2	-4.1	99.14
c.3254G>A	R1085Q	Likely Benign		Uncertain		1	6-33443806-G-A	5	3.16e-6	-3.843	Likely Benign	0.589	Likely Pathogenic	Likely Benign	0.224	Likely Benign										-1.43	Neutral	0.998	Probably Damaging	0.988	Probably Damaging	2.73	Benign	0.02	Affected	3.77	5	1	1	1.0	-28.06
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.1802C>T	A601V (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-10.447	Likely Pathogenic	0.853	Likely Pathogenic	Ambiguous	0.535	Likely Pathogenic	1.64	Ambiguous	0.1	0.35	Likely Benign	1.00	Ambiguous	0.81	Ambiguous	-3.98	Deleterious	1.000	Probably Damaging	0.989	Probably Damaging	2.74	Benign	0.03	Affected	3.37	35	0	0	2.4	28.05	228.5	-45.5	0.0	0.0	0.4	0.5						X		Potentially Benign	The methyl side chain of Ala601, located on an α helix (res. Glu582-Met603), packs hydrophobically against other hydrophobic residues in the inter-helix space (e.g., Phe597, Leu598, Leu506, Phe608).In the variant simulations, Val601, which has similar size and physicochemical properties to alanine, resides in the inter-helix hydrophobic space in a similar manner to Ala601 in the WT, causing no apparent negative effect on the protein structure. However, the effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations.
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.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.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.3638A>C	N1213T	Likely Benign	Coiled-coil	Conflicting		2	6-33446630-A-C	46	2.85e-5	-5.428	Likely Benign	0.266	Likely Benign	Likely Benign	0.097	Likely Benign										-1.08	Neutral	0.959	Probably Damaging	0.721	Possibly Damaging	2.74	Benign	1.00	Tolerated	3.77	5	0	0	2.8	-13.00
c.1784T>A	L595Q (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-15.101	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	0.733	Likely Pathogenic	0.79	Ambiguous	0.1	1.40	Ambiguous	1.10	Ambiguous	1.99	Destabilizing	-5.97	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.75	Benign	0.00	Affected	3.37	35	-2	-2	-7.3	14.97
c.2282G>A	R761Q	Likely Benign		Uncertain		1	6-33441747-G-A	11	6.81e-6	-4.187	Likely Benign	0.202	Likely Benign	Likely Benign	0.191	Likely Benign										-0.63	Neutral	0.996	Probably Damaging	0.878	Possibly Damaging	2.75	Benign	0.40	Tolerated	3.99	5	1	1	1.0	-28.06
c.2695A>G	I899V	Likely Benign		Benign		1	6-33443247-A-G	6	3.72e-6	-2.569	Likely Benign	0.074	Likely Benign	Likely Benign	0.040	Likely Benign										0.09	Neutral	0.220	Benign	0.078	Benign	2.75	Benign	0.92	Tolerated	4.32	4	4	3	-0.3	-14.03
c.3022G>A	D1008N	Likely Benign		Likely Benign		1	6-33443574-G-A	3	1.86e-6	-4.045	Likely Benign	0.714	Likely Pathogenic	Likely Benign	0.128	Likely Benign										-2.15	Neutral	0.999	Probably Damaging	0.997	Probably Damaging	2.75	Benign	0.01	Affected	3.77	5	2	1	0.0	-0.98
c.3116T>C	I1039T	Likely Benign		Uncertain		1	6-33443668-T-C	12	7.43e-6	-2.465	Likely Benign	0.645	Likely Pathogenic	Likely Benign	0.193	Likely Benign										0.45	Neutral	0.004	Benign	0.008	Benign	2.75	Benign	0.10	Tolerated	3.77	5	-1	0	-5.2	-12.05
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.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.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.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.3293G>A	S1098N	Likely Benign		Conflicting		2	6-33443845-G-A	6	3.89e-6	-5.120	Likely Benign	0.156	Likely Benign	Likely Benign	0.063	Likely Benign										-0.58	Neutral	0.369	Benign	0.120	Benign	2.76	Benign	0.36	Tolerated	3.77	5	1	1	-2.7	27.03
c.3344T>C	I1115T	Likely Benign		Benign		9	6-33443896-T-C	20536	1.36e-2	-2.670	Likely Benign	0.068	Likely Benign	Likely Benign	0.100	Likely Benign										-0.04	Neutral	0.000	Benign	0.001	Benign	2.76	Benign	0.23	Tolerated	4.32	2	0	-1	-5.2	-12.05
c.3848C>T	P1283L	Likely Benign		Benign		1	6-33447896-C-T	32	2.06e-5	-3.740	Likely Benign	0.093	Likely Benign	Likely Benign	0.047	Likely Benign										-1.04	Neutral	0.005	Benign	0.003	Benign	2.76	Benign	0.06	Tolerated	3.77	5	-3	-3	5.4	16.04
c.3860C>T	P1287L	Likely Benign		Conflicting		2	6-33447908-C-T			-2.800	Likely Benign	0.117	Likely Benign	Likely Benign	0.061	Likely Benign										-1.66	Neutral	0.021	Benign	0.017	Benign	2.76	Benign	0.02	Affected	3.77	5	-3	-3	5.4	16.04
c.1778T>C	L593P (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-13.961	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.777	Likely Pathogenic	5.75	Destabilizing	0.9	10.77	Destabilizing	8.26	Destabilizing	2.43	Destabilizing	-6.77	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.77	Benign	0.00	Affected			-3	-3	-5.4	-16.04
c.2200C>T	P734S	Likely Benign		Uncertain		2	6-33441665-C-T	2	1.24e-6	-4.291	Likely Benign	0.077	Likely Benign	Likely Benign	0.030	Likely Benign										-2.44	Neutral	0.344	Benign	0.048	Benign	2.77	Benign	0.11	Tolerated	3.64	6	1	-1	0.8	-10.04																10.1016/j.ajhg.2020.11.011
c.1778T>A	L593H (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-16.504	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.812	Likely Pathogenic	2.52	Destabilizing	0.2	2.32	Destabilizing	2.42	Destabilizing	2.75	Destabilizing	-6.77	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.77	Benign	0.00	Affected	3.37	35	-2	-3	-7.0	23.98	222.0	20.7	0.0	0.0	0.2	0.0		X					X	Potentially Pathogenic	The iso-propyl side chain of Leu593, located in an α helix (res. Glu582-Met603), packs favourably with multiple hydrophobic residues in the inter-helix space (e.g., Leu598, Ile589, Phe594, Phe561).In the variant simulations, His593 retains a similar packing arrangement via its aromatic imidazole ring. However, the polar nitrogen atoms introduce hydrogen bond donors and acceptors into the previously hydrophobic space. The epsilon protonated nitrogen of His593 forms a stable hydrogen bond with the phenol group of the Tyr505 side chain in an α helix (res. Gln503-Tyr518).While the residue swap could affect the tertiary assembly and the underlying protein folding process, it is difficult to determine if the mutation would be tolerated based solely on the variant simulations.
c.2818G>A	G940S	Likely Benign		Uncertain		1	6-33443370-G-A	1	6.20e-7	-5.451	Likely Benign	0.084	Likely Benign	Likely Benign	0.135	Likely Benign										0.45	Neutral	0.409	Benign	0.253	Benign	2.77	Benign	0.44	Tolerated	3.77	5	1	0	-0.4	30.03
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.3310C>T	P1104S	Likely Benign		Benign		1	6-33443862-C-T	1	6.54e-7	-2.330	Likely Benign	0.073	Likely Benign	Likely Benign	0.088	Likely Benign										-0.30	Neutral	0.770	Possibly Damaging	0.404	Benign	2.77	Benign	0.10	Tolerated	3.77	5	-1	1	0.8	-10.04
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.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.2729G>C	G910A	Likely Benign		Uncertain		1	6-33443281-G-C	1	6.20e-7	-3.587	Likely Benign	0.361	Ambiguous	Likely Benign	0.209	Likely Benign										-1.43	Neutral	0.999	Probably Damaging	0.999	Probably Damaging	2.78	Benign	0.10	Tolerated	3.77	5	1	0	2.2	14.03
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.3859C>A	P1287T	Likely Benign		Uncertain		1	6-33447907-C-A			-3.940	Likely Benign	0.077	Likely Benign	Likely Benign	0.044	Likely Benign										-0.22	Neutral	0.126	Benign	0.041	Benign	2.78	Benign	0.04	Affected	3.77	5	-1	0	0.9	3.99
c.2699C>T	T900M	Likely Benign		Conflicting		2	6-33443251-C-T	14	8.68e-6	-3.852	Likely Benign	0.176	Likely Benign	Likely Benign	0.015	Likely Benign										-0.81	Neutral	0.060	Benign	0.016	Benign	2.79	Benign	0.08	Tolerated	4.32	4	-1	-1	2.6	30.09
c.3902C>A	P1301H	Likely Benign		Conflicting		2	6-33451776-C-A	5	3.10e-6	-5.756	Likely Benign	0.104	Likely Benign	Likely Benign	0.232	Likely Benign										-1.13	Neutral	0.642	Possibly Damaging	0.378	Benign	2.79	Benign	0.04	Affected	3.77	5	0	-2	-1.6	40.02
c.2710A>G	M904V	Likely Benign		Likely Benign		2	6-33443262-A-G	77	4.78e-5	-2.907	Likely Benign	0.112	Likely Benign	Likely Benign	0.058	Likely Benign										-0.33	Neutral	0.039	Benign	0.023	Benign	2.80	Benign	0.10	Tolerated	3.77	5	2	1	2.3	-32.06
c.3902C>G	P1301R	Likely Benign		Uncertain		1	6-33451776-C-G	15	9.30e-6	-4.753	Likely Benign	0.162	Likely Benign	Likely Benign	0.076	Likely Benign										-1.13	Neutral	0.077	Benign	0.059	Benign	2.81	Benign	0.10	Tolerated	3.77	5	0	-2	-2.9	59.07
c.1862G>A	R621Q (3D Viewer)	Likely Pathogenic	GAP	Likely Benign		1	6-33440914-G-A	19	1.18e-5	-14.682	Likely Pathogenic	0.910	Likely Pathogenic	Ambiguous	0.621	Likely Pathogenic	0.81	Ambiguous	0.1	1.13	Ambiguous	0.97	Ambiguous	1.35	Destabilizing	-3.98	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	2.82	Benign	0.01	Affected	3.37	35	1	1	1.0	-28.06	243.7	54.3	0.0	0.0	-0.4	0.2		X		X				Potentially Pathogenic	The guanidinium group of Arg621, located in an α helix (res. Glu617-Asn635), forms a salt bridge with Glu525 in a nearby loop and stacks with Leu635. In the variant simulations, the carboxamide side chain of Gln621, which can act as both a hydrogen bond acceptor and donor, also stacks with Leu635 but can only sporadically hydrogen bond with Glu525.Accordingly, the residue swap could affect the tertiary structure integrity by disrupting the salt bridge formation. Additionally, due to its location at the GAP-Ras interface, the residue swap could impact the complex formation with the GTPase, but this cannot be investigated using solvent-only simulations.
c.3638A>G	N1213S	Likely Benign	Coiled-coil	Benign		1	6-33446630-A-G	13	8.05e-6	-4.086	Likely Benign	0.081	Likely Benign	Likely Benign	0.094	Likely Benign										-0.56	Neutral	0.906	Possibly Damaging	0.551	Possibly Damaging	2.82	Benign	0.68	Tolerated	3.77	5	1	1	2.7	-27.03																10.1016/j.ajhg.2020.11.011
c.3920C>A	P1307Q	Likely Benign		Uncertain		1	6-33451794-C-A			-4.227	Likely Benign	0.114	Likely Benign	Likely Benign	0.192	Likely Benign										-0.88	Neutral	0.988	Probably Damaging	0.765	Possibly Damaging	2.82	Benign	0.03	Affected	3.77	5	0	-1	-1.9	31.01
c.3920C>T	P1307L	Likely Benign		Benign		1	6-33451794-C-T	11	6.82e-6	-4.044	Likely Benign	0.144	Likely Benign	Likely Benign	0.292	Likely Benign										-1.49	Neutral	0.779	Possibly Damaging	0.220	Benign	2.82	Benign	0.04	Affected	3.77	5	-3	-3	5.4	16.04
c.2277G>A	M759I	Likely Benign		Uncertain		1	6-33441742-G-A	1	6.20e-7	-4.058	Likely Benign	0.393	Ambiguous	Likely Benign	0.075	Likely Benign										-0.88	Neutral	0.454	Possibly Damaging	0.192	Benign	2.83	Benign	0.34	Tolerated	3.99	5	1	2	2.6	-18.03
c.2275A>C	M759L	Likely Benign		Uncertain		1	6-33441740-A-C	2	1.24e-6	-2.431	Likely Benign	0.093	Likely Benign	Likely Benign	0.048	Likely Benign										-0.53	Neutral	0.002	Benign	0.005	Benign	2.84	Benign	1.00	Tolerated	3.99	5	4	2	1.9	-18.03
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.1991T>C	L664S (3D Viewer)	Likely Pathogenic	GAP	Likely Benign		1	6-33441250-T-C	1	6.20e-7	-16.498	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.543	Likely Pathogenic	3.75	Destabilizing	0.2	3.63	Destabilizing	3.69	Destabilizing	2.77	Destabilizing	-5.99	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	2.85	Benign	0.00	Affected	3.38	28	-3	-2	-4.6	-26.08	215.5	50.1	0.0	0.0	-0.2	0.2						X		Potentially Benign	The iso-butyl side chain of L664, located on an α-helix (res. Ser641-Glu666), hydrophobically interacts with residues in the inter-helix space between three helices (res. Glu617-Asn635, res. Glu582-Met603, and res. Ser641-Glu666), such as Ile589, Phe663, and Met660. In the variant simulations, the hydroxyl group of Ser664 forms hydrogen bonds with the backbone carbonyl oxygen of another helix residue, such as Met660 or Gln661. This interaction is known to destabilize hydrogen bonding in the α-helix, but this effect was not observed in the simulations. Additionally, Ser664 occasionally forms hydrogen bonds with the carboxylate group of Asp586 on another α-helix (res. Glu582-Met603), which could minimally influence the tertiary structure assembly. Despite these interactions, no major negative effects on the protein structure were observed during the simulations.
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.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.2349G>A	M783I	Likely Benign		Benign		1	6-33442901-G-A	6	3.72e-6	-3.560	Likely Benign	0.418	Ambiguous	Likely Benign	0.042	Likely Benign										-0.54	Neutral	0.004	Benign	0.006	Benign	2.87	Benign	0.22	Tolerated	3.64	6	1	2	2.6	-18.03
c.2860C>T	P954S	Likely Benign		Likely Benign		1	6-33443412-C-T	1	6.20e-7	-3.525	Likely Benign	0.062	Likely Benign	Likely Benign	0.143	Likely Benign										-0.25	Neutral	0.954	Possibly Damaging	0.812	Possibly Damaging	2.87	Benign	1.00	Tolerated	3.77	5	1	-1	0.8	-10.04
c.1540A>T	I514F (3D Viewer)	Likely Pathogenic	GAP	Uncertain		1				-13.383	Likely Pathogenic	0.962	Likely Pathogenic	Likely Pathogenic	0.601	Likely Pathogenic	2.35	Destabilizing	0.3	3.74	Destabilizing	3.05	Destabilizing	0.93	Ambiguous	-3.98	Deleterious	0.997	Probably Damaging	0.993	Probably Damaging	2.89	Benign	0.00	Affected	3.37	35	0	1	-1.7	34.02
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.2434C>T	P812S	Likely Benign	SH3-binding motif	Uncertain		1	6-33442986-C-T	1	6.20e-7	-5.689	Likely Benign	0.456	Ambiguous	Likely Benign	0.162	Likely Benign										-0.62	Neutral	0.999	Probably Damaging	0.966	Probably Damaging	2.89	Benign	0.95	Tolerated	4.32	4	1	-1	0.8	-10.04
c.1292T>C	L431P (3D Viewer)	Likely Pathogenic	GAP	Likely Pathogenic		1				-14.222	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.659	Likely Pathogenic	6.78	Destabilizing	0.3	11.59	Destabilizing	9.19	Destabilizing	2.29	Destabilizing	-6.39	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	2.91	Benign	0.05	Affected	3.37	29	-3	-3	-5.4	-16.04	222.4	62.8	0.1	0.0	0.1	0.0	X							Potentially Pathogenic	The iso-butyl side chain of Leu431, located in an α helix (res. Met414-Glu436), packs against other hydrophobic residues in an interhelix space (e.g., Val434, Leu435, Leu696, Leu711) in the WT simulations. While the backbone amide group of Leu431 forms an H-bond with the carbonyl group of His427, the cyclic five-membered pyrrolidine ring of Pro431, lacking the necessary amide group, cannot do the same. Thus, although the cyclic five-membered pyrrolidine ring of Pro431 packs almost as favorably as the side chain of Leu431 in the hydrophobic niche, the residue swap causes the α helix to partially unfold in the variant simulations.
c.2221C>T	P741S	Likely Benign		Uncertain		2	6-33441686-C-T	3	1.86e-6	-3.700	Likely Benign	0.063	Likely Benign	Likely Benign	0.076	Likely Benign										-0.27	Neutral	0.270	Benign	0.136	Benign	2.92	Benign	0.00	Affected	4.32	2	1	-1	0.8	-10.04																10.1016/j.ajhg.2020.11.011
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.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.3995C>T	T1332M			Likely Benign		1	6-33451869-C-T	20	1.86e-5	-4.107	Likely Benign	0.948	Likely Pathogenic	Ambiguous	0.252	Likely Benign										-3.63	Deleterious	1.000	Probably Damaging	0.991	Probably Damaging	2.95	Benign	0.00	Affected	3.77	5	-1	-1	2.6	30.09
c.3858A>T	E1286D	Likely Benign		Conflicting		4	6-33447906-A-T	143	9.22e-5	-4.010	Likely Benign	0.081	Likely Benign	Likely Benign	0.036	Likely Benign										1.02	Neutral	0.001	Benign	0.004	Benign	2.96	Benign	1.00	Tolerated	3.77	5	3	2	0.0	-14.03																10.1016/j.ajhg.2020.11.011
c.3929C>T	T1310M	Likely Benign		Benign		1	6-33451803-C-T	17	1.05e-5	-4.822	Likely Benign	0.117	Likely Benign	Likely Benign	0.069	Likely Benign										2.19	Neutral	0.021	Benign	0.005	Benign	2.98	Benign	0.93	Tolerated	3.77	5	-1	-1	2.6	30.09
c.1474A>G	K492E (3D Viewer)	Likely Pathogenic	GAP	Conflicting		2				-16.175	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.510	Likely Pathogenic	1.53	Ambiguous	0.1	1.90	Ambiguous	1.72	Ambiguous	1.42	Destabilizing	-3.98	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	2.99	Benign	0.01	Affected	3.37	35	1	0	0.4	0.94
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.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.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.1904A>G	N635S (3D Viewer)		GAP	Conflicting		4	6-33440956-A-G	10	6.20e-6	-9.002	Likely Pathogenic	0.101	Likely Benign	Likely Benign	0.104	Likely Benign	0.80	Ambiguous	0.1	0.67	Ambiguous	0.74	Ambiguous	0.95	Ambiguous	-4.45	Deleterious	0.261	Benign	0.044	Benign	3.06	Benign	0.05	Affected	3.37	34	1	1	2.7	-27.03	196.0	30.9	0.1	0.0	-0.3	0.2				X				Uncertain	In the WT simulations, the carboxamide side chain of Asn635, located on the outer surface of an α helix (res. Glu617-Asn635), forms hydrogen bonds with Gln631 on the same α helix and with the hydroxyl side chain of Ser590 on an opposing α helix (res. Glu582-Met603).In the variant simulations, the side chain of Ser635 is shorter than asparagine and thus prefers to hydrogen bond with the carbonyl group of Gln631 on the same helix and, to a lesser extent, with Ser590 compared to Asn635 in the WT. Ser635 forms hydrogen bonds with the backbone atoms of the same helix, which may destabilize the helix, although this is not clearly evident in the simulations. The weakening of the hydrogen bond between Ser635 and Ser590 in the variant may also weaken the tertiary structure assembly between the helices.Additionally, Asn635 is at the GTPase interface. However, the implication of the residue swap on the complex formation with the GTPase cannot be investigated using solvent-only simulations.