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

c.dna	Variant	SGM Consensus	Domain and Structure information: based on WT protein												Annotated databases						Deep learning-based pathogenicity predictions					Folding stability-based pathogenicity predictions									Sequence/structure-based pathogenicity predictions														Phase Separation			Evolutionary/physical properties				Molecular Dynamics-based analysis															DOI
			Domain	IUPred2		ANCHOR2		AlphaFold		MobiDB	PhosphoSitePlus				ClinVar			gnomAD			ESM1b		AlphaMissense			FoldX			Rosetta		Foldetta		PremPS		REVEL		PROVEAN		PolyPhen-2 HumDiv		PolyPhen-2 HumVar		FATHMM		SIFT				PSMutPred			PAM		Physical		SASA		Normalized B-factor backbone		Normalized B-factor sidechain		SynGAP Structural Annotation
				Score	Prediction	Score	Prediction	pLDDT	disorder	disorder	LTP	HTP	KL	PTM	Clinical Status	Review	Subm.	ID	Allele count	Allele freq.	LLR score	Prediction	Pathogenicity	Class	Optimized	Average ΔΔG	Prediction	StdDev	ΔΔG	Prediction	ΔΔG	Prediction	ΔΔG	Prediction	Score	Prediction	Score	Prediction	pph2_prob	Prediction	pph2_prob	Prediction	Nervous System Score	Prediction	Prediction	Status	Conservation	Sequences	IP RF	SP RF	Prediction	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.688T>G	C230G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reached a consensus fall into two groups: benign predictions come from polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain or inconclusive results from FoldX, Rosetta, Foldetta, and premPS are treated as unavailable and do not influence the overall assessment. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also Likely Pathogenic; Foldetta remains uncertain. Based on the aggregate predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.268042	Structured	0.308076	Uncertain	0.870	0.308	0.000											-10.888	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.72	Ambiguous	0.1	0.86	Ambiguous	0.79	Ambiguous	0.81	Ambiguous	0.775	Likely Pathogenic	-9.95	Deleterious	0.001	Benign	0.004	Benign	5.85	Benign	0.03	Affected			0.3313	0.2574		-3	-3	-2.9	-46.09
c.689G>A	C230Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230Y is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that indicate a benign effect include FoldX, Rosetta, premPS, SIFT, and FATHMM, whereas those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic,” and the Foldetta stability assessment is “Uncertain.” High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.268042	Structured	0.308076	Uncertain	0.870	0.308	0.000											-8.978	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	-0.03	Likely Benign	0.1	-2.24	Stabilizing	-1.14	Ambiguous	0.00	Likely Benign	0.816	Likely Pathogenic	-8.46	Deleterious	0.940	Possibly Damaging	0.641	Possibly Damaging	6.17	Benign	0.14	Tolerated			0.1159	0.3655		0	-2	-3.8	60.04
c.689G>C	C230S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant C230S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools cluster into two groups: benign calls come from FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; pathogenic calls come from REVEL, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. No prediction or stability result is missing. Overall, the predictions are evenly split between benign and pathogenic, leaving the variant’s functional impact uncertain. This uncertainty does not contradict ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.268042	Structured	0.308076	Uncertain	0.870	0.308	0.000											-9.994	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.42	Likely Benign	0.1	0.05	Likely Benign	0.24	Likely Benign	1.08	Destabilizing	0.844	Likely Pathogenic	-8.24	Deleterious	0.421	Benign	0.115	Benign	5.91	Benign	0.07	Tolerated			0.4926	0.1822		0	-1	-3.3	-16.06
c.689G>T	C230F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Foldetta and premPS give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that C230F is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.268042	Structured	0.308076	Uncertain	0.870	0.308	0.000											-11.134	Likely Pathogenic	0.988	Likely Pathogenic	Likely Pathogenic	-0.09	Likely Benign	0.1	-2.03	Stabilizing	-1.06	Ambiguous	0.51	Ambiguous	0.840	Likely Pathogenic	-8.73	Deleterious	0.940	Possibly Damaging	0.641	Possibly Damaging	5.96	Benign	0.03	Affected			0.1329	0.4173		-4	-2	0.3	44.04
c.68A>C	D23A 2D AIThe SynGAP1 D23A missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic versus four benign) suggest a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.			0.557691	Disordered	0.440341	Uncertain	0.369	0.892	0.375											-2.732	Likely Benign	0.777	Likely Pathogenic	Likely Benign										0.112	Likely Benign	-2.57	Deleterious	0.909	Possibly Damaging	0.539	Possibly Damaging	3.52	Benign	0.00	Affected			0.4613	0.8203		0	-2	5.3	-44.01
c.68A>G	D23G 2D AIThe SynGAP1 missense variant D23G is listed in ClinVar (ID 3644551.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification but leans toward a benign interpretation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.557691	Disordered	0.440341	Uncertain	0.369	0.892	0.375					Uncertain		1				-2.622	Likely Benign	0.684	Likely Pathogenic	Likely Benign										0.100	Likely Benign	-2.45	Neutral	0.805	Possibly Damaging	0.539	Possibly Damaging	3.50	Benign	0.00	Affected			0.4682	0.7632		1	-1	3.1	-58.04
c.68A>T	D23V 2D AIThe SynGAP1 D23V missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus unavailable; Foldetta predictions are not provided. Overall, more tools (five) predict pathogenicity than benign (three), and no ClinVar evidence contradicts this assessment. Therefore, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.			0.557691	Disordered	0.440341	Uncertain	0.369	0.892	0.375											-3.244	Likely Benign	0.842	Likely Pathogenic	Ambiguous										0.137	Likely Benign	-2.72	Deleterious	0.972	Probably Damaging	0.804	Possibly Damaging	3.48	Benign	0.00	Affected			0.1515	0.8367		-2	-3	7.7	-15.96
c.690C>G	C230W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by FATHMM and FoldX, whereas the majority of other in silico predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic impact for C230W, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.268042	Structured	0.308076	Uncertain	0.870	0.308	0.000											-11.022	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	-0.21	Likely Benign	0.0	-1.87	Ambiguous	-1.04	Ambiguous	0.74	Ambiguous	0.739	Likely Pathogenic	-8.79	Deleterious	0.983	Probably Damaging	0.841	Possibly Damaging	5.84	Benign	0.01	Affected			0.1589	0.3663		-8	-2	-3.4	83.07
c.691T>A	F231I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta’s stability prediction is uncertain and thus not considered evidence. No other tools provide definitive pathogenic or benign conclusions. Based on the preponderance of pathogenic predictions and the lack of contrary evidence, the variant is most likely pathogenic; this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-13.827	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.16	Ambiguous	0.4	1.65	Ambiguous	1.41	Ambiguous	0.94	Ambiguous	0.894	Likely Pathogenic	-5.01	Deleterious	0.759	Possibly Damaging	0.328	Benign	5.76	Benign	0.00	Affected			0.2122	0.2813		1	0	1.7	-34.02
c.691T>C	F231L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact for F231L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-9.482	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.07	Ambiguous	0.3	1.26	Ambiguous	1.17	Ambiguous	0.85	Ambiguous	0.801	Likely Pathogenic	-5.08	Deleterious	0.390	Benign	0.142	Benign	6.04	Benign	0.01	Affected			0.2338	0.3794		2	0	1.0	-34.02
c.691T>G	F231V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates pathogenicity. Taken together, the evidence overwhelmingly points to a pathogenic effect for F231V, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-13.201	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	2.16	Destabilizing	0.3	2.30	Destabilizing	2.23	Destabilizing	1.13	Destabilizing	0.910	Likely Pathogenic	-5.90	Deleterious	0.759	Possibly Damaging	0.328	Benign	5.72	Benign	0.00	Affected			0.2212	0.3030		-1	-1	1.4	-48.04
c.692T>A	F231Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign effects include Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are inconclusive. High‑accuracy methods give AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of standard tools lean benign, but the two most accurate predictors and the consensus vote favor pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no classification for F231Y. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-9.831	Likely Pathogenic	0.980	Likely Pathogenic	Likely Pathogenic	0.69	Ambiguous	0.1	0.00	Likely Benign	0.35	Likely Benign	0.85	Ambiguous	0.687	Likely Pathogenic	-2.60	Deleterious	0.437	Benign	0.079	Benign	5.50	Benign	0.12	Tolerated			0.1355	0.2732		7	3	-4.1	16.00
c.692T>C	F231S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-14.655	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	2.89	Destabilizing	0.4	4.22	Destabilizing	3.56	Destabilizing	2.22	Destabilizing	0.909	Likely Pathogenic	-6.92	Deleterious	0.608	Possibly Damaging	0.205	Benign	5.48	Benign	0.00	Affected			0.4297	0.0544		-3	-2	-3.6	-60.10
c.692T>G	F231C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231C is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-13.315	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	2.26	Destabilizing	0.3	2.82	Destabilizing	2.54	Destabilizing	2.04	Destabilizing	0.937	Likely Pathogenic	-6.89	Deleterious	0.992	Probably Damaging	0.707	Possibly Damaging	5.49	Benign	0.00	Affected			0.2527	0.1612		-4	-2	-0.3	-44.04
c.693T>A	F231L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact for F231L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-9.482	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.07	Ambiguous	0.3	1.26	Ambiguous	1.17	Ambiguous	0.85	Ambiguous	0.662	Likely Pathogenic	-5.08	Deleterious	0.390	Benign	0.142	Benign	6.04	Benign	0.01	Affected			0.2338	0.3794		2	0	1.0	-34.02
c.693T>G	F231L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar and FATHMM, whereas REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized all predict a pathogenic effect. The SGM‑Consensus score is labeled Likely Pathogenic, and the remaining tools (FoldX, Rosetta, Foldetta, premPS) are inconclusive. High‑accuracy methods give a pathogenic verdict from AlphaMissense‑Optimized, a Likely Pathogenic result from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain outcome from Foldetta. Overall, the majority of evidence points to a pathogenic impact for F231L, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-9.482	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.07	Ambiguous	0.3	1.26	Ambiguous	1.17	Ambiguous	0.85	Ambiguous	0.661	Likely Pathogenic	-5.08	Deleterious	0.390	Benign	0.142	Benign	6.04	Benign	0.01	Affected			0.2338	0.3794		2	0	1.0	-34.02
c.694G>A	A232T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232T is listed in ClinVar as Benign (ClinVar ID 1165963.0) and is present in gnomAD (ID 6‑33435545‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. Predictions that are inconclusive are premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports Benign. Overall, the majority of evidence supports a benign impact, which is consistent with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.254060	Structured	0.307228	Uncertain	0.878	0.305	0.000					Benign		1	6-33435545-G-A	1	6.20e-7	-7.655	In-Between	0.874	Likely Pathogenic	Ambiguous	0.47	Likely Benign	0.1	-0.04	Likely Benign	0.22	Likely Benign	0.61	Ambiguous	0.469	Likely Benign	-1.42	Neutral	0.608	Possibly Damaging	0.240	Benign	5.80	Benign	0.09	Tolerated	3.40	14	0.1621	0.6488		1	0	-2.5	30.03	210.8	-42.0	0.5	0.1	0.4	0.5						X		Uncertain	The hydroxyl group of Thr232, located at the end of an anti-parallel β sheet strand (res. Thr228-Ala232), forms hydrogen bonds with nearby residues Glu217, Cys233, and Cys219 in the variant simulations. These hydrogen-bonding interactions at the β sheet surface contribute to the stability of the secondary structure element and prevent it from unfolding. The new hydrogen bond interactions may be more favorable for structural stability than the steric interactions of the methyl side chain of Ala with the side chains of Gln216 and Cys219 in the WT. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.694G>C	A232P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, SIFT, and FATHMM. Tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from Rosetta, premPS, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, and Foldetta remains uncertain. Overall, the majority of evaluated tools predict a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.254060	Structured	0.307228	Uncertain	0.878	0.305	0.000											-12.697	Likely Pathogenic	0.977	Likely Pathogenic	Likely Pathogenic	0.05	Likely Benign	0.8	1.25	Ambiguous	0.65	Ambiguous	0.71	Ambiguous	0.748	Likely Pathogenic	-2.75	Deleterious	0.917	Possibly Damaging	0.502	Possibly Damaging	5.78	Benign	0.06	Tolerated			0.2163	0.5259		1	-1	-3.4	26.04
c.694G>T	A232S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Across the evaluated in‑silico predictors, all tools except AlphaMissense‑Default converge on a benign interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all predict benign. AlphaMissense‑Default is uncertain, while AlphaMissense‑Optimized predicts benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.254060	Structured	0.307228	Uncertain	0.878	0.305	0.000											-3.264	Likely Benign	0.344	Ambiguous	Likely Benign	0.23	Likely Benign	0.1	-0.23	Likely Benign	0.00	Likely Benign	-0.20	Likely Benign	0.378	Likely Benign	0.54	Neutral	0.057	Benign	0.025	Benign	5.95	Benign	1.00	Tolerated			0.2777	0.5300		1	1	-2.6	16.00
c.695C>A	A232D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232D is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus. Uncertain or inconclusive results are reported for Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as pathogenic, while Foldetta remains uncertain. Overall, the majority of available predictions support a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.254060	Structured	0.307228	Uncertain	0.878	0.305	0.000											-13.956	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.14	Likely Benign	0.2	1.55	Ambiguous	0.85	Ambiguous	0.77	Ambiguous	0.725	Likely Pathogenic	-2.50	Deleterious	0.845	Possibly Damaging	0.348	Benign	5.78	Benign	0.02	Affected			0.2066	0.2896		0	-2	-5.3	44.01
c.695C>G	A232G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A232G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the change as benign include REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Those that predict pathogenicity are polyPhen‑2 HumDiv and AlphaMissense‑Default. Uncertain or inconclusive results come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a benign effect; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.254060	Structured	0.307228	Uncertain	0.878	0.305	0.000											-4.924	Likely Benign	0.835	Likely Pathogenic	Ambiguous	0.43	Likely Benign	0.1	1.43	Ambiguous	0.93	Ambiguous	0.53	Ambiguous	0.453	Likely Benign	-1.39	Neutral	0.608	Possibly Damaging	0.172	Benign	5.81	Benign	0.11	Tolerated			0.2012	0.4724		1	0	-2.2	-14.03
c.695C>T	A232V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A232V is catalogued in gnomAD (ID 6‑33435546‑C‑T) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, SIFT, and FATHMM, whereas pathogenic calls are reported by REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, and the Foldetta stability assessment predicts benign. premPS is inconclusive and therefore not considered. Overall, the majority of independent predictors lean toward pathogenicity, but the stability‑based Foldetta suggests a benign effect. With no ClinVar classification to contradict, the variant is most likely pathogenic according to the prevailing computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.254060	Structured	0.307228	Uncertain	0.878	0.305	0.000								6-33435546-C-T	2	1.24e-6	-9.418	Likely Pathogenic	0.962	Likely Pathogenic	Likely Pathogenic	0.40	Likely Benign	0.1	0.23	Likely Benign	0.32	Likely Benign	0.55	Ambiguous	0.539	Likely Pathogenic	-2.99	Deleterious	0.608	Possibly Damaging	0.240	Benign	5.85	Benign	0.06	Tolerated	3.40	14	0.1202	0.6027		0	0	2.4	28.05
c.697T>A	C233S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors pathogenicity (3 pathogenic vs 1 benign). Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.306787	Uncertain	0.868	0.322	0.000											-10.862	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.61	Ambiguous	0.1	1.25	Ambiguous	0.93	Ambiguous	1.50	Destabilizing	0.764	Likely Pathogenic	-8.89	Deleterious	0.421	Benign	0.080	Benign	5.79	Benign	0.03	Affected			0.4528	0.2833		0	-1	-3.3	-16.06
c.697T>C	C233R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and gnomAD presence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.306787	Uncertain	0.868	0.322	0.000											-16.789	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.79	Destabilizing	3.4	2.17	Destabilizing	2.98	Destabilizing	1.75	Destabilizing	0.830	Likely Pathogenic	-10.68	Deleterious	0.002	Benign	0.002	Benign	5.71	Benign	0.01	Affected			0.1733	0.2212		-4	-3	-7.0	53.05
c.697T>G	C233G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233G is not reported in ClinVar (ClinVar ID = None) and has no entry in gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta are inconclusive and are treated as unavailable. High‑accuracy predictions: AlphaMissense‑Optimized reports Pathogenic; SGM‑Consensus reports Likely Pathogenic; Foldetta is Uncertain. Overall, the majority of available predictions indicate a pathogenic impact. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.306787	Uncertain	0.868	0.322	0.000											-14.155	Likely Pathogenic	0.988	Likely Pathogenic	Likely Pathogenic	1.29	Ambiguous	0.1	1.01	Ambiguous	1.15	Ambiguous	1.31	Destabilizing	0.849	Likely Pathogenic	-10.68	Deleterious	0.596	Possibly Damaging	0.107	Benign	5.79	Benign	0.09	Tolerated			0.3317	0.3570		-3	-3	-2.9	-46.09
c.698G>A	C233Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233Y is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are Rosetta and FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic (3 pathogenic vs. 1 benign); and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.306787	Uncertain	0.868	0.322	0.000											-17.893	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	13.15	Destabilizing	4.6	0.04	Likely Benign	6.60	Destabilizing	0.71	Ambiguous	0.904	Likely Pathogenic	-9.79	Deleterious	0.940	Possibly Damaging	0.459	Possibly Damaging	5.71	Benign	0.00	Affected	4.29	391	0.1324	0.5284		0	-2	-3.8	60.04	248.9	-63.0	0.0	0.3	0.0	0.4	X						X	Potentially Pathogenic	The introduced residue Tyr233 is located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Ala232) and an α helix (residues Ala236-Val250). Although the thiol group of a cysteine side chain is not a strong hydrogen bond acceptor or donor, it facilitates hydrogen bonding between Cys233 and the backbone carbonyl of Ala232 in the WT simulations. In the variant simulations, the bulky phenol ring of the Tyr233 side chain stacks with the indole ring of the Trp242 side chain. This interaction could alter the tertiary assembly of the β sheet and α helix due to the residue swap. Indeed, in the second replica simulation, the protein structure begins to unfold to accommodate the introduced Tyr233 side chain.	10.1016/j.ajhg.2020.11.011
c.698G>C	C233S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of evidence points to a pathogenic impact for C233S, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.306787	Uncertain	0.868	0.322	0.000											-10.862	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.61	Ambiguous	0.1	1.25	Ambiguous	0.93	Ambiguous	1.50	Destabilizing	0.830	Likely Pathogenic	-8.89	Deleterious	0.421	Benign	0.080	Benign	5.79	Benign	0.03	Affected			0.4528	0.2833		0	-1	-3.3	-16.06
c.698G>T	C233F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include Rosetta, premPS, and FATHMM, whereas the remaining tools—REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and Foldetta—predict a pathogenic or likely pathogenic impact. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence supports a pathogenic effect, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.306787	Uncertain	0.868	0.322	0.000											-14.564	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	9.36	Destabilizing	3.0	-0.19	Likely Benign	4.59	Destabilizing	0.37	Likely Benign	0.901	Likely Pathogenic	-9.79	Deleterious	0.940	Possibly Damaging	0.459	Possibly Damaging	5.73	Benign	0.00	Affected			0.1524	0.5231		-4	-2	0.3	44.04
c.699T>G	C233W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233W is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a benign outcome, while Rosetta and premPS are uncertain. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Taken together, the overwhelming majority of evidence indicates that C233W is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.306787	Uncertain	0.868	0.322	0.000											-17.899	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	14.72	Destabilizing	6.6	1.07	Ambiguous	7.90	Destabilizing	0.54	Ambiguous	0.772	Likely Pathogenic	-9.79	Deleterious	0.983	Probably Damaging	0.715	Possibly Damaging	5.71	Benign	0.00	Affected			0.1727	0.5292		-8	-2	-3.4	83.07
c.69T>A	D23E 2D AIThe SynGAP1 D23E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.557691	Disordered	0.440341	Uncertain	0.369	0.892	0.375											-3.329	Likely Benign	0.565	Likely Pathogenic	Likely Benign										0.084	Likely Benign	-1.35	Neutral	0.643	Possibly Damaging	0.417	Benign	3.59	Benign	0.00	Affected	4.32	1	0.2420	0.8363		2	3	0.0	14.03
c.69T>G	D23E 2D AIThe SynGAP1 missense variant D23E is listed in gnomAD (ID 6‑33423478‑T‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence—including the consensus and high‑accuracy tools—points to a benign effect, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.557691	Disordered	0.440341	Uncertain	0.369	0.892	0.375								6-33423478-T-G	15	9.29e-6	-3.329	Likely Benign	0.565	Likely Pathogenic	Likely Benign										0.084	Likely Benign	-1.35	Neutral	0.643	Possibly Damaging	0.417	Benign	3.59	Benign	0.00	Affected	4.32	1	0.2420	0.8363		2	3	0.0	14.03
c.6C>A	S2R 2D AIThe SynGAP1 missense variant S2R is present in gnomAD (ID 6‑33420270‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score all report benign or likely benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.671169	Disordered	0.543646	Binding	0.382	0.922	0.750								6-33420270-C-A	1	6.52e-7	-3.684	Likely Benign	0.426	Ambiguous	Likely Benign										0.070	Likely Benign	-0.44	Neutral	0.117	Benign	0.008	Benign	4.05	Benign	0.00	Affected	4.32	1	0.0996	0.4503		-1	0	-3.7	69.11
c.6C>G	S2R 2D AIThe SynGAP1 missense variant S2R is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the preponderance of evidence from multiple prediction tools and high‑accuracy methods indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.671169	Disordered	0.543646	Binding	0.382	0.922	0.750											-3.684	Likely Benign	0.426	Ambiguous	Likely Benign										0.065	Likely Benign	-0.44	Neutral	0.117	Benign	0.008	Benign	4.05	Benign	0.00	Affected	4.32	1	0.0996	0.4503		-1	0	-3.7	69.11
c.700C>G	R234G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that agree on a pathogenic effect are REVEL, PROVEAN, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of individual predictors lean toward pathogenicity, and the high‑accuracy consensus also supports a pathogenic classification. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.239899	Structured	0.311558	Uncertain	0.804	0.322	0.000											-7.163	In-Between	0.923	Likely Pathogenic	Ambiguous	1.50	Ambiguous	0.2	0.88	Ambiguous	1.19	Ambiguous	0.61	Ambiguous	0.724	Likely Pathogenic	-4.31	Deleterious	0.276	Benign	0.103	Benign	5.82	Benign	0.12	Tolerated			0.3194	0.3426		-3	-2	4.1	-99.14
c.700C>T	R234W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234W missense variant is listed in ClinVar (ID 856396.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33435551‑C‑T). Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) indicate a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain”; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is “Uncertain.” Overall, the preponderance of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertainty rather than a benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.311558	Uncertain	0.804	0.322	0.000					Uncertain		1	6-33435551-C-T	3	1.86e-6	-12.625	Likely Pathogenic	0.947	Likely Pathogenic	Ambiguous	0.96	Ambiguous	0.3	0.69	Ambiguous	0.83	Ambiguous	0.13	Likely Benign	0.805	Likely Pathogenic	-5.52	Deleterious	0.997	Probably Damaging	0.803	Possibly Damaging	5.76	Benign	0.01	Affected	3.40	14	0.1302	0.4035		2	-3	3.6	30.03	262.8	39.6	-0.1	0.0	-0.2	0.2		X						Potentially Pathogenic	The guanidinium group of Arg234, located in a β-α loop between an anti-parallel β sheet strand (residues Gly227-Phe231) and an α helix (res. Ala236-Val250), forms a salt bridge with the carboxylate group of Glu238 in the α helix. Occasionally, it also bonds with the GAP domain residues Ser678 and Glu680. Thus, the positively charged Arg234 could contribute to the tertiary structure assembly between the PH and GAP domains. In contrast, the indole side chain of Trp234 in the variant is located on the protein surface in the variant simulations and is unable to form any interactions.
c.701G>A	R234Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234Q missense variant is not reported in ClinVar (ClinVar ID = None) but is present in gnomAD (ID = 6‑33435552‑G‑A). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default; premPS is uncertain and treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of evidence points to a benign effect. The variant’s predicted benign status does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.239899	Structured	0.311558	Uncertain	0.804	0.322	0.000								6-33435552-G-A	8	4.96e-6	-9.675	Likely Pathogenic	0.666	Likely Pathogenic	Likely Benign	0.21	Likely Benign	0.1	0.27	Likely Benign	0.24	Likely Benign	0.57	Ambiguous	0.627	Likely Pathogenic	-2.32	Neutral	0.892	Possibly Damaging	0.213	Benign	5.81	Benign	0.11	Tolerated	3.40	14	0.3256	0.2520		1	1	1.0	-28.06
c.701G>C	R234P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R234P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of evaluated algorithms (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.311558	Uncertain	0.804	0.322	0.000											-10.126	Likely Pathogenic	0.972	Likely Pathogenic	Likely Pathogenic	1.33	Ambiguous	0.6	1.36	Ambiguous	1.35	Ambiguous	0.13	Likely Benign	0.826	Likely Pathogenic	-4.43	Deleterious	0.929	Possibly Damaging	0.519	Possibly Damaging	5.93	Benign	0.04	Affected			0.1972	0.4336		0	-2	2.9	-59.07
c.701G>T	R234L 2D AIThe SynGAP1 missense variant R234L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, polyPhen‑2 HumVar, SIFT, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (7 pathogenic vs. 4 benign) and the pathogenic consensus from the high‑accuracy SGM‑Consensus suggest that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.311558	Uncertain	0.804	0.322	0.000											-11.153	Likely Pathogenic	0.935	Likely Pathogenic	Ambiguous	1.38	Ambiguous	0.9	0.50	Ambiguous	0.94	Ambiguous	0.20	Likely Benign	0.734	Likely Pathogenic	-4.64	Deleterious	0.649	Possibly Damaging	0.199	Benign	5.78	Benign	0.11	Tolerated			0.1846	0.4783		-3	-2	8.3	-43.03
c.703T>A	S235T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while FoldX, Rosetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or folding result is missing or inconclusive. Based on the overall consensus of the available tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.250310	Structured	0.319150	Uncertain	0.743	0.331	0.000											-9.422	Likely Pathogenic	0.451	Ambiguous	Likely Benign	0.80	Ambiguous	0.0	-0.54	Ambiguous	0.13	Likely Benign	0.21	Likely Benign	0.453	Likely Benign	-2.02	Neutral	0.057	Benign	0.020	Benign	5.75	Benign	0.13	Tolerated			0.1674	0.6337		1	1	0.1	14.03
c.703T>C	S235P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235P is listed in ClinVar as Pathogenic (ClinVar ID 1067856.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. No predictions or stability results are missing or inconclusive. **Based on the collective predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.250310	Structured	0.319150	Uncertain	0.743	0.331	0.000					Likely Pathogenic		1				-14.857	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	4.02	Destabilizing	0.1	6.91	Destabilizing	5.47	Destabilizing	1.23	Destabilizing	0.870	Likely Pathogenic	-4.24	Deleterious	0.917	Possibly Damaging	0.446	Benign	5.47	Benign	0.01	Affected	3.40	14	0.2432	0.5307		1	-1	-0.8	10.04	201.5	17.0	0.1	0.0	-0.6	0.0		X						Potentially Pathogenic	In the WT, the hydroxyl group of Ser235, located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Phe231) and an α helix (residues Ala236-Val250), forms hydrogen bonds with the GAP domain loop residue Glu680 and with the backbone amide groups of Ala237 and Glu238 from the α helix. In the variant simulations, the pyrrolidine ring of Pro235 cannot stabilize the α helix end or maintain tertiary bonding interactions between the PH and GAP domains via hydrogen bonding as effectively as serine.
c.703T>G	S235A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235A has no ClinVar entry and is not present in gnomAD. Prediction tools that indicate benign effects include Rosetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic; Foldetta remains uncertain. Overall, the balance of evidence leans toward a benign interpretation, but the SGM Consensus introduces a pathogenic signal, resulting in a conflicting prediction profile. This assessment does not contradict ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.250310	Structured	0.319150	Uncertain	0.743	0.331	0.000											-10.861	Likely Pathogenic	0.707	Likely Pathogenic	Likely Benign	1.92	Ambiguous	0.1	0.19	Likely Benign	1.06	Ambiguous	0.48	Likely Benign	0.646	Likely Pathogenic	-2.52	Deleterious	0.002	Benign	0.004	Benign	5.49	Benign	0.01	Affected			0.5168	0.4563	Weaken	1	1	2.6	-16.00
c.704C>A	S235Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FATHMM and Rosetta, whereas the majority of other in silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. Two tools give inconclusive results: Foldetta (protein‑folding stability) and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for S235Y, and this conclusion is not contradicted by any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.250310	Structured	0.319150	Uncertain	0.743	0.331	0.000											-15.842	Likely Pathogenic	0.977	Likely Pathogenic	Likely Pathogenic	3.53	Destabilizing	1.8	0.43	Likely Benign	1.98	Ambiguous	0.66	Ambiguous	0.887	Likely Pathogenic	-5.14	Deleterious	0.971	Probably Damaging	0.641	Possibly Damaging	5.45	Benign	0.00	Affected			0.0733	0.5269		-3	-2	-0.5	76.10
c.704C>G	S235C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FATHMM and Rosetta, whereas a majority of tools (REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Results from high‑accuracy methods are mixed: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta is uncertain. Because the uncertain predictions are treated as unavailable, the overall evidence still favors pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.250310	Structured	0.319150	Uncertain	0.743	0.331	0.000											-11.350	Likely Pathogenic	0.800	Likely Pathogenic	Ambiguous	1.74	Ambiguous	0.1	0.42	Likely Benign	1.08	Ambiguous	0.76	Ambiguous	0.878	Likely Pathogenic	-4.24	Deleterious	0.977	Probably Damaging	0.620	Possibly Damaging	5.45	Benign	0.00	Affected			0.1284	0.6015		0	-1	3.3	16.06
c.704C>T	S235F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235F is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FATHMM and Rosetta, whereas the majority of other in silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. Two tools give inconclusive results: Foldetta (protein‑folding stability) and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.250310	Structured	0.319150	Uncertain	0.743	0.331	0.000											-14.456	Likely Pathogenic	0.988	Likely Pathogenic	Likely Pathogenic	3.03	Destabilizing	1.7	0.46	Likely Benign	1.75	Ambiguous	0.56	Ambiguous	0.919	Likely Pathogenic	-5.14	Deleterious	0.917	Possibly Damaging	0.548	Possibly Damaging	5.45	Benign	0.00	Affected			0.0617	0.5393		-3	-2	3.6	60.10
c.706G>A	A236T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A236T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and thus unavailable. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, six tools favor pathogenicity versus three favor benign, and no high‑confidence consensus tool contradicts this trend. Therefore, the variant is most likely pathogenic, and this assessment does not conflict with any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.185198	Structured	0.329926	Uncertain	0.775	0.330	0.000											-8.319	Likely Pathogenic	0.240	Likely Benign	Likely Benign	0.73	Ambiguous	0.2	1.58	Ambiguous	1.16	Ambiguous	0.83	Ambiguous	0.811	Likely Pathogenic	-3.35	Deleterious	0.982	Probably Damaging	0.747	Possibly Damaging	5.79	Benign	0.03	Affected			0.1342	0.6926		1	0	-2.5	30.03
c.706G>C	A236P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A236P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include Foldetta, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas those that predict a pathogenic outcome are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and AlphaMissense‑Default; the remaining tools (FoldX, Rosetta, premPS, ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. No prediction or stability result is missing or inconclusive. Overall, the majority of individual tools lean toward pathogenicity, but the two most reliable high‑accuracy methods (AlphaMissense‑Optimized and Foldetta) suggest a benign effect, while the SGM Consensus indicates pathogenicity. Given the mixed evidence, the variant is most likely benign based on the strongest high‑accuracy predictions, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.185198	Structured	0.329926	Uncertain	0.775	0.330	0.000											-7.932	In-Between	0.621	Likely Pathogenic	Likely Benign	-0.99	Ambiguous	0.1	1.44	Ambiguous	0.23	Likely Benign	0.67	Ambiguous	0.862	Likely Pathogenic	-4.31	Deleterious	0.995	Probably Damaging	0.880	Possibly Damaging	5.78	Benign	0.12	Tolerated			0.1980	0.4897		1	-1	-3.4	26.04
c.706G>T	A236S 2D AIThe SynGAP1 A236S variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Predictions that are inconclusive or uncertain are Rosetta, Foldetta, premPS, and ESM1b. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for A236S, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.185198	Structured	0.329926	Uncertain	0.775	0.330	0.000											-7.845	In-Between	0.106	Likely Benign	Likely Benign	0.40	Likely Benign	0.5	1.24	Ambiguous	0.82	Ambiguous	0.65	Ambiguous	0.648	Likely Pathogenic	-2.30	Neutral	0.948	Possibly Damaging	0.588	Possibly Damaging	5.83	Benign	0.13	Tolerated			0.2641	0.5547		1	1	-2.6	16.00
c.707C>A	A236E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A236E is not reported in ClinVar and is present in gnomAD (ID 6‑33435558‑C‑A). Functional prediction tools show a split assessment: benign calls come from FATHMM, Rosetta, and the protein‑folding stability method Foldetta; pathogenic calls come from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. When grouped by agreement, the benign‑predicting tools (FATHMM, Rosetta, Foldetta) represent one consensus, while the pathogenic‑predicting tools (REVEL, premPS, PROVEAN, polyPhen‑2, SIFT, ESM1b, AlphaMissense‑Default, SGM‑Consensus) form the opposing consensus. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain; SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely pathogenic; Foldetta, combining FoldX‑MD and Rosetta outputs, is benign. Overall, the majority of predictions lean toward pathogenicity, and this does not contradict the ClinVar status, which has no reported classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.185198	Structured	0.329926	Uncertain	0.775	0.330	0.000								6-33435558-C-A	1	6.20e-7	-10.844	Likely Pathogenic	0.835	Likely Pathogenic	Ambiguous	-0.75	Ambiguous	0.2	0.28	Likely Benign	-0.24	Likely Benign	1.08	Destabilizing	0.844	Likely Pathogenic	-4.24	Deleterious	0.998	Probably Damaging	0.900	Possibly Damaging	6.06	Benign	0.02	Affected	3.40	14	0.1075	0.1970		-1	0	-5.3	58.04
c.707C>G	A236G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A236G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, premPS, and PROVEAN. Four tools (FoldX, Rosetta, Foldetta, and ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign, while Foldetta remains uncertain. Overall, the majority of available predictions support a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.185198	Structured	0.329926	Uncertain	0.775	0.330	0.000											-7.412	In-Between	0.162	Likely Benign	Likely Benign	0.92	Ambiguous	0.1	1.15	Ambiguous	1.04	Ambiguous	1.09	Destabilizing	0.615	Likely Pathogenic	-3.35	Deleterious	0.067	Benign	0.028	Benign	5.74	Benign	0.07	Tolerated			0.2200	0.3899		1	0	-2.2	-14.03
c.707C>T	A236V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A236V is listed in ClinVar as Benign (ID 469162.0) and is present in gnomAD (6‑33435558‑C‑T). Prediction tools that report benign include polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, and ESM1b. Four tools give uncertain or inconclusive results: FoldX, Rosetta, Foldetta, and premPS. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because the votes are evenly split. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as uncertain, and the SGM Consensus as unavailable. Consequently, the overall prediction profile is mixed, but the most reliable high‑accuracy evidence points toward a benign effect. Therefore, the variant is most likely benign, which aligns with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.185198	Structured	0.329926	Uncertain	0.775	0.330	0.000					Benign/Likely benign		2	6-33435558-C-T	6	3.72e-6	-8.752	Likely Pathogenic	0.267	Likely Benign	Likely Benign	0.61	Ambiguous	0.2	1.08	Ambiguous	0.85	Ambiguous	0.64	Ambiguous	0.777	Likely Pathogenic	-3.55	Deleterious	0.981	Probably Damaging	0.446	Benign	5.79	Benign	0.03	Affected	3.40	14	0.0913	0.5859		0	0	2.4	28.05	213.8	-44.7	0.0	0.0	-0.2	0.2						X		Potentially Benign	The methyl side chain of Ala236, located on an α helix (residues Ala236-Val250) facing an anti-parallel β sheet strand (residues Ile205-Val209), interacts hydrophobically with nearby residues such as Arg239 and Phe218. In the variant simulations, the isopropyl branched hydrocarbon side chain of Val236 maintains similar hydrophobic interactions as alanine in the WT, with an overall arrangement remarkably similar to Ala236. The residue swap does not affect the protein structure based on the simulations.
c.709G>A	A237T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A237T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 (HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv), and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) return uncertain results. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split; Foldetta also yields an inconclusive stability assessment. Overall, the majority of evidence leans toward a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.200174	Structured	0.334699	Uncertain	0.719	0.352	0.000											-8.664	Likely Pathogenic	0.213	Likely Benign	Likely Benign	0.74	Ambiguous	0.3	0.55	Ambiguous	0.65	Ambiguous	0.71	Ambiguous	0.539	Likely Pathogenic	-2.66	Deleterious	0.900	Possibly Damaging	0.348	Benign	5.80	Benign	0.06	Tolerated			0.0975	0.5737		1	0	-2.5	30.03
c.709G>C	A237P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, Rosetta, and Foldetta. High‑accuracy assessments further support pathogenicity: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, Foldetta is pathogenic, and AlphaMissense‑Optimized is uncertain (treated as unavailable). Overall, the preponderance of evidence indicates that A237P is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar status is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.200174	Structured	0.334699	Uncertain	0.719	0.352	0.000											-9.119	Likely Pathogenic	0.827	Likely Pathogenic	Ambiguous	0.10	Likely Benign	0.5	4.20	Destabilizing	2.15	Destabilizing	1.04	Destabilizing	0.752	Likely Pathogenic	-3.68	Deleterious	0.995	Probably Damaging	0.832	Possibly Damaging	5.77	Benign	0.03	Affected			0.1593	0.3724		1	-1	-3.4	26.04
c.709G>T	A237S 2D AIThe SynGAP1 missense variant A237S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and FATHMM. No tool predicts a pathogenic outcome; the only inconclusive results come from premPS and ESM1b, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.200174	Structured	0.334699	Uncertain	0.719	0.352	0.000											-7.696	In-Between	0.112	Likely Benign	Likely Benign	0.48	Likely Benign	0.6	0.34	Likely Benign	0.41	Likely Benign	0.61	Ambiguous	0.421	Likely Benign	-1.41	Neutral	0.259	Benign	0.048	Benign	5.82	Benign	0.31	Tolerated			0.2209	0.4357		1	1	-2.6	16.00
c.70G>A	V24I 2D AIThe SynGAP1 missense variant V24I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33423479-G-A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, the overwhelming majority of computational evidence supports a benign impact for V24I, and this conclusion does not contradict the ClinVar designation, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438970	Uncertain	0.382	0.890	0.500					Uncertain		1	6-33423479-G-A	9	5.58e-6	-3.701	Likely Benign	0.137	Likely Benign	Likely Benign										0.069	Likely Benign	-0.25	Neutral	0.043	Benign	0.031	Benign	3.96	Benign	0.00	Affected	4.32	1	0.0844	0.4564		3	4	0.3	14.03
c.70G>C	V24L 2D AIThe SynGAP1 missense variant V24L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for V24L, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438970	Uncertain	0.382	0.890	0.500											-2.590	Likely Benign	0.320	Likely Benign	Likely Benign										0.053	Likely Benign	-0.62	Neutral	0.043	Benign	0.011	Benign	3.94	Benign	0.00	Affected			0.1102	0.5226		2	1	-0.4	14.03
c.70G>T	V24L 2D AIThe SynGAP1 missense variant V24L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for V24L, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438970	Uncertain	0.382	0.890	0.500											-2.590	Likely Benign	0.320	Likely Benign	Likely Benign										0.053	Likely Benign	-0.62	Neutral	0.043	Benign	0.011	Benign	3.94	Benign	0.00	Affected			0.1102	0.5226		2	1	-0.4	14.03
c.710C>A	A237D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237D is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining tools—SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict pathogenicity. Two tools, FoldX and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support a deleterious impact: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenicity, AlphaMissense‑Optimized is uncertain, and Foldetta predicts a destabilizing, pathogenic effect. Overall, the evidence overwhelmingly indicates that the variant is pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.200174	Structured	0.334699	Uncertain	0.719	0.352	0.000											-8.880	Likely Pathogenic	0.921	Likely Pathogenic	Ambiguous	1.23	Ambiguous	0.4	3.49	Destabilizing	2.36	Destabilizing	1.20	Destabilizing	0.769	Likely Pathogenic	-3.97	Deleterious	0.969	Probably Damaging	0.704	Possibly Damaging	5.88	Benign	0.05	Affected			0.1419	0.2302		0	-2	-5.3	44.01
c.710C>G	A237G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237G is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Given the balance of evidence, the majority of high‑confidence predictions lean toward a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.200174	Structured	0.334699	Uncertain	0.719	0.352	0.000											-6.647	Likely Benign	0.316	Likely Benign	Likely Benign	1.00	Ambiguous	0.0	2.01	Destabilizing	1.51	Ambiguous	1.14	Destabilizing	0.538	Likely Pathogenic	-2.91	Deleterious	0.900	Possibly Damaging	0.430	Benign	5.81	Benign	0.05	Affected			0.1809	0.2910		1	0	-2.2	-14.03
c.710C>T	A237V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237V is not reported in ClinVar and is absent from gnomAD. Standard in‑silico predictors are divided: benign calls come from premPS, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 HumDiv, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) are uncertain. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a pathogenic outcome from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain result from Foldetta. Because the majority of conventional predictors and the optimized AlphaMissense model favor benign, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.200174	Structured	0.334699	Uncertain	0.719	0.352	0.000											-8.927	Likely Pathogenic	0.397	Ambiguous	Likely Benign	0.87	Ambiguous	0.4	0.97	Ambiguous	0.92	Ambiguous	0.18	Likely Benign	0.565	Likely Pathogenic	-3.26	Deleterious	0.900	Possibly Damaging	0.430	Benign	5.87	Benign	0.10	Tolerated			0.0771	0.4853		0	0	2.4	28.05
c.712G>A	E238K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238K missense change is not reported in ClinVar and is absent from gnomAD. In silico predictors cluster into two groups: a single benign call from FATHMM, and a consensus of pathogenic predictions from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are not considered evidence. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, while Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E238K. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.194234	Structured	0.332638	Uncertain	0.796	0.326	0.000											-13.475	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.56	Ambiguous	0.4	1.83	Ambiguous	1.20	Ambiguous	0.83	Ambiguous	0.858	Likely Pathogenic	-3.63	Deleterious	0.995	Probably Damaging	0.695	Possibly Damaging	5.46	Benign	0.01	Affected	4.29	391	0.2812	0.5524		0	1	-0.4	-0.94	209.0	55.9	0.0	0.0	-0.1	0.0		X						Potentially Pathogenic	The negatively charged residue Glu238, located in an α helix (res. Ala236-Val250), is replaced by the positively charged residue Lys238. This charge reversal removes the periodically formed salt bridge between the carboxylate group of Glu238 and the guanidinium group of Arg234 observed in the WT simulations. In the variant simulations, both Lys238 and Arg234 form alternative salt bridges with the carboxylate group of Glu680 in the GAP domain loop. Although not visible in the simulations, the absence of the Glu238-Arg234 salt bridge could weaken the integrity of the α helix (residues Ala236-Val250) and potentially affect the tertiary assembly between the PH and GAP domains.
c.712G>C	E238Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two consensus groups: benign predictions come from SIFT and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Stability‑based methods (FoldX, Rosetta, premPS) and Foldetta give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.194234	Structured	0.332638	Uncertain	0.796	0.326	0.000											-11.476	Likely Pathogenic	0.986	Likely Pathogenic	Likely Pathogenic	0.63	Ambiguous	0.5	0.59	Ambiguous	0.61	Ambiguous	0.52	Ambiguous	0.723	Likely Pathogenic	-2.72	Deleterious	0.996	Probably Damaging	0.891	Possibly Damaging	5.44	Benign	0.06	Tolerated			0.1372	0.5412		2	2	0.0	-0.98
c.713A>C	E238A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E238A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: FATHMM predicts benign, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. Four methods (FoldX, Rosetta, Foldetta, premPS) return uncertain results and are treated as unavailable. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta is uncertain. Overall, the preponderance of evidence indicates that E238A is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.194234	Structured	0.332638	Uncertain	0.796	0.326	0.000											-13.252	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	0.91	Ambiguous	0.3	1.89	Ambiguous	1.40	Ambiguous	0.57	Ambiguous	0.879	Likely Pathogenic	-5.44	Deleterious	0.970	Probably Damaging	0.681	Possibly Damaging	5.44	Benign	0.04	Affected			0.4164	0.5610		0	-1	5.3	-58.04
c.713A>G	E238G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E238G is reported in gnomAD (variant ID 6‑33435564‑A‑G) but has no entry in ClinVar. Functional prediction tools largely agree on a deleterious effect: the benign‑predicting tool FATHMM is the only one that classifies it as benign, whereas the pathogenic‑predicting tools (REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Pathogenic” call) all predict a harmful impact. Predictions of uncertain status (FoldX, premPS) are treated as unavailable. High‑accuracy assessments reinforce the pathogenic view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among high‑confidence tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.194234	Structured	0.332638	Uncertain	0.796	0.326	0.000								6-33435564-A-G	1	6.19e-7	-12.582	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	1.09	Ambiguous	0.2	3.42	Destabilizing	2.26	Destabilizing	0.87	Ambiguous	0.889	Likely Pathogenic	-6.35	Deleterious	0.970	Probably Damaging	0.607	Possibly Damaging	5.39	Benign	0.00	Affected	3.40	14	0.3137	0.4833		-2	0	3.1	-72.06
c.713A>T	E238V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E238V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E238V. This conclusion is not contradicted by ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.194234	Structured	0.332638	Uncertain	0.796	0.326	0.000											-14.329	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.88	Ambiguous	0.4	0.75	Ambiguous	0.82	Ambiguous	0.45	Likely Benign	0.890	Likely Pathogenic	-6.35	Deleterious	0.997	Probably Damaging	0.879	Possibly Damaging	5.42	Benign	0.00	Affected			0.0848	0.6093		-2	-2	7.7	-29.98
c.714A>C	E238D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; the remaining methods (FoldX, Rosetta, Foldetta, premPS, ESM1b) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. The variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.194234	Structured	0.332638	Uncertain	0.796	0.326	0.000											-7.861	In-Between	0.995	Likely Pathogenic	Likely Pathogenic	1.25	Ambiguous	0.4	1.72	Ambiguous	1.49	Ambiguous	0.78	Ambiguous	0.691	Likely Pathogenic	-2.72	Deleterious	0.868	Possibly Damaging	0.504	Possibly Damaging	5.57	Benign	0.05	Affected			0.1975	0.3619		3	2	0.0	-14.03
c.714A>T	E238D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; the remaining methods (FoldX, Rosetta, Foldetta, premPS, ESM1b) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. The variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.194234	Structured	0.332638	Uncertain	0.796	0.326	0.000											-7.861	In-Between	0.995	Likely Pathogenic	Likely Pathogenic	1.25	Ambiguous	0.4	1.72	Ambiguous	1.49	Ambiguous	0.78	Ambiguous	0.691	Likely Pathogenic	-2.72	Deleterious	0.868	Possibly Damaging	0.504	Possibly Damaging	5.57	Benign	0.05	Affected			0.1975	0.3619		3	2	0.0	-14.03
c.715A>G	R239G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239G missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining twelve tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.170161	Structured	0.336504	Uncertain	0.854	0.319	0.000											-12.133	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	4.05	Destabilizing	0.1	3.41	Destabilizing	3.73	Destabilizing	1.33	Destabilizing	0.912	Likely Pathogenic	-6.26	Deleterious	0.982	Probably Damaging	0.533	Possibly Damaging	5.62	Benign	0.02	Affected			0.3415	0.3154		-3	-2	4.1	-99.14
c.716G>A	R239K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239K missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM, while the majority of other in silico predictors (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default) indicate a pathogenic impact. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Because uncertain or unavailable results are not taken as evidence for or against pathogenicity, the overall evidence still leans toward a deleterious effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.170161	Structured	0.336504	Uncertain	0.854	0.319	0.000											-12.492	Likely Pathogenic	0.897	Likely Pathogenic	Ambiguous	1.93	Ambiguous	0.2	1.62	Ambiguous	1.78	Ambiguous	1.41	Destabilizing	0.719	Likely Pathogenic	-2.52	Deleterious	0.882	Possibly Damaging	0.428	Benign	5.78	Benign	0.03	Affected			0.5222	0.4000	Weaken	3	2	0.6	-28.01
c.716G>C	R239T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R239T is recorded in gnomAD (ID 6‑33435567‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions arise from REVEL, Rosetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX reports an uncertain effect and is therefore not considered. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Consequently, the variant is most likely pathogenic according to the available computational evidence, and this assessment does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.170161	Structured	0.336504	Uncertain	0.854	0.319	0.000								6-33435567-G-C	1	6.19e-7	-14.792	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.96	Ambiguous	0.3	2.44	Destabilizing	2.20	Destabilizing	1.21	Destabilizing	0.869	Likely Pathogenic	-5.35	Deleterious	0.259	Benign	0.064	Benign	5.66	Benign	0.01	Affected	3.40	14	0.1805	0.4414		-1	-1	3.8	-55.08
c.716G>T	R239I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R239I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.170161	Structured	0.336504	Uncertain	0.854	0.319	0.000											-19.414	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.32	Destabilizing	0.5	2.53	Destabilizing	3.43	Destabilizing	0.83	Ambiguous	0.890	Likely Pathogenic	-7.16	Deleterious	0.985	Probably Damaging	0.724	Possibly Damaging	5.69	Benign	0.00	Affected			0.1480	0.3985		-2	-3	9.0	-43.03
c.717A>C	R239S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.170161	Structured	0.336504	Uncertain	0.854	0.319	0.000											-13.418	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.67	Destabilizing	0.1	2.94	Destabilizing	3.31	Destabilizing	1.26	Destabilizing	0.813	Likely Pathogenic	-5.31	Deleterious	0.900	Possibly Damaging	0.376	Benign	5.64	Benign	0.02	Affected			0.3160	0.3788		0	-1	3.7	-69.11
c.717A>T	R239S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.170161	Structured	0.336504	Uncertain	0.854	0.319	0.000											-13.418	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.67	Destabilizing	0.1	2.94	Destabilizing	3.31	Destabilizing	1.26	Destabilizing	0.813	Likely Pathogenic	-5.31	Deleterious	0.900	Possibly Damaging	0.376	Benign	5.64	Benign	0.02	Affected			0.3160	0.3788		0	-1	3.7	-69.11
c.718G>A	D240N 2D AIThe SynGAP1 missense variant D240N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Benign predictions are provided by FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. High‑accuracy methods give a split: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts pathogenic, and Foldetta predicts benign. Overall, the majority of tools favor a benign effect, and this consensus does not contradict the ClinVar uncertain status. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.343480	Uncertain	0.822	0.333	0.000					Uncertain		1				-12.942	Likely Pathogenic	0.755	Likely Pathogenic	Likely Benign	0.22	Likely Benign	0.9	0.47	Likely Benign	0.35	Likely Benign	0.37	Likely Benign	0.701	Likely Pathogenic	-4.37	Deleterious	0.993	Probably Damaging	0.984	Probably Damaging	5.88	Benign	0.01	Affected			0.0993	0.4973		2	1	0.0	-0.98
c.718G>C	D240H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240H missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy methods give a pathogenic verdict: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the consensus of the available predictions indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.343480	Uncertain	0.822	0.333	0.000											-14.551	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	1.14	Ambiguous	0.0	0.61	Ambiguous	0.88	Ambiguous	0.19	Likely Benign	0.865	Likely Pathogenic	-6.12	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	5.78	Benign	0.00	Affected			0.1223	0.5398		1	-1	0.3	22.05
c.718G>T	D240Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240Y missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, premPS, and FATHMM; pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore not considered evidence. Taken together, the overwhelming majority of reliable predictors indicate a pathogenic effect for D240Y. This conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.343480	Uncertain	0.822	0.333	0.000											-16.890	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	0.29	Likely Benign	0.3	1.07	Ambiguous	0.68	Ambiguous	-0.01	Likely Benign	0.899	Likely Pathogenic	-7.90	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	5.77	Benign	0.00	Affected			0.0439	0.4932		-4	-3	2.2	48.09
c.719A>C	D240A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are premPS and FATHMM, while the remaining pathogenic‑predicting tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently flag the variant as deleterious. Tools with uncertain outcomes (FoldX, Rosetta, Foldetta) provide no definitive guidance. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.343480	Uncertain	0.822	0.333	0.000											-12.935	Likely Pathogenic	0.980	Likely Pathogenic	Likely Pathogenic	0.75	Ambiguous	0.1	0.99	Ambiguous	0.87	Ambiguous	0.22	Likely Benign	0.872	Likely Pathogenic	-7.03	Deleterious	0.998	Probably Damaging	0.991	Probably Damaging	5.80	Benign	0.05	Affected			0.3317	0.4992		0	-2	5.3	-44.01
c.719A>G	D240G 2D AIThe SynGAP1 missense variant D240G is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Benign predictions are provided by premPS and FATHMM, whereas pathogenic predictions are made by REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. FoldX‑MD is inconclusive, and AlphaMissense‑Optimized is uncertain. High‑accuracy methods show that AlphaMissense‑Optimized is inconclusive, SGM Consensus predicts pathogenic, and Foldetta predicts pathogenic. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.343480	Uncertain	0.822	0.333	0.000					Uncertain		1				-12.825	Likely Pathogenic	0.951	Likely Pathogenic	Ambiguous	1.85	Ambiguous	0.1	2.72	Destabilizing	2.29	Destabilizing	0.24	Likely Benign	0.912	Likely Pathogenic	-6.19	Deleterious	0.993	Probably Damaging	0.984	Probably Damaging	5.79	Benign	0.01	Affected			0.3474	0.4989		1	-1	3.1	-58.04
c.719A>T	D240V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, FATHMM, and premPS, whereas the majority of algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score—classify the change as pathogenic or likely pathogenic. FoldX and Foldetta return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for D240V. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.343480	Uncertain	0.822	0.333	0.000											-15.095	Likely Pathogenic	0.986	Likely Pathogenic	Likely Pathogenic	1.32	Ambiguous	0.1	0.28	Likely Benign	0.80	Ambiguous	0.11	Likely Benign	0.894	Likely Pathogenic	-7.94	Deleterious	0.998	Probably Damaging	0.994	Probably Damaging	5.82	Benign	0.00	Affected			0.0610	0.4949		-2	-3	7.7	-15.96
c.71T>A	V24E 2D AIThe SynGAP1 missense variant V24E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, the SGM‑Consensus also indicates Likely Benign, and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438970	Uncertain	0.382	0.890	0.500											-3.397	Likely Benign	0.517	Ambiguous	Likely Benign										0.171	Likely Benign	-1.73	Neutral	0.198	Benign	0.074	Benign	3.77	Benign	0.00	Affected			0.1133	0.2415		-2	-2	-7.7	29.98
c.71T>C	V24A 2D AIThe SynGAP1 missense variant V24A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only SIFT predicts pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign impact for V24A. This prediction is consistent with the lack of ClinVar evidence and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438970	Uncertain	0.382	0.890	0.500											-2.980	Likely Benign	0.299	Likely Benign	Likely Benign										0.074	Likely Benign	-1.09	Neutral	0.000	Benign	0.001	Benign	3.83	Benign	0.00	Affected			0.3117	0.3350		0	0	-2.4	-28.05
c.71T>G	V24G 2D AIThe SynGAP1 missense variant V24G is not reported in ClinVar (ClinVar status: not present) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.			0.541878	Disordered	0.438970	Uncertain	0.382	0.890	0.500											-2.673	Likely Benign	0.256	Likely Benign	Likely Benign										0.178	Likely Benign	-1.67	Neutral	0.026	Benign	0.049	Benign	3.77	Benign	0.00	Affected			0.2081	0.3105		-1	-3	-4.6	-42.08
c.720C>A	D240E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240E missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated predictors (seven pathogenic vs. four benign) lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.343480	Uncertain	0.822	0.333	0.000											-8.619	Likely Pathogenic	0.796	Likely Pathogenic	Ambiguous	0.49	Likely Benign	0.1	0.51	Ambiguous	0.50	Ambiguous	0.28	Likely Benign	0.713	Likely Pathogenic	-3.43	Deleterious	0.984	Probably Damaging	0.967	Probably Damaging	5.84	Benign	0.10	Tolerated			0.1155	0.5066		3	2	0.0	14.03
c.720C>G	D240E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D240E is a missense change in the PH domain. No ClinVar entry exists for this variant, and it is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from SIFT, FoldX, premPS, and FATHMM, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—AlphaMissense‑Optimized, Rosetta, and Foldetta—are treated as unavailable. High‑accuracy assessments show the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifying the variant as Likely Pathogenic, whereas AlphaMissense‑Optimized and Foldetta provide no definitive verdict. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.343480	Uncertain	0.822	0.333	0.000											-8.619	Likely Pathogenic	0.796	Likely Pathogenic	Ambiguous	0.49	Likely Benign	0.1	0.51	Ambiguous	0.50	Ambiguous	0.28	Likely Benign	0.713	Likely Pathogenic	-3.43	Deleterious	0.984	Probably Damaging	0.967	Probably Damaging	5.84	Benign	0.10	Tolerated			0.1155	0.5066		3	2	0.0	14.03
c.721A>C	K241Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K241Q missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, FATHMM, and Foldetta, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, nine tools predict pathogenicity versus four predicting benign, with no ClinVar evidence to contradict these findings. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.196879	Structured	0.349250	Uncertain	0.797	0.347	0.000											-10.593	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	0.33	Likely Benign	0.0	0.46	Likely Benign	0.40	Likely Benign	0.63	Ambiguous	0.767	Likely Pathogenic	-3.33	Deleterious	0.995	Probably Damaging	0.914	Probably Damaging	5.83	Benign	0.04	Affected			0.4225	0.1527		1	1	0.4	-0.04
c.721A>G	K241E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K241E missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include SIFT and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.196879	Structured	0.349250	Uncertain	0.797	0.347	0.000											-12.582	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.75	Ambiguous	0.1	1.36	Ambiguous	1.06	Ambiguous	0.68	Ambiguous	0.878	Likely Pathogenic	-3.43	Deleterious	0.982	Probably Damaging	0.679	Possibly Damaging	6.00	Benign	0.10	Tolerated			0.3610	0.1179		0	1	0.4	0.94
c.722A>C	K241T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are reported by Rosetta and FATHMM. Two tools (Foldetta and premPS) give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta remains uncertain. Overall, the consensus of the majority of evidence points to a pathogenic effect for K241T, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.196879	Structured	0.349250	Uncertain	0.797	0.347	0.000											-10.911	Likely Pathogenic	0.987	Likely Pathogenic	Likely Pathogenic	2.00	Destabilizing	0.4	0.06	Likely Benign	1.03	Ambiguous	0.60	Ambiguous	0.853	Likely Pathogenic	-5.14	Deleterious	0.995	Probably Damaging	0.747	Possibly Damaging	5.74	Benign	0.03	Affected			0.2021	0.3951		0	-1	3.2	-27.07
c.722A>G	K241R 2D AIThe SynGAP1 missense variant K241R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.196879	Structured	0.349250	Uncertain	0.797	0.347	0.000											-4.615	Likely Benign	0.444	Ambiguous	Likely Benign	-0.23	Likely Benign	0.5	-0.03	Likely Benign	-0.13	Likely Benign	0.43	Likely Benign	0.602	Likely Pathogenic	-2.12	Neutral	0.982	Probably Damaging	0.679	Possibly Damaging	5.89	Benign	0.14	Tolerated			0.4571	0.1242		3	2	-0.6	28.01
c.722A>T	K241I 2D 3DClick to see structure in 3D Viewer AISynGAP1 K241I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta, premPS, and FATHMM. Those that predict a damaging effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX and Foldetta return uncertain results. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized reports pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta remains inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.196879	Structured	0.349250	Uncertain	0.797	0.347	0.000											-14.370	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	1.31	Ambiguous	0.5	0.28	Likely Benign	0.80	Ambiguous	0.41	Likely Benign	0.852	Likely Pathogenic	-6.96	Deleterious	0.985	Probably Damaging	0.704	Possibly Damaging	5.71	Benign	0.01	Affected			0.1176	0.3868		-2	-3	8.4	-15.01
c.723A>C	K241N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.196879	Structured	0.349250	Uncertain	0.797	0.347	0.000											-10.198	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.92	Ambiguous	0.1	1.13	Ambiguous	1.03	Ambiguous	0.89	Ambiguous	0.663	Likely Pathogenic	-4.23	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	5.81	Benign	0.03	Affected			0.3426	0.1872		1	0	0.4	-14.07
c.723A>T	K241N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported for FoldX, Rosetta, Foldetta, and premPS and are not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.196879	Structured	0.349250	Uncertain	0.797	0.347	0.000											-10.198	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.92	Ambiguous	0.1	1.13	Ambiguous	1.03	Ambiguous	0.89	Ambiguous	0.663	Likely Pathogenic	-4.23	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	5.81	Benign	0.03	Affected			0.3426	0.1872		1	0	0.4	-14.07
c.724T>A	W242R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant W242R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess evolutionary conservation and protein function uniformly indicate a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Consequently, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.328603	Structured	0.352582	Uncertain	0.847	0.341	0.000											-11.948	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.85	Ambiguous	0.5	1.15	Ambiguous	1.00	Ambiguous	1.34	Destabilizing	0.859	Likely Pathogenic	-12.71	Deleterious	0.995	Probably Damaging	0.854	Possibly Damaging	1.52	Pathogenic	0.00	Affected	3.40	14	0.4206	0.0771		-3	2	-3.6	-30.03
c.724T>C	W242R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242R is reported in gnomAD (ID 6‑33435575‑T‑C) but has no ClinVar entry. Across the evaluated predictors, every tool that provides a definitive call classifies the substitution as pathogenic: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No predictor reports a benign effect. FoldX, Rosetta, and Foldetta return uncertain results and are treated as unavailable evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta remains inconclusive. Consequently, the variant is most likely pathogenic based on the consensus of pathogenic predictions, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.328603	Structured	0.352582	Uncertain	0.847	0.341	0.000								6-33435575-T-C	2	1.24e-6	-11.948	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.85	Ambiguous	0.5	1.15	Ambiguous	1.00	Ambiguous	1.34	Destabilizing	0.858	Likely Pathogenic	-12.71	Deleterious	0.995	Probably Damaging	0.854	Possibly Damaging	1.52	Pathogenic	0.00	Affected	3.40	14	0.4206	0.0771		-3	2	-3.6	-30.03
c.724T>G	W242G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD, so no population frequency data are available. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the single uncertain call from premPS is treated as unavailable. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.328603	Structured	0.352582	Uncertain	0.847	0.341	0.000											-14.319	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	2.70	Destabilizing	0.3	2.48	Destabilizing	2.59	Destabilizing	0.83	Ambiguous	0.883	Likely Pathogenic	-11.80	Deleterious	0.900	Possibly Damaging	0.452	Possibly Damaging	1.52	Pathogenic	0.00	Affected			0.4378	0.1851		-7	-2	0.5	-129.16
c.725G>C	W242S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242S, located in the PH domain, is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy assessments further support a harmful impact: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic,” while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the consensus of available predictions indicates that W242S is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.328603	Structured	0.352582	Uncertain	0.847	0.341	0.000											-14.674	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.96	Ambiguous	0.2	1.97	Ambiguous	1.97	Ambiguous	0.83	Ambiguous	0.797	Likely Pathogenic	-12.71	Deleterious	0.900	Possibly Damaging	0.535	Possibly Damaging	1.52	Pathogenic	0.00	Affected			0.4424	0.1418		-2	-3	0.1	-99.14
c.725G>T	W242L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (FoldX, Rosetta, Foldetta, premPS) and pathogenic predictions (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Pathogenic). High‑accuracy assessments further support this dichotomy: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. Overall, the majority of evidence points toward a pathogenic impact for W242L. This conclusion is consistent with the absence of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.328603	Structured	0.352582	Uncertain	0.847	0.341	0.000											-12.297	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	-0.29	Likely Benign	0.3	0.12	Likely Benign	-0.09	Likely Benign	0.44	Likely Benign	0.799	Likely Pathogenic	-11.80	Deleterious	0.948	Possibly Damaging	0.533	Possibly Damaging	1.52	Pathogenic	0.01	Affected			0.2370	0.2986		-2	-2	4.7	-73.05
c.726G>C	W242C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 W242C missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS, and no tools predict a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the collective predictions, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as ClinVar has not yet classified the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.328603	Structured	0.352582	Uncertain	0.847	0.341	0.000											-13.117	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.77	Ambiguous	0.4	1.62	Ambiguous	1.70	Ambiguous	0.63	Ambiguous	0.889	Likely Pathogenic	-11.80	Deleterious	0.999	Probably Damaging	0.887	Possibly Damaging	1.52	Pathogenic	0.00	Affected			0.3626	0.1617		-8	-2	3.4	-83.07
c.726G>T	W242C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS, and no tools predict a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the collective predictions, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as ClinVar has not yet classified the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.328603	Structured	0.352582	Uncertain	0.847	0.341	0.000											-13.117	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.77	Ambiguous	0.4	1.62	Ambiguous	1.70	Ambiguous	0.63	Ambiguous	0.889	Likely Pathogenic	-11.80	Deleterious	0.999	Probably Damaging	0.887	Possibly Damaging	1.52	Pathogenic	0.00	Affected			0.3626	0.1617		-8	-2	3.4	-83.07
c.727A>C	I243L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I243L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from AlphaMissense‑Default and ESM1b, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields benign; and Foldetta also predicts benign. Overall, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.363090	Structured	0.344471	Uncertain	0.842	0.347	0.000											-7.890	In-Between	0.524	Ambiguous	Likely Benign	-0.03	Likely Benign	0.2	-0.35	Likely Benign	-0.19	Likely Benign	0.32	Likely Benign	0.380	Likely Benign	-0.33	Neutral	0.048	Benign	0.039	Benign	5.74	Benign	0.19	Tolerated			0.0626	0.2891		2	2	-0.7	0.00
c.727A>G	I243V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243V is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. FoldX and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.363090	Structured	0.344471	Uncertain	0.842	0.347	0.000											-8.237	Likely Pathogenic	0.314	Likely Benign	Likely Benign	1.09	Ambiguous	0.1	0.19	Likely Benign	0.64	Ambiguous	0.39	Likely Benign	0.445	Likely Benign	-0.39	Neutral	0.617	Possibly Damaging	0.140	Benign	5.71	Benign	0.15	Tolerated			0.1019	0.2591		4	3	-0.3	-14.03
c.727A>T	I243F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I243F missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give inconclusive results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus unavailable; Foldetta is uncertain. Overall, the majority of available predictions (7 pathogenic vs. 3 benign) indicate a likely pathogenic impact. This assessment does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.363090	Structured	0.344471	Uncertain	0.842	0.347	0.000											-12.559	Likely Pathogenic	0.934	Likely Pathogenic	Ambiguous	2.92	Destabilizing	2.5	0.53	Ambiguous	1.73	Ambiguous	0.42	Likely Benign	0.793	Likely Pathogenic	-2.21	Neutral	0.985	Probably Damaging	0.724	Possibly Damaging	5.53	Benign	0.02	Affected			0.0409	0.2205		1	0	-1.7	34.02
c.728T>A	I243N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant I243N is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into three groups: benign (FATHMM), pathogenic (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized), and uncertain (FoldX, Rosetta, Foldetta). High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.363090	Structured	0.344471	Uncertain	0.842	0.347	0.000											-14.784	Likely Pathogenic	0.988	Likely Pathogenic	Likely Pathogenic	1.90	Ambiguous	0.2	1.43	Ambiguous	1.67	Ambiguous	1.76	Destabilizing	0.811	Likely Pathogenic	-4.46	Deleterious	0.995	Probably Damaging	0.854	Possibly Damaging	5.49	Benign	0.00	Affected			0.0899	0.0212		-2	-3	-8.0	0.94
c.728T>C	I243T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all classify the variant as pathogenic. Only FATHMM predicts a benign outcome, while Foldetta, AlphaMissense‑Optimized, and Rosetta return uncertain results, which are treated as unavailable evidence. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that I243T is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.363090	Structured	0.344471	Uncertain	0.842	0.347	0.000											-9.102	Likely Pathogenic	0.922	Likely Pathogenic	Ambiguous	2.15	Destabilizing	0.2	1.52	Ambiguous	1.84	Ambiguous	1.72	Destabilizing	0.816	Likely Pathogenic	-3.06	Deleterious	0.982	Probably Damaging	0.702	Possibly Damaging	5.55	Benign	0.01	Affected			0.1027	0.0541		0	-1	-5.2	-12.05
c.728T>G	I243S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.363090	Structured	0.344471	Uncertain	0.842	0.347	0.000											-14.097	Likely Pathogenic	0.975	Likely Pathogenic	Likely Pathogenic	2.52	Destabilizing	0.2	2.22	Destabilizing	2.37	Destabilizing	1.71	Destabilizing	0.802	Likely Pathogenic	-3.55	Deleterious	0.995	Probably Damaging	0.795	Possibly Damaging	5.52	Benign	0.00	Affected			0.2658	0.0600		-1	-2	-5.3	-26.08
c.729T>G	I243M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243M has no ClinVar entry (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign”; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign effect. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates that the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.363090	Structured	0.344471	Uncertain	0.842	0.347	0.000											-4.305	Likely Benign	0.175	Likely Benign	Likely Benign	0.09	Likely Benign	0.1	0.16	Likely Benign	0.13	Likely Benign	-0.01	Likely Benign	0.474	Likely Benign	0.58	Neutral	0.985	Probably Damaging	0.798	Possibly Damaging	5.61	Benign	0.94	Tolerated			0.0553	0.2200		2	1	-2.6	18.03
c.730G>A	E244K 2D AISynGAP1 missense variant E244K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from FoldX, Rosetta, Foldetta, SIFT, and FATHMM, whereas pathogenic predictions are reported by REVEL, PROVEAN, both polyPhen‑2 HumDiv and HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). The high‑accuracy methods give a clearer picture: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. With the majority of consensus tools leaning toward pathogenic and the two high‑accuracy pathogenic predictions outweighing the benign Foldetta result, the variant is most likely pathogenic. This assessment does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.450668	Structured	0.329406	Uncertain	0.778	0.360	0.000											-13.975	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.40	Likely Benign	1.0	0.45	Likely Benign	0.43	Likely Benign	0.80	Ambiguous	0.841	Likely Pathogenic	-3.37	Deleterious	0.990	Probably Damaging	0.760	Possibly Damaging	5.82	Benign	0.07	Tolerated			0.1887	0.6177		0	1	-0.4	-0.94
c.730G>C	E244Q 2D AIThe SynGAP1 E244Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, six tools predict pathogenicity versus five predicting benignity, with no ClinVar evidence to contradict these findings. Thus, the variant is most likely pathogenic based on the current predictive landscape. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.450668	Structured	0.329406	Uncertain	0.778	0.360	0.000											-10.245	Likely Pathogenic	0.928	Likely Pathogenic	Ambiguous	0.23	Likely Benign	0.9	-0.77	Ambiguous	-0.27	Likely Benign	0.40	Likely Benign	0.695	Likely Pathogenic	-2.49	Neutral	0.990	Probably Damaging	0.815	Possibly Damaging	5.78	Benign	0.05	Affected			0.1016	0.5610		2	2	0.0	-0.98
c.731A>C	E244A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244A missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, and FATHMM, while pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign stability. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.450668	Structured	0.329406	Uncertain	0.778	0.360	0.000											-11.227	Likely Pathogenic	0.969	Likely Pathogenic	Likely Pathogenic	0.39	Likely Benign	0.1	-0.45	Likely Benign	-0.03	Likely Benign	0.82	Ambiguous	0.865	Likely Pathogenic	-4.99	Deleterious	0.970	Probably Damaging	0.584	Possibly Damaging	5.74	Benign	0.01	Affected			0.2672	0.4926		0	-1	5.3	-58.04
c.731A>G	E244G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of computational evidence points to the variant being most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.450668	Structured	0.329406	Uncertain	0.778	0.360	0.000											-10.452	Likely Pathogenic	0.958	Likely Pathogenic	Likely Pathogenic	1.28	Ambiguous	0.0	0.74	Ambiguous	1.01	Ambiguous	1.01	Destabilizing	0.900	Likely Pathogenic	-5.67	Deleterious	0.990	Probably Damaging	0.815	Possibly Damaging	5.73	Benign	0.01	Affected			0.2266	0.5252		0	-2	3.1	-72.06
c.731A>T	E244V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244V missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.450668	Structured	0.329406	Uncertain	0.778	0.360	0.000											-12.118	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	1.04	Ambiguous	0.1	1.02	Ambiguous	1.03	Ambiguous	0.56	Ambiguous	0.925	Likely Pathogenic	-5.90	Deleterious	0.997	Probably Damaging	0.879	Possibly Damaging	5.68	Benign	0.00	Affected			0.0636	0.6073		-2	-2	7.7	-29.98
c.732G>C	E244D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic classification for E244D, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.450668	Structured	0.329406	Uncertain	0.778	0.360	0.000											-7.839	In-Between	0.979	Likely Pathogenic	Likely Pathogenic	0.46	Likely Benign	0.1	1.61	Ambiguous	1.04	Ambiguous	0.93	Ambiguous	0.730	Likely Pathogenic	-2.53	Deleterious	0.976	Probably Damaging	0.675	Possibly Damaging	5.78	Benign	0.03	Affected			0.1740	0.3783		3	2	0.0	-14.03
c.732G>T	E244D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results come from Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence points to a likely pathogenic effect for E244D, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.450668	Structured	0.329406	Uncertain	0.778	0.360	0.000											-7.839	In-Between	0.979	Likely Pathogenic	Likely Pathogenic	0.46	Likely Benign	0.1	1.61	Ambiguous	1.04	Ambiguous	0.93	Ambiguous	0.730	Likely Pathogenic	-2.53	Deleterious	0.976	Probably Damaging	0.675	Possibly Damaging	5.78	Benign	0.03	Affected			0.1740	0.3783		3	2	0.0	-14.03
c.733A>C	N245H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245H is not reported in ClinVar and is absent from gnomAD. Among in‑silico predictors, benign calls come from FoldX, Rosetta, and FATHMM, whereas pathogenic calls are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. The overall pattern of predictions leans toward pathogenicity, with a majority of tools indicating a deleterious effect. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.454136	Structured	0.315864	Uncertain	0.831	0.351	0.000											-11.536	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.23	Likely Benign	0.1	-0.20	Likely Benign	0.02	Likely Benign	0.55	Ambiguous	0.825	Likely Pathogenic	-4.15	Deleterious	0.995	Probably Damaging	0.880	Possibly Damaging	5.84	Benign	0.01	Affected			0.1437	0.7271		2	1	0.3	23.04
c.733A>G	N245D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, SIFT, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools, premPS and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions (six pathogenic vs five benign) and the consensus of high‑accuracy methods lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.454136	Structured	0.315864	Uncertain	0.831	0.351	0.000											-7.847	In-Between	0.998	Likely Pathogenic	Likely Pathogenic	0.27	Likely Benign	0.0	0.09	Likely Benign	0.18	Likely Benign	0.79	Ambiguous	0.712	Likely Pathogenic	-3.62	Deleterious	0.982	Probably Damaging	0.679	Possibly Damaging	5.84	Benign	0.13	Tolerated			0.1953	0.4599		2	1	0.0	0.98
c.733A>T	N245Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N245Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, and FATHMM, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a pathogenic majority (3/4). AlphaMissense‑Optimized independently predicts pathogenicity, while Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. premPS remains uncertain. Overall, the majority of evidence points toward a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Thus, the variant is most likely pathogenic, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.454136	Structured	0.315864	Uncertain	0.831	0.351	0.000											-12.476	Likely Pathogenic	0.982	Likely Pathogenic	Likely Pathogenic	-0.36	Likely Benign	0.1	0.11	Likely Benign	-0.13	Likely Benign	0.59	Ambiguous	0.855	Likely Pathogenic	-6.68	Deleterious	0.995	Probably Damaging	0.880	Possibly Damaging	5.86	Benign	0.00	Affected			0.0706	0.6771		-2	-2	2.2	49.07
c.734A>C	N245T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include FATHMM, Rosetta, and Foldetta, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support this dichotomy: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic, while Foldetta predicts a benign effect. No predictions are missing or inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for the variant, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.454136	Structured	0.315864	Uncertain	0.831	0.351	0.000											-11.955	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	0.52	Ambiguous	0.1	0.04	Likely Benign	0.28	Likely Benign	0.76	Ambiguous	0.794	Likely Pathogenic	-4.79	Deleterious	0.948	Possibly Damaging	0.588	Possibly Damaging	5.87	Benign	0.01	Affected			0.1397	0.7734		0	0	2.8	-13.00
c.734A>G	N245S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence (8 benign vs. 5 pathogenic) supports a benign classification. This conclusion does not contradict ClinVar, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.454136	Structured	0.315864	Uncertain	0.831	0.351	0.000											-6.792	Likely Benign	0.987	Likely Pathogenic	Likely Pathogenic	0.46	Likely Benign	0.1	-0.16	Likely Benign	0.15	Likely Benign	0.42	Likely Benign	0.524	Likely Pathogenic	-3.75	Deleterious	0.787	Possibly Damaging	0.404	Benign	5.90	Benign	0.07	Tolerated			0.3557	0.7229		1	1	2.7	-27.03
c.734A>T	N245I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245I is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include Rosetta, Foldetta, and FATHMM, while those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.454136	Structured	0.315864	Uncertain	0.831	0.351	0.000											-14.527	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	-0.56	Ambiguous	0.1	0.04	Likely Benign	-0.26	Likely Benign	0.60	Ambiguous	0.831	Likely Pathogenic	-7.46	Deleterious	0.995	Probably Damaging	0.832	Possibly Damaging	5.88	Benign	0.00	Affected			0.0672	0.6999		-2	-3	8.0	-0.94
c.735T>A	N245K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM, aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and yields a majority pathogenic verdict. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, classifies the variant as benign. Overall, the majority of individual predictors and the SGM consensus favor a pathogenic effect, while Foldetta and a subset of benign tools suggest stability preservation. Given the predominance of pathogenic predictions and the absence of ClinVar annotation, the variant is most likely pathogenic and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.454136	Structured	0.315864	Uncertain	0.831	0.351	0.000											-12.110	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	-0.32	Likely Benign	0.1	0.01	Likely Benign	-0.16	Likely Benign	0.83	Ambiguous	0.474	Likely Benign	-4.86	Deleterious	0.948	Possibly Damaging	0.588	Possibly Damaging	5.88	Benign	0.01	Affected			0.2271	0.5645		1	0	-0.4	14.07
c.735T>G	N245K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a Benign effect. Overall, the preponderance of evidence—including the high‑accuracy tools—points to a pathogenic impact for N245K, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.454136	Structured	0.315864	Uncertain	0.831	0.351	0.000											-12.110	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	-0.32	Likely Benign	0.1	0.01	Likely Benign	-0.16	Likely Benign	0.83	Ambiguous	0.474	Likely Benign	-4.86	Deleterious	0.948	Possibly Damaging	0.588	Possibly Damaging	5.88	Benign	0.01	Affected			0.2271	0.5645		1	0	-0.4	14.07
c.736C>A	L246M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L246M has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN and FATHMM, while a majority (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are uncertain. High‑accuracy methods are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Thus no high‑accuracy tool provides a definitive verdict. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any ClinVar status because no ClinVar record exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.472492	Structured	0.302312	Uncertain	0.859	0.364	0.000											-11.386	Likely Pathogenic	0.922	Likely Pathogenic	Ambiguous	0.65	Ambiguous	0.2	0.76	Ambiguous	0.71	Ambiguous	0.87	Ambiguous	0.661	Likely Pathogenic	-1.79	Neutral	0.997	Probably Damaging	0.916	Probably Damaging	4.72	Benign	0.01	Affected			0.0710	0.3511		4	2	-1.9	18.03
c.736C>G	L246V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L246V is reported in gnomAD (variant ID 6‑33435587‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Only FATHMM predicts a benign outcome. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. The overwhelming majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.472492	Structured	0.302312	Uncertain	0.859	0.364	0.000								6-33435587-C-G	1	6.20e-7	-12.092	Likely Pathogenic	0.935	Likely Pathogenic	Ambiguous	2.09	Destabilizing	0.1	1.52	Ambiguous	1.81	Ambiguous	1.13	Destabilizing	0.736	Likely Pathogenic	-2.60	Deleterious	0.930	Possibly Damaging	0.504	Possibly Damaging	4.71	Benign	0.01	Affected	3.41	14	0.1434	0.3607		1	2	0.4	-14.03
c.737T>A	L246Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L246Q missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; Rosetta is uncertain and is not grouped. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the overwhelming majority of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.472492	Structured	0.302312	Uncertain	0.859	0.364	0.000											-15.420	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	2.82	Destabilizing	0.3	1.79	Ambiguous	2.31	Destabilizing	1.69	Destabilizing	0.921	Likely Pathogenic	-5.43	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	4.67	Benign	0.00	Affected			0.1092	0.0758		-2	-2	-7.3	14.97
c.737T>C	L246P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L246P is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from FATHMM, while all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.472492	Structured	0.302312	Uncertain	0.859	0.364	0.000											-16.581	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	6.42	Destabilizing	0.3	8.72	Destabilizing	7.57	Destabilizing	1.79	Destabilizing	0.944	Likely Pathogenic	-6.30	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	4.67	Benign	0.00	Affected			0.3731	0.1582		-3	-3	-5.4	-16.04
c.737T>G	L246R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L246R missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.472492	Structured	0.302312	Uncertain	0.859	0.364	0.000											-13.849	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	3.94	Destabilizing	0.8	2.77	Destabilizing	3.36	Destabilizing	1.72	Destabilizing	0.925	Likely Pathogenic	-5.43	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	4.67	Benign	0.00	Affected			0.1266	0.0600		-3	-2	-8.3	43.03
c.739C>A	Q247K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247K (PH domain) is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are REVEL, polyPhen2_HumDiv, and ESM1b. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic). High‑accuracy methods all support benignity: AlphaMissense‑Optimized is benign, the SGM Consensus is benign, and Foldetta (combining FoldX‑MD and Rosetta) is benign. Uncertain results from AlphaMissense‑Default and Rosetta are treated as unavailable. Overall, the collective evidence points to a benign impact for Q247K, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.490133	Structured	0.283012	Uncertain	0.822	0.339	0.250											-10.377	Likely Pathogenic	0.502	Ambiguous	Likely Benign	-0.28	Likely Benign	0.1	0.74	Ambiguous	0.23	Likely Benign	-0.13	Likely Benign	0.529	Likely Pathogenic	-0.44	Neutral	0.787	Possibly Damaging	0.351	Benign	5.89	Benign	0.13	Tolerated			0.1366	0.2758		1	1	-0.4	0.04
c.739C>G	Q247E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Tools that predict a pathogenic effect are premPS, SIFT, and ESM1b. AlphaMissense‑Default is uncertain, while AlphaMissense‑Optimized predicts benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign consensus (2 benign vs. 1 pathogenic, with the uncertain result treated as unavailable). High‑accuracy assessments confirm benignity: AlphaMissense‑Optimized is benign, Foldetta (combining FoldX‑MD and Rosetta outputs) is benign, and the SGM Consensus is benign. Overall, the collective evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.490133	Structured	0.283012	Uncertain	0.822	0.339	0.250											-13.564	Likely Pathogenic	0.373	Ambiguous	Likely Benign	0.42	Likely Benign	0.1	-0.26	Likely Benign	0.08	Likely Benign	1.04	Destabilizing	0.474	Likely Benign	-1.46	Neutral	0.128	Benign	0.039	Benign	5.80	Benign	0.03	Affected			0.1055	0.1476		2	2	0.0	0.98
c.73C>G	R25G 2D AIThe SynGAP1 missense variant R25G is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. When high‑accuracy tools are considered separately, AlphaMissense‑Optimized predicts a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome, and Foldetta data are unavailable. Overall, the majority of robust predictors lean toward a benign interpretation. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.461924	Structured	0.438941	Uncertain	0.373	0.890	0.375											-3.533	Likely Benign	0.373	Ambiguous	Likely Benign										0.122	Likely Benign	-1.69	Neutral	0.686	Possibly Damaging	0.630	Possibly Damaging	3.95	Benign	0.00	Affected			0.3621	0.3572		-3	-2	4.1	-99.14
c.73C>T	R25W 2D AIThe SynGAP1 missense variant R25W is listed in ClinVar with an “Uncertain” status (ClinVar ID 2993054.0) and is present in gnomAD (ID 6‑33423482‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.461924	Structured	0.438941	Uncertain	0.373	0.890	0.375					Uncertain		2	6-33423482-C-T	6	3.72e-6	-5.133	Likely Benign	0.549	Ambiguous	Likely Benign										0.158	Likely Benign	-1.60	Neutral	0.994	Probably Damaging	0.919	Probably Damaging	3.92	Benign	0.00	Affected	4.32	1	0.1224	0.3938		-3	2	3.6	30.03
c.740A>C	Q247P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact; premPS is uncertain and therefore treated as unavailable. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.490133	Structured	0.283012	Uncertain	0.822	0.339	0.250											-14.361	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	3.43	Destabilizing	0.2	7.83	Destabilizing	5.63	Destabilizing	0.81	Ambiguous	0.770	Likely Pathogenic	-3.56	Deleterious	0.995	Probably Damaging	0.795	Possibly Damaging	5.69	Benign	0.02	Affected			0.1768	0.3631		0	-1	1.9	-31.01
c.740A>G	Q247R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Uncertain predictions come from premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing or inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy methods, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.490133	Structured	0.283012	Uncertain	0.822	0.339	0.250											-4.022	Likely Benign	0.442	Ambiguous	Likely Benign	-0.38	Likely Benign	0.0	0.21	Likely Benign	-0.09	Likely Benign	-0.91	Ambiguous	0.471	Likely Benign	1.22	Neutral	0.948	Possibly Damaging	0.533	Possibly Damaging	5.91	Benign	1.00	Tolerated			0.1196	0.1324		1	1	-1.0	28.06
c.740A>T	Q247L 2D AIThe SynGAP1 missense variant Q247L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence (seven pathogenic versus three benign predictions) points to a pathogenic impact, and this conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.490133	Structured	0.283012	Uncertain	0.822	0.339	0.250											-10.554	Likely Pathogenic	0.352	Ambiguous	Likely Benign	-0.86	Ambiguous	0.5	-1.14	Ambiguous	-1.00	Ambiguous	0.38	Likely Benign	0.687	Likely Pathogenic	-3.89	Deleterious	0.982	Probably Damaging	0.628	Possibly Damaging	5.70	Benign	0.02	Affected			0.0573	0.4129		-2	-2	7.3	-14.97
c.741G>C	Q247H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247H is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include SGM‑Consensus, FoldX, Rosetta, Foldetta, ESM1b, FATHMM, AlphaMissense‑Optimized, and PROVEAN. Tools that predict a pathogenic outcome are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No predictions are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.490133	Structured	0.283012	Uncertain	0.822	0.339	0.250											-6.239	Likely Benign	0.583	Likely Pathogenic	Likely Benign	0.37	Likely Benign	0.2	0.02	Likely Benign	0.20	Likely Benign	0.58	Ambiguous	0.579	Likely Pathogenic	-2.10	Neutral	0.995	Probably Damaging	0.854	Possibly Damaging	5.71	Benign	0.02	Affected			0.0932	0.2558		3	0	0.3	9.01
c.741G>T	Q247H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, ESM1b, FATHMM, AlphaMissense‑Optimized, and PROVEAN. Those that predict a pathogenic impact are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default, while premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as benign. No prediction or folding stability result is missing or inconclusive. Based on the overall balance of evidence—seven benign versus five pathogenic predictions, and all high‑accuracy tools indicating benign—the variant is most likely benign. This conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.490133	Structured	0.283012	Uncertain	0.822	0.339	0.250											-6.239	Likely Benign	0.583	Likely Pathogenic	Likely Benign	0.37	Likely Benign	0.2	0.02	Likely Benign	0.20	Likely Benign	0.58	Ambiguous	0.579	Likely Pathogenic	-2.10	Neutral	0.995	Probably Damaging	0.854	Possibly Damaging	5.71	Benign	0.02	Affected			0.0932	0.2558		3	0	0.3	9.01
c.742C>G	R248G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R248G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.267126	Uncertain	0.781	0.346	0.250											-13.413	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	2.23	Destabilizing	0.7	2.67	Destabilizing	2.45	Destabilizing	1.33	Destabilizing	0.770	Likely Pathogenic	-6.07	Deleterious	0.958	Probably Damaging	0.502	Possibly Damaging	5.70	Benign	0.00	Affected			0.3011	0.3385		-3	-2	4.1	-99.14
c.742C>T	R248W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248W is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Rosetta, Foldetta, and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results from FoldX and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.267126	Uncertain	0.781	0.346	0.250					Uncertain		1				-11.647	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	1.17	Ambiguous	0.3	-0.20	Likely Benign	0.49	Likely Benign	0.89	Ambiguous	0.699	Likely Pathogenic	-6.98	Deleterious	1.000	Probably Damaging	0.948	Probably Damaging	5.62	Benign	0.00	Affected	3.41	14	0.1124	0.4037		2	-3	3.6	30.03	266.4	42.3	0.0	0.0	0.3	0.1		X						Potentially Pathogenic	The guanidinium group of Arg248, located on an α helix (res. Ala236-Val250), forms two very stable salt bridges with Asp255 (from a short α helical section, res. Lys254-Asn256) and Glu244 (from a nearby loop) in the WT simulations. In the variant simulations, the indole group of Trp248 cannot form any salt bridges, which could negatively affect the tertiary structure assembly of the PH domain. Instead, in the variant simulations, the indole ring of Trp248 stacks against Pro252, which makes a turn after the α helix.
c.743G>A	R248Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248Q is catalogued in gnomAD (ID 6‑33435594‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: benign predictions come from FoldX and FATHMM, whereas pathogenic predictions are made by REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R248Q, and this conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.267126	Uncertain	0.781	0.346	0.250								6-33435594-G-A	2	1.24e-6	-10.573	Likely Pathogenic	0.979	Likely Pathogenic	Likely Pathogenic	0.45	Likely Benign	0.2	1.67	Ambiguous	1.06	Ambiguous	1.05	Destabilizing	0.739	Likely Pathogenic	-3.34	Deleterious	0.999	Probably Damaging	0.715	Possibly Damaging	5.74	Benign	0.01	Affected	3.41	14	0.2572	0.2549		1	1	1.0	-28.06
c.743G>C	R248P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R248P is listed in ClinVar as Pathogenic (ClinVar ID 1065478.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the overwhelming consensus of pathogenic predictions and the high‑accuracy tool results, the variant is most likely pathogenic, which aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.267126	Uncertain	0.781	0.346	0.250					Likely Pathogenic		1				-10.751	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.09	Destabilizing	0.6	8.87	Destabilizing	5.98	Destabilizing	1.21	Destabilizing	0.848	Likely Pathogenic	-5.97	Deleterious	0.998	Probably Damaging	0.878	Possibly Damaging	5.64	Benign	0.00	Affected	3.41	14	0.1943	0.4528		0	-2	2.9	-59.07	223.8	126.6	0.0	0.0	-0.2	0.1	X	X						Potentially Pathogenic	The guanidinium group of Arg248, located on an α helix (residues Ala236-Val250), forms two very stable salt bridges with Asp255 (from a short α helical section, res. Lys254-Asn256) and Glu244 (from a nearby loop) in the WT simulations. In the variant simulations, the pyrrolidine side chain of Pro248 cannot form any salt bridges, which could negatively affect the tertiary structure assembly of the PH domain. Additionally, Pro248 lacks a free amide group needed for hydrogen bonding with the backbone carbonyl group of Asn245, disrupting the continuity of the α helix.
c.743G>T	R248L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta and FATHMM, whereas the majority of algorithms predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions labeled uncertain are FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the consensus of the available evidence points to a pathogenic effect for R248L, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.267126	Uncertain	0.781	0.346	0.250											-12.110	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	1.13	Ambiguous	0.5	0.01	Likely Benign	0.57	Ambiguous	0.67	Ambiguous	0.825	Likely Pathogenic	-6.06	Deleterious	0.979	Probably Damaging	0.680	Possibly Damaging	5.66	Benign	0.03	Affected			0.1616	0.4741		-3	-2	8.3	-43.03
c.745G>A	A249T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A249T is listed in ClinVar (ID 1031675.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, and FATHMM, whereas polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. Overall, the balance of evidence favors a benign interpretation, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.505461	Disordered	0.255452	Uncertain	0.810	0.336	0.125					Uncertain		1				-3.564	Likely Benign	0.805	Likely Pathogenic	Ambiguous	1.50	Ambiguous	0.6	1.39	Ambiguous	1.45	Ambiguous	0.30	Likely Benign	0.487	Likely Benign	-0.96	Neutral	0.990	Probably Damaging	0.815	Possibly Damaging	5.65	Benign	0.40	Tolerated	3.39	15	0.0909	0.4972		1	0	-2.5	30.03	214.5	-43.3	0.0	0.0	0.5	0.2						X		Potentially Benign	The methyl group of Ala249, located on the surface of an α helix (res. Ala236-Val250) facing an anti-parallel β sheet strand (res. Ile205-Val209), packs against nearby hydrophobic residues such as Leu200, Leu246, and Val250. In the variant simulations, the hydroxyl group of Thr249, which is not suitable for hydrophobic packing, forms a stable hydrogen bond with the backbone carbonyl of Asn245 in the same helix. Although this interaction could theoretically weaken the structural integrity of the α helix, this destabilizing effect is not observed in the variant simulations.
c.745G>C	A249P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is therefore pathogenic (3 pathogenic vs. 1 benign). High‑accuracy assessments are consistent: AlphaMissense‑Optimized indicates pathogenicity; the SGM‑Consensus (majority vote) is pathogenic; and Foldetta, integrating FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. **Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.505461	Disordered	0.255452	Uncertain	0.810	0.336	0.125											-10.727	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	2.76	Destabilizing	0.4	8.40	Destabilizing	5.58	Destabilizing	1.04	Destabilizing	0.756	Likely Pathogenic	-3.32	Deleterious	0.176	Benign	0.039	Benign	5.57	Benign	0.03	Affected			0.1429	0.3537		1	-1	-3.4	26.04
c.745G>T	A249S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. Protein‑stability assessments are mixed: FoldX indicates a benign effect, while Rosetta and Foldetta are uncertain. High‑accuracy predictions show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the preponderance of evidence—including the high‑accuracy tools—suggests that A249S is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.505461	Disordered	0.255452	Uncertain	0.810	0.336	0.125											-5.707	Likely Benign	0.634	Likely Pathogenic	Likely Benign	0.48	Likely Benign	0.3	0.84	Ambiguous	0.66	Ambiguous	0.33	Likely Benign	0.465	Likely Benign	-1.40	Neutral	0.990	Probably Damaging	0.681	Possibly Damaging	5.63	Benign	0.19	Tolerated			0.1962	0.3393		1	1	-2.6	16.00
c.746C>A	A249E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249E has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are SIFT and FATHMM. The majority of other in‑silico predictors (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic; FoldX is uncertain and is not counted as evidence for either side. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of benign evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.505461	Disordered	0.255452	Uncertain	0.810	0.336	0.125											-13.519	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	1.60	Ambiguous	1.2	2.59	Destabilizing	2.10	Destabilizing	1.02	Destabilizing	0.818	Likely Pathogenic	-3.29	Deleterious	0.997	Probably Damaging	0.879	Possibly Damaging	5.64	Benign	0.09	Tolerated			0.0799	0.1509		0	-1	-5.3	58.04
c.746C>G	A249G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A249G is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Only FATHMM predicts a benign outcome. Uncertain results are reported by FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show SGM‑Consensus as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta remain inconclusive. Overall, the preponderance of evidence supports a pathogenic classification for A249G, and this conclusion does not conflict with ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.505461	Disordered	0.255452	Uncertain	0.810	0.336	0.125											-9.678	Likely Pathogenic	0.947	Likely Pathogenic	Ambiguous	1.04	Ambiguous	0.2	2.02	Destabilizing	1.53	Ambiguous	1.19	Destabilizing	0.607	Likely Pathogenic	-2.97	Deleterious	0.990	Probably Damaging	0.760	Possibly Damaging	5.59	Benign	0.04	Affected			0.1667	0.2675		1	0	-2.2	-14.03
c.746C>T	A249V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A249V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, no high‑accuracy tool provides a definitive pathogenic or benign verdict. Overall, the majority of available predictions (seven pathogenic vs. three benign) lean toward a pathogenic interpretation. This assessment does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.505461	Disordered	0.255452	Uncertain	0.810	0.336	0.125											-9.417	Likely Pathogenic	0.856	Likely Pathogenic	Ambiguous	1.48	Ambiguous	0.6	0.51	Ambiguous	1.00	Ambiguous	0.41	Likely Benign	0.652	Likely Pathogenic	-2.47	Neutral	0.990	Probably Damaging	0.760	Possibly Damaging	5.76	Benign	0.03	Affected			0.0737	0.4677		0	0	2.4	28.05
c.748G>A	V250I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V250I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in silico predictors classify the change as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The high‑accuracy tools likewise predict a benign effect: AlphaMissense‑Optimized is benign, the SGM Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.447574	Structured	0.244075	Uncertain	0.778	0.324	0.125											-6.696	Likely Benign	0.085	Likely Benign	Likely Benign	-0.44	Likely Benign	0.1	-0.01	Likely Benign	-0.23	Likely Benign	0.35	Likely Benign	0.362	Likely Benign	-0.79	Neutral	0.384	Benign	0.070	Benign	6.09	Benign	0.13	Tolerated			0.0571	0.3644		4	3	0.3	14.03
c.748G>C	V250L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250L variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict pathogenicity are REVEL, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—Foldetta and premPS—are noted as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is ambiguous (two pathogenic vs. two benign votes), and Foldetta remains uncertain. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.447574	Structured	0.244075	Uncertain	0.778	0.324	0.125											-11.649	Likely Pathogenic	0.587	Likely Pathogenic	Likely Benign	-0.23	Likely Benign	0.1	2.47	Destabilizing	1.12	Ambiguous	0.66	Ambiguous	0.690	Likely Pathogenic	-2.47	Neutral	0.767	Possibly Damaging	0.344	Benign	5.81	Benign	0.04	Affected			0.0698	0.4229		2	1	-0.4	14.03
c.748G>T	V250L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250L variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict pathogenicity are REVEL, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—Foldetta and premPS—are noted as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is ambiguous (two pathogenic vs. two benign votes), and Foldetta remains uncertain. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.447574	Structured	0.244075	Uncertain	0.778	0.324	0.125											-11.649	Likely Pathogenic	0.587	Likely Pathogenic	Likely Benign	-0.23	Likely Benign	0.1	2.47	Destabilizing	1.12	Ambiguous	0.66	Ambiguous	0.690	Likely Pathogenic	-2.47	Neutral	0.767	Possibly Damaging	0.344	Benign	5.81	Benign	0.04	Affected			0.0698	0.4229		2	1	-0.4	14.03
c.749T>A	V250E 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V250E is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, whereas the remaining 12 tools (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the change as pathogenic. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. No prediction or stability result is inconclusive. Consequently, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.447574	Structured	0.244075	Uncertain	0.778	0.324	0.125											-15.723	Likely Pathogenic	0.983	Likely Pathogenic	Likely Pathogenic	1.85	Ambiguous	0.1	3.34	Destabilizing	2.60	Destabilizing	2.01	Destabilizing	0.906	Likely Pathogenic	-5.13	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	5.74	Benign	0.00	Affected			0.0787	0.1564		-2	-2	-7.7	29.98
c.749T>C	V250A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250A missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a pathogenic effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all indicate pathogenicity, whereas ESM1b and FATHMM predict a benign outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) and AlphaMissense‑Optimized return uncertain results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is balanced and therefore unavailable, and Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for V250A, and this assessment does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.447574	Structured	0.244075	Uncertain	0.778	0.324	0.125											-6.385	Likely Benign	0.852	Likely Pathogenic	Ambiguous	0.82	Ambiguous	0.1	1.22	Ambiguous	1.02	Ambiguous	1.48	Destabilizing	0.818	Likely Pathogenic	-3.11	Deleterious	0.930	Possibly Damaging	0.584	Possibly Damaging	5.82	Benign	0.02	Affected			0.2491	0.2151		0	0	-2.4	-28.05
c.749T>G	V250G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default, while only FATHMM predicts a benign outcome. Uncertain results are reported by FoldX and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, AlphaMissense‑Optimized remains uncertain, and Foldetta is pathogenic. Taken together, the overwhelming majority of evidence indicates a pathogenic effect. This conclusion is consistent with the absence of a ClinVar classification; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.447574	Structured	0.244075	Uncertain	0.778	0.324	0.125											-11.255	Likely Pathogenic	0.917	Likely Pathogenic	Ambiguous	1.65	Ambiguous	0.3	3.18	Destabilizing	2.42	Destabilizing	2.08	Destabilizing	0.900	Likely Pathogenic	-5.90	Deleterious	0.879	Possibly Damaging	0.997	Probably Damaging	5.75	Benign	0.00	Affected			0.1884	0.1996		-1	-3	-4.6	-42.08
c.74G>A	R25Q 2D AIThe SynGAP1 missense variant R25Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33423483‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.461924	Structured	0.438941	Uncertain	0.373	0.890	0.375					Uncertain		1	6-33423483-G-A	15	9.29e-6	-4.126	Likely Benign	0.212	Likely Benign	Likely Benign										0.038	Likely Benign	-0.70	Neutral	0.829	Possibly Damaging	0.614	Possibly Damaging	4.01	Benign	0.00	Affected	4.32	1	0.3447	0.2566		1	1	1.0	-28.06
c.74G>C	R25P 2D AIThe SynGAP1 missense variant R25P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.461924	Structured	0.438941	Uncertain	0.373	0.890	0.375											-3.394	Likely Benign	0.424	Ambiguous	Likely Benign										0.155	Likely Benign	-1.56	Neutral	0.841	Possibly Damaging	0.809	Possibly Damaging	3.94	Benign	0.00	Affected			0.2217	0.4571		0	-2	2.9	-59.07
c.74G>T	R25L 2D AIThe SynGAP1 missense variant R25L is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic impact. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools specifically highlight a benign prediction: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta data are missing. Taken together, the majority of robust predictors and the consensus analysis support a benign classification for R25L. This conclusion is consistent with the lack of ClinVar evidence and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.461924	Structured	0.438941	Uncertain	0.373	0.890	0.375											-3.443	Likely Benign	0.484	Ambiguous	Likely Benign										0.121	Likely Benign	-1.59	Neutral	0.686	Possibly Damaging	0.630	Possibly Damaging	3.97	Benign	0.00	Affected			0.2045	0.4792		-3	-2	8.3	-43.03
c.751A>C	K251Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar, while premPS and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, the majority of evidence supports a benign classification for K251Q, and this conclusion does not contradict the absence of a ClinVar entry. Based on the aggregate predictions, K251Q is most likely benign, and this is consistent with its absence from ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.447574	Structured	0.226632	Uncertain	0.758	0.312	0.125											-5.869	Likely Benign	0.362	Ambiguous	Likely Benign	0.36	Likely Benign	0.1	0.42	Likely Benign	0.39	Likely Benign	-0.62	Ambiguous	0.465	Likely Benign	0.55	Neutral	0.997	Probably Damaging	0.879	Possibly Damaging	5.86	Benign	0.63	Tolerated			0.4466	0.1085		1	1	0.4	-0.04
c.751A>G	K251E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K251E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, SIFT, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain results. High‑accuracy methods are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, with a small but notable benign signal. Therefore, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.447574	Structured	0.226632	Uncertain	0.758	0.312	0.125											-12.812	Likely Pathogenic	0.906	Likely Pathogenic	Ambiguous	0.88	Ambiguous	0.2	0.99	Ambiguous	0.94	Ambiguous	0.40	Likely Benign	0.571	Likely Pathogenic	-0.54	Neutral	0.970	Probably Damaging	0.584	Possibly Damaging	5.80	Benign	0.46	Tolerated			0.3929	0.0860		0	1	0.4	0.94
c.752A>C	K251T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include premPS, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports a pathogenic prediction, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the balance of evidence favors a pathogenic effect for K251T, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.447574	Structured	0.226632	Uncertain	0.758	0.312	0.125											-10.552	Likely Pathogenic	0.841	Likely Pathogenic	Ambiguous	1.21	Ambiguous	0.4	0.50	Ambiguous	0.86	Ambiguous	0.46	Likely Benign	0.742	Likely Pathogenic	-2.72	Deleterious	0.970	Probably Damaging	0.749	Possibly Damaging	5.76	Benign	0.28	Tolerated			0.2353	0.2852		0	-1	3.2	-27.07
c.752A>G	K251R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Rosetta and Foldetta give uncertain results. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.447574	Structured	0.226632	Uncertain	0.758	0.312	0.125											-4.355	Likely Benign	0.123	Likely Benign	Likely Benign	-0.37	Likely Benign	0.0	-0.64	Ambiguous	-0.51	Ambiguous	0.14	Likely Benign	0.531	Likely Pathogenic	-0.61	Neutral	0.970	Probably Damaging	0.681	Possibly Damaging	5.92	Benign	0.34	Tolerated			0.4756	0.1049		3	2	-0.6	28.01
c.752A>T	K251M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K251M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, premPS, PROVEAN, and FATHMM. Those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a benign effect. Overall, the evidence is evenly split between benign and pathogenic predictions, with the most reliable high‑accuracy tools leaning toward a benign outcome. Thus, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.447574	Structured	0.226632	Uncertain	0.758	0.312	0.125											-10.678	Likely Pathogenic	0.796	Likely Pathogenic	Ambiguous	0.14	Likely Benign	0.1	0.10	Likely Benign	0.12	Likely Benign	0.05	Likely Benign	0.751	Likely Pathogenic	-2.36	Neutral	0.999	Probably Damaging	0.970	Probably Damaging	5.73	Benign	0.05	Affected			0.1271	0.3475		0	-1	5.8	3.02
c.753G>C	K251N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM (nine tools). Only AlphaMissense‑Default predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the preponderance of evidence indicates that K251N is most likely benign, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.447574	Structured	0.226632	Uncertain	0.758	0.312	0.125											-7.978	In-Between	0.930	Likely Pathogenic	Ambiguous	0.29	Likely Benign	0.1	0.21	Likely Benign	0.25	Likely Benign	0.32	Likely Benign	0.298	Likely Benign	-1.29	Neutral	0.384	Benign	0.070	Benign	5.73	Benign	0.39	Tolerated			0.3848	0.1196		1	0	0.4	-14.07
c.753G>T	K251N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM (nine tools). Only AlphaMissense‑Default predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the preponderance of evidence indicates that K251N is most likely benign, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.447574	Structured	0.226632	Uncertain	0.758	0.312	0.125											-7.978	In-Between	0.930	Likely Pathogenic	Ambiguous	0.29	Likely Benign	0.1	0.21	Likely Benign	0.25	Likely Benign	0.32	Likely Benign	0.298	Likely Benign	-1.29	Neutral	0.384	Benign	0.070	Benign	5.73	Benign	0.39	Tolerated			0.3848	0.1196		1	0	0.4	-14.07
c.754C>A	P252T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P252T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized and the SGM‑Consensus score (Likely Pathogenic). Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are treated as unavailable. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; Foldetta’s stability assessment is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.461924	Structured	0.211606	Uncertain	0.753	0.304	0.250											-11.824	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	1.24	Ambiguous	0.1	1.89	Ambiguous	1.57	Ambiguous	0.71	Ambiguous	0.828	Likely Pathogenic	-7.35	Deleterious	0.384	Benign	0.177	Benign	5.78	Benign	0.01	Affected			0.1514	0.4842		0	-1	0.9	3.99
c.754C>G	P252A 2D 3DClick to see structure in 3D Viewer AISynGAP1 P252A is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: a single benign call from FATHMM, and a majority of pathogenic calls from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for P252A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.461924	Structured	0.211606	Uncertain	0.753	0.304	0.250											-10.587	Likely Pathogenic	0.977	Likely Pathogenic	Likely Pathogenic	0.97	Ambiguous	0.1	1.74	Ambiguous	1.36	Ambiguous	0.69	Ambiguous	0.831	Likely Pathogenic	-7.35	Deleterious	0.941	Possibly Damaging	0.607	Possibly Damaging	5.87	Benign	0.03	Affected			0.3490	0.4161		1	-1	3.4	-26.04
c.754C>T	P252S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P252S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. Predictions that are uncertain (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the evidence strongly favors a pathogenic effect for P252S, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.461924	Structured	0.211606	Uncertain	0.753	0.304	0.250											-10.926	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.76	Ambiguous	0.1	1.81	Ambiguous	1.29	Ambiguous	0.79	Ambiguous	0.840	Likely Pathogenic	-7.35	Deleterious	0.941	Possibly Damaging	0.531	Possibly Damaging	5.79	Benign	0.05	Affected			0.3508	0.4361		1	-1	0.8	-10.04
c.755C>A	P252H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P252H missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence indicates that P252H is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.461924	Structured	0.211606	Uncertain	0.753	0.304	0.250											-11.991	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	1.06	Ambiguous	0.2	1.96	Ambiguous	1.51	Ambiguous	0.82	Ambiguous	0.845	Likely Pathogenic	-8.27	Deleterious	0.999	Probably Damaging	0.936	Probably Damaging	5.76	Benign	0.00	Affected			0.1592	0.4128		0	-2	-1.6	40.02
c.755C>G	P252R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P252R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Computational predictors that classify the variant as benign are FoldX and FATHMM, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. Predictions that are inconclusive are Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that P252R is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.461924	Structured	0.211606	Uncertain	0.753	0.304	0.250											-14.648	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	0.40	Likely Benign	0.1	1.23	Ambiguous	0.82	Ambiguous	0.81	Ambiguous	0.890	Likely Pathogenic	-8.27	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	5.80	Benign	0.00	Affected			0.1413	0.2848		0	-2	-2.9	59.07
c.755C>T	P252L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P252L missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign are premPS and FATHMM, while the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic effect. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore do not contribute to the overall assessment. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.461924	Structured	0.211606	Uncertain	0.753	0.304	0.250											-10.181	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.93	Ambiguous	0.0	1.56	Ambiguous	1.25	Ambiguous	0.47	Likely Benign	0.794	Likely Pathogenic	-9.19	Deleterious	0.991	Probably Damaging	0.781	Possibly Damaging	5.81	Benign	0.00	Affected			0.2027	0.6475		-3	-3	5.4	16.04
c.757A>C	N253H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N253H is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include FoldX, FATHMM, and premPS, whereas a larger group predicts pathogenicity: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, while AlphaMissense‑Optimized and Foldetta provide inconclusive results and are treated as unavailable. No contradictory evidence is present in ClinVar. Overall, the preponderance of evidence from multiple in‑silico predictors points to a pathogenic effect for the variant, and this conclusion does not conflict with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.201744	Uncertain	0.771	0.298	0.250											-12.199	Likely Pathogenic	0.899	Likely Pathogenic	Ambiguous	0.31	Likely Benign	0.1	0.76	Ambiguous	0.54	Ambiguous	-0.06	Likely Benign	0.832	Likely Pathogenic	-4.39	Deleterious	0.998	Probably Damaging	0.991	Probably Damaging	5.51	Benign	0.01	Affected			0.1936	0.8033		2	1	0.3	23.04
c.757A>G	N253D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N253D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on benign effects include FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM, while those that predict pathogenicity are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicating likely pathogenic, whereas Foldetta predicts a benign effect on protein stability. Overall, the majority of tools (8/15) favor a pathogenic outcome, with no conflict with ClinVar status because the variant is not yet catalogued. Thus, the variant is most likely pathogenic based on current computational predictions, and this assessment does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.201744	Uncertain	0.771	0.298	0.250											-14.105	Likely Pathogenic	0.977	Likely Pathogenic	Likely Pathogenic	0.25	Likely Benign	0.0	0.37	Likely Benign	0.31	Likely Benign	0.09	Likely Benign	0.742	Likely Pathogenic	-4.13	Deleterious	0.993	Probably Damaging	0.971	Probably Damaging	5.60	Benign	0.09	Tolerated			0.2248	0.5186		2	1	0.0	0.98
c.757A>T	N253Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253Y is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX, FATHMM, and premPS, whereas a larger set—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Because the majority of evidence points to a deleterious impact, the variant is most likely pathogenic; this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.201744	Uncertain	0.771	0.298	0.250											-14.749	Likely Pathogenic	0.920	Likely Pathogenic	Ambiguous	0.27	Likely Benign	0.1	1.13	Ambiguous	0.70	Ambiguous	0.29	Likely Benign	0.896	Likely Pathogenic	-7.01	Deleterious	0.998	Probably Damaging	0.994	Probably Damaging	5.55	Benign	0.01	Affected			0.0642	0.7055		-2	-2	2.2	49.07
c.758A>C	N253T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253T is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default) predict a pathogenic outcome. High‑accuracy methods give a consistent pathogenic signal: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta) also predicts pathogenic. AlphaMissense‑Optimized is uncertain and is treated as unavailable. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.201744	Uncertain	0.771	0.298	0.250											-11.656	Likely Pathogenic	0.929	Likely Pathogenic	Ambiguous	1.96	Ambiguous	0.3	2.67	Destabilizing	2.32	Destabilizing	0.16	Likely Benign	0.739	Likely Pathogenic	-5.01	Deleterious	0.993	Probably Damaging	0.971	Probably Damaging	5.54	Benign	0.06	Tolerated			0.1640	0.8665		0	0	2.8	-13.00
c.758A>G	N253S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253S is listed in ClinVar with no submitted interpretation and is present in gnomAD (ID 6‑33435609‑A‑G). Prediction tools that agree on a benign effect include premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the evidence is mixed, but the single high‑accuracy tool that is available points to a benign effect. Therefore, the variant is most likely benign based on current predictions, and this assessment does not contradict the ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.513880	Disordered	0.201744	Uncertain	0.771	0.298	0.250								6-33435609-A-G			-7.197	In-Between	0.541	Ambiguous	Likely Benign	0.60	Ambiguous	0.1	1.19	Ambiguous	0.90	Ambiguous	-0.03	Likely Benign	0.716	Likely Pathogenic	-4.26	Deleterious	0.993	Probably Damaging	0.956	Probably Damaging	5.56	Benign	0.09	Tolerated	3.39	15	0.3960	0.7764		1	1	2.7	-27.03
c.758A>T	N253I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253I is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (ID 6‑33435609‑A‑T). Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are limited to premPS and FATHMM. High‑accuracy assessments reinforce the pathogenic view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.201744	Uncertain	0.771	0.298	0.250								6-33435609-A-T	1	6.20e-7	-15.241	Likely Pathogenic	0.970	Likely Pathogenic	Likely Pathogenic	2.95	Destabilizing	0.1	5.56	Destabilizing	4.26	Destabilizing	0.25	Likely Benign	0.836	Likely Pathogenic	-7.83	Deleterious	0.998	Probably Damaging	0.991	Probably Damaging	5.57	Benign	0.01	Affected	3.39	15	0.0803	0.7553		-3	-2	8.0	-0.94
c.759C>A	N253K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253K resides in the PH domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Functional prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, and FATHMM. In contrast, the majority of predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—label it pathogenic or likely pathogenic. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus also indicates likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect. This assessment is not contradicted by ClinVar, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.201744	Uncertain	0.771	0.298	0.250											-15.834	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.05	Likely Benign	0.0	0.90	Ambiguous	0.48	Likely Benign	0.17	Likely Benign	0.663	Likely Pathogenic	-5.21	Deleterious	0.993	Probably Damaging	0.979	Probably Damaging	5.53	Benign	0.03	Affected			0.2640	0.6592		1	0	-0.4	14.07
c.759C>G	N253K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools fall into two groups: benign predictions come from FoldX, FATHMM, premPS, and Foldetta, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Benign. Overall, the majority of tools predict pathogenicity, and the two most reliable predictors also lean pathogenic, whereas only one high‑accuracy tool suggests benign. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.201744	Uncertain	0.771	0.298	0.250											-15.834	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.05	Likely Benign	0.0	0.90	Ambiguous	0.48	Likely Benign	0.17	Likely Benign	0.663	Likely Pathogenic	-5.21	Deleterious	0.993	Probably Damaging	0.979	Probably Damaging	5.53	Benign	0.03	Affected			0.2640	0.6592		1	0	-0.4	14.07
c.760A>C	K254Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K254Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, SIFT, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools, Rosetta and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.207751	Uncertain	0.799	0.285	0.375											-12.332	Likely Pathogenic	0.979	Likely Pathogenic	Likely Pathogenic	0.13	Likely Benign	0.1	-0.61	Ambiguous	-0.24	Likely Benign	0.90	Ambiguous	0.737	Likely Pathogenic	-3.04	Deleterious	0.997	Probably Damaging	0.879	Possibly Damaging	5.91	Benign	0.11	Tolerated			0.3749	0.1483		1	1	0.4	-0.04
c.760A>G	K254E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: FATHMM is the sole benign predictor, while the remaining 13 tools (REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus) predict pathogenicity; FoldX and Foldetta are uncertain. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized indicates pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the preponderance of evidence supports a pathogenic classification for K254E, and this conclusion does not conflict with ClinVar, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.207751	Uncertain	0.799	0.285	0.375											-14.745	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.72	Ambiguous	0.1	2.34	Destabilizing	1.53	Ambiguous	1.17	Destabilizing	0.860	Likely Pathogenic	-3.27	Deleterious	0.970	Probably Damaging	0.584	Possibly Damaging	5.87	Benign	0.05	Affected			0.3224	0.1352		0	1	0.4	0.94
c.761A>C	K254T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, PROVEAN, both polyPhen‑2 HumDiv and HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Benign predictions are limited to SIFT and FATHMM. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a pathogenic effect for K254T, and this conclusion does not conflict with ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.207751	Uncertain	0.799	0.285	0.375											-13.793	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.51	Ambiguous	0.0	1.92	Ambiguous	1.22	Ambiguous	0.62	Ambiguous	0.883	Likely Pathogenic	-5.14	Deleterious	0.970	Probably Damaging	0.749	Possibly Damaging	5.88	Benign	0.06	Tolerated			0.1825	0.2562		0	-1	3.2	-27.07
c.761A>G	K254R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K254R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority (2 benign vs. 1 pathogenic, 1 uncertain); Foldetta is uncertain. Taken together, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.513880	Disordered	0.207751	Uncertain	0.799	0.285	0.375											-11.064	Likely Pathogenic	0.528	Ambiguous	Likely Benign	-0.44	Likely Benign	0.1	-1.13	Ambiguous	-0.79	Ambiguous	0.76	Ambiguous	0.604	Likely Pathogenic	-2.36	Neutral	0.970	Probably Damaging	0.681	Possibly Damaging	5.81	Benign	0.09	Tolerated			0.4070	0.1658		3	2	-0.6	28.01
c.761A>T	K254M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show discordant results: benign predictions come from FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are reported by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight the conflict: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No prediction or stability result is missing or inconclusive. Overall, the majority of tools and the high‑accuracy consensus lean toward a pathogenic effect, and this assessment does not contradict ClinVar status, which currently has no entry for it. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.207751	Uncertain	0.799	0.285	0.375											-12.832	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	-0.35	Likely Benign	0.5	0.48	Likely Benign	0.07	Likely Benign	0.23	Likely Benign	0.864	Likely Pathogenic	-5.08	Deleterious	0.999	Probably Damaging	0.970	Probably Damaging	5.78	Benign	0.00	Affected			0.1073	0.3562		0	-1	5.8	3.02
c.762G>C	K254N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The majority of other in silico predictors—REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—indicate a pathogenic effect. Stability‑based methods FoldX, Rosetta, and Foldetta returned uncertain results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as unavailable. Overall, the preponderance of evidence supports a pathogenic classification, which contradicts the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.207751	Uncertain	0.799	0.285	0.375					Uncertain		1				-13.306	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.73	Ambiguous	0.2	1.87	Ambiguous	1.30	Ambiguous	1.19	Destabilizing	0.757	Likely Pathogenic	-4.23	Deleterious	0.384	Benign	0.070	Benign	5.93	Benign	0.01	Affected	3.39	15	0.3200	0.1488		1	0	0.4	-14.07	215.3	-21.0	-1.0	1.7	0.2	0.3		X						Potentially Pathogenic	The amino group of Lys254, located in an α-β loop connecting the PH and C2 domains (res. Lys251-Arg258), forms salt bridges with the carboxylate groups of Glu244 and Asp684. Since the neutral carboxamide group of the Asn254 side chain cannot form salt bridges with acidic residues, the residue swap potentially weakens the tertiary structure assembly and/or influences the loop positioning. Regardless, in both the variant and WT simulations, all hydrogen bonds formed by the residue’s side chain were broken, and the residue rotated outwards. The partially α helical conformation of the loop, which extends to a nearby α helix (res. Met414-Asn426), is dynamic, making it unclear if the mutation affects it.
c.762G>T	K254N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K254N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic” (3 pathogenic vs. 1 benign). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Based on the overall pattern of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not currently catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.207751	Uncertain	0.799	0.285	0.375											-13.306	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.73	Ambiguous	0.2	1.87	Ambiguous	1.30	Ambiguous	1.19	Destabilizing	0.757	Likely Pathogenic	-4.23	Deleterious	0.384	Benign	0.070	Benign	5.93	Benign	0.01	Affected	3.39	15	0.3200	0.1488		1	0	0.4	-14.07	215.3	-21.0	-1.0	1.7	0.2	0.3		X						Potentially Pathogenic	The amino group of Lys254, located in an α-β loop connecting the PH and C2 domains (res. Lys251-Arg258), forms salt bridges with the carboxylate groups of Glu244 and Asp684. Since the neutral carboxamide group of the Asn254 side chain cannot form salt bridges with acidic residues, the residue swap potentially weakens the tertiary structure assembly and/or influences the loop positioning. Regardless, in both the variant and WT simulations, all hydrogen bonds formed by the residue’s side chain were broken, and the residue rotated outwards. The partially α helical conformation of the loop, which extends to a nearby α helix (res. Met414-Asn426), is dynamic, making it unclear if the mutation affects it.
c.763G>A	D255N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. FoldX, Rosetta, and Foldetta provide uncertain results. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta remains inconclusive. Overall, the consensus of the available predictions points to a pathogenic effect for D255N, and this conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.501700	Disordered	0.219132	Uncertain	0.801	0.273	0.250											-12.251	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.86	Ambiguous	0.1	1.48	Ambiguous	1.17	Ambiguous	0.38	Likely Benign	0.682	Likely Pathogenic	-4.30	Deleterious	0.997	Probably Damaging	0.989	Probably Damaging	5.84	Benign	0.01	Affected			0.1117	0.4774		2	1	0.0	-0.98
c.763G>C	D255H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, while pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce the pathogenic interpretation: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains Uncertain. Overall, the consensus of the available predictions points to a pathogenic effect for D255H, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.501700	Disordered	0.219132	Uncertain	0.801	0.273	0.250											-14.645	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.72	Ambiguous	0.2	1.17	Ambiguous	1.45	Ambiguous	0.44	Likely Benign	0.808	Likely Pathogenic	-5.93	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	5.76	Benign	0.00	Affected			0.1447	0.5211		1	-1	0.3	22.05
c.763G>T	D255Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include premPS and FATHMM, while the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.501700	Disordered	0.219132	Uncertain	0.801	0.273	0.250											-13.180	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	1.25	Ambiguous	0.2	0.96	Ambiguous	1.11	Ambiguous	0.13	Likely Benign	0.832	Likely Pathogenic	-7.77	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	5.73	Benign	0.00	Affected			0.0464	0.5178		-4	-3	2.2	48.09
c.764A>C	D255A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D255A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Pathogenic” vote) predict a pathogenic impact. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore do not contribute evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.501700	Disordered	0.219132	Uncertain	0.801	0.273	0.250											-11.789	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.48	Ambiguous	0.2	1.04	Ambiguous	1.26	Ambiguous	0.35	Likely Benign	0.829	Likely Pathogenic	-6.85	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	5.80	Benign	0.01	Affected			0.3363	0.4805		0	-2	5.3	-44.01
c.764A>G	D255G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D255G missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include premPS and FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are therefore not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.501700	Disordered	0.219132	Uncertain	0.801	0.273	0.250											-12.652	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	1.72	Ambiguous	0.1	1.34	Ambiguous	1.53	Ambiguous	0.31	Likely Benign	0.885	Likely Pathogenic	-6.13	Deleterious	0.997	Probably Damaging	0.989	Probably Damaging	5.86	Benign	0.01	Affected			0.3211	0.5185		1	-1	3.1	-58.04
c.764A>T	D255V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, while pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce the pathogenic interpretation: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains Uncertain. Overall, the consensus of available predictions points to a pathogenic effect for D255V, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.501700	Disordered	0.219132	Uncertain	0.801	0.273	0.250											-13.575	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.76	Ambiguous	0.2	1.07	Ambiguous	1.42	Ambiguous	0.16	Likely Benign	0.895	Likely Pathogenic	-7.77	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	5.75	Benign	0.00	Affected			0.0684	0.5162		-2	-3	7.7	-15.96
c.765C>A	D255E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change D255E is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include premPS, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, the majority of available predictions (seven pathogenic vs. four benign) point to a likely pathogenic impact. This conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.			0.501700	Disordered	0.219132	Uncertain	0.801	0.273	0.250											-6.876	Likely Benign	0.989	Likely Pathogenic	Likely Pathogenic	0.80	Ambiguous	0.3	0.90	Ambiguous	0.85	Ambiguous	0.15	Likely Benign	0.508	Likely Pathogenic	-2.98	Deleterious	0.994	Probably Damaging	0.978	Probably Damaging	5.89	Benign	0.08	Tolerated			0.1365	0.5067		3	2	0.0	14.03
c.765C>G	D255E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255E is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include premPS, SIFT, ESM1b, and FATHMM, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The remaining tools (FoldX, Rosetta, Foldetta) provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta is also inconclusive. Overall, the majority of available predictions (7 pathogenic vs. 4 benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.			0.501700	Disordered	0.219132	Uncertain	0.801	0.273	0.250											-6.876	Likely Benign	0.989	Likely Pathogenic	Likely Pathogenic	0.80	Ambiguous	0.3	0.90	Ambiguous	0.85	Ambiguous	0.15	Likely Benign	0.509	Likely Pathogenic	-2.98	Deleterious	0.994	Probably Damaging	0.978	Probably Damaging	5.89	Benign	0.08	Tolerated			0.1365	0.5067		3	2	0.0	14.03
c.766A>C	N256H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256H is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta, Foldetta, premPS, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250											-8.090	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	0.56	Ambiguous	0.3	0.26	Likely Benign	0.41	Likely Benign	0.08	Likely Benign	0.698	Likely Pathogenic	-4.06	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	5.82	Benign	0.05	Affected			0.1233	0.5646		2	1	0.3	23.04
c.766A>G	N256D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N256D is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, Foldetta, premPS, and FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX is uncertain and therefore not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Taken together, the overall consensus leans toward a pathogenic effect, with 10 tools supporting pathogenicity versus 4 supporting benignity. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250											-12.478	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.69	Ambiguous	0.3	0.21	Likely Benign	0.45	Likely Benign	0.44	Likely Benign	0.701	Likely Pathogenic	-4.36	Deleterious	0.997	Probably Damaging	0.980	Probably Damaging	5.81	Benign	0.03	Affected			0.1890	0.3514		2	1	0.0	0.98
c.766A>T	N256Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, and FATHMM, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—label it pathogenic. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the preponderance of evidence from standard predictors and the two high‑accuracy pathogenic calls suggests that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250											-10.881	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	0.17	Likely Benign	0.2	-0.80	Ambiguous	-0.32	Likely Benign	0.30	Likely Benign	0.868	Likely Pathogenic	-6.85	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	5.83	Benign	0.00	Affected			0.0493	0.5881		-2	-2	2.2	49.07
c.767A>C	N256T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). The high‑accuracy AlphaMissense‑Optimized model classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while the Foldetta stability assessment reports a benign effect. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250											-12.212	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.88	Ambiguous	0.1	-0.18	Likely Benign	0.35	Likely Benign	0.49	Likely Benign	0.819	Likely Pathogenic	-5.25	Deleterious	0.997	Probably Damaging	0.980	Probably Damaging	5.85	Benign	0.01	Affected			0.1249	0.5848		0	0	2.8	-13.00
c.767A>G	N256S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256S is listed in ClinVar as Pathogenic (ClinVar ID 2584352.0) and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic calls come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy subset gives AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of predictions support a pathogenic effect, aligning with the ClinVar classification. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250					Likely Pathogenic		1				-10.640	Likely Pathogenic	0.950	Likely Pathogenic	Ambiguous	0.31	Likely Benign	0.2	0.36	Likely Benign	0.34	Likely Benign	0.48	Likely Benign	0.707	Likely Pathogenic	-4.33	Deleterious	0.997	Probably Damaging	0.970	Probably Damaging	5.87	Benign	0.02	Affected	3.39	15	0.3024	0.5864		1	1	2.7	-27.03
c.767A>T	N256I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, premPS, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give a pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250											-14.050	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.64	Ambiguous	0.4	0.45	Likely Benign	0.55	Ambiguous	0.31	Likely Benign	0.849	Likely Pathogenic	-7.91	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	5.87	Benign	0.00	Affected			0.0596	0.6260		-2	-3	8.0	-0.94
c.768C>A	N256K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and FATHMM. Those that predict pathogenicity comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools favor a pathogenic effect, whereas a minority suggest benign. Thus, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250											-13.814	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.22	Likely Benign	0.3	-0.10	Likely Benign	0.06	Likely Benign	0.55	Ambiguous	0.569	Likely Pathogenic	-5.02	Deleterious	0.997	Probably Damaging	0.986	Probably Damaging	5.90	Benign	0.01	Affected			0.1702	0.5240		1	0	-0.4	14.07
c.768C>G	N256K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and FATHMM. Those that predict pathogenicity comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools support a pathogenic effect, whereas a minority suggest benign. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250											-13.814	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.22	Likely Benign	0.3	-0.10	Likely Benign	0.06	Likely Benign	0.55	Ambiguous	0.569	Likely Pathogenic	-5.02	Deleterious	0.997	Probably Damaging	0.986	Probably Damaging	5.90	Benign	0.01	Affected			0.1702	0.5240		1	0	-0.4	14.07
c.769A>C	S257R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta and Foldetta are uncertain. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for S257R. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.258293	Uncertain	0.847	0.272	0.250											-11.746	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	-0.18	Likely Benign	0.0	-1.33	Ambiguous	-0.76	Ambiguous	0.29	Likely Benign	0.754	Likely Pathogenic	-3.38	Deleterious	0.998	Probably Damaging	0.986	Probably Damaging	5.81	Benign	0.13	Tolerated			0.0762	0.3068		0	-1	-3.7	69.11
c.769A>G	S257G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257G is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD status: None). Prediction tools that agree on a benign effect include SIFT, FATHMM, and AlphaMissense‑Optimized. In contrast, a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support this view: AlphaMissense‑Optimized indicates a benign change, whereas the SGM‑Consensus (majority vote) indicates likely pathogenic. The Foldetta stability prediction is unavailable and therefore does not influence the overall assessment. Based on the preponderance of pathogenic predictions and the lack of any ClinVar annotation, the variant is most likely pathogenic, with no contradiction from existing ClinVar data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.258293	Uncertain	0.847	0.272	0.250											-11.206	Likely Pathogenic	0.624	Likely Pathogenic	Likely Benign	0.61	Ambiguous	0.3	0.60	Ambiguous	0.61	Ambiguous	0.62	Ambiguous	0.703	Likely Pathogenic	-2.95	Deleterious	0.982	Probably Damaging	0.952	Probably Damaging	5.79	Benign	0.11	Tolerated			0.2087	0.3589		1	0	0.4	-30.03
c.769A>T	S257C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, Rosetta) and pathogenic predictions (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar). The high‑accuracy consensus methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta—each indicate a benign effect. No folding‑stability assessment is available beyond the benign Foldetta result. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar assertion. Thus, the variant is most likely benign, and this is not contradicted by ClinVar status, which has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.384043	Structured	0.258293	Uncertain	0.847	0.272	0.250											-3.553	Likely Benign	0.189	Likely Benign	Likely Benign	0.50	Ambiguous	0.4	-0.33	Likely Benign	0.09	Likely Benign	-0.46	Likely Benign	0.611	Likely Pathogenic	0.02	Neutral	0.999	Probably Damaging	0.993	Probably Damaging	5.76	Benign	0.18	Tolerated			0.0880	0.5151		0	-1	3.3	16.06
c.76G>A	G26R 2D AIThe SynGAP1 missense variant G26R is listed in ClinVar as a benign alteration (ClinVar ID 1521495.0) and is present in the gnomAD database (gnomAD ID 6‑33423485‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence supports a benign impact, aligning with the ClinVar designation and indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.486429	Structured	0.438291	Uncertain	0.351	0.878	0.375					Benign		1	6-33423485-G-A	3	1.86e-6	-2.946	Likely Benign	0.678	Likely Pathogenic	Likely Benign										0.189	Likely Benign	-2.22	Neutral	0.994	Probably Damaging	0.990	Probably Damaging	3.87	Benign	0.00	Affected	4.32	1	0.1097	0.4407		-3	-2	-4.1	99.14
c.76G>C	G26R 2D AIThe SynGAP1 missense variant G26R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of the four high‑accuracy tools) also yields benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy consensus—indicates that G26R is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.486429	Structured	0.438291	Uncertain	0.351	0.878	0.375											-2.946	Likely Benign	0.678	Likely Pathogenic	Likely Benign										0.189	Likely Benign	-2.22	Neutral	0.994	Probably Damaging	0.990	Probably Damaging	3.87	Benign	0.00	Affected	4.32	1	0.1097	0.4407		-3	-2	-4.1	99.14
c.770G>A	S257N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S257N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split consensus: benign calls come from FoldX, Rosetta, Foldetta, PROVEAN, SIFT, and FATHMM, while pathogenic calls come from REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments give an inconclusive SGM Consensus (a tie between AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), an uncertain AlphaMissense‑Optimized result, and a benign Foldetta prediction. No evidence of pathogenicity is supported by the protein‑stability analysis, which indicates a benign effect. Overall, the predictions are mixed, but the majority of high‑accuracy tools lean toward a benign interpretation. This assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.384043	Structured	0.258293	Uncertain	0.847	0.272	0.250											-10.508	Likely Pathogenic	0.820	Likely Pathogenic	Ambiguous	0.25	Likely Benign	0.1	-0.18	Likely Benign	0.04	Likely Benign	0.85	Ambiguous	0.533	Likely Pathogenic	-2.30	Neutral	0.993	Probably Damaging	0.968	Probably Damaging	5.82	Benign	0.16	Tolerated			0.0985	0.3596		1	1	-2.7	27.03
c.770G>C	S257T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority benign) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that S257T is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.384043	Structured	0.258293	Uncertain	0.847	0.272	0.250											-8.603	Likely Pathogenic	0.243	Likely Benign	Likely Benign	0.42	Likely Benign	0.1	-0.16	Likely Benign	0.13	Likely Benign	0.06	Likely Benign	0.472	Likely Benign	-1.58	Neutral	0.982	Probably Damaging	0.952	Probably Damaging	5.83	Benign	0.48	Tolerated			0.1073	0.4898		1	1	0.1	14.03
c.770G>T	S257I 2D AIThe SynGAP1 missense variant S257I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating likely pathogenic, and Foldetta predicting a benign outcome. FoldX and Rosetta results are uncertain and therefore not considered. Overall, the balance of evidence leans toward a pathogenic interpretation, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.258293	Uncertain	0.847	0.272	0.250											-12.126	Likely Pathogenic	0.595	Likely Pathogenic	Likely Benign	0.78	Ambiguous	1.0	-1.17	Ambiguous	-0.20	Likely Benign	0.30	Likely Benign	0.739	Likely Pathogenic	-2.97	Deleterious	0.998	Probably Damaging	0.991	Probably Damaging	5.81	Benign	0.07	Tolerated			0.0681	0.5209		-1	-2	5.3	26.08
c.771C>A	S257R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools show a split: benign calls come from FoldX, premPS, SIFT, and FATHMM, whereas pathogenic calls are made by REVEL, PROVEAN, both polyPhen‑2 versions, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain outcomes include Rosetta and Foldetta. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta’s stability analysis is inconclusive. Overall, the majority of reliable predictors indicate a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Therefore, the variant is most likely pathogenic, and this assessment is consistent with its lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.258293	Uncertain	0.847	0.272	0.250											-11.746	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	-0.18	Likely Benign	0.0	-1.33	Ambiguous	-0.76	Ambiguous	0.29	Likely Benign	0.707	Likely Pathogenic	-3.38	Deleterious	0.998	Probably Damaging	0.986	Probably Damaging	5.81	Benign	0.13	Tolerated			0.0762	0.3068		0	-1	-3.7	69.11
c.771C>G	S257R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, whereas those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (7 pathogenic vs. 4 benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.258293	Uncertain	0.847	0.272	0.250											-11.746	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	-0.18	Likely Benign	0.0	-1.33	Ambiguous	-0.76	Ambiguous	0.29	Likely Benign	0.707	Likely Pathogenic	-3.38	Deleterious	0.998	Probably Damaging	0.986	Probably Damaging	5.81	Benign	0.13	Tolerated			0.0762	0.3068		0	-1	-3.7	69.11
c.772C>A	R258S 2D AIThe SynGAP1 missense variant R258S is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect are limited to FATHMM, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect for R258S, and this conclusion is consistent with the absence of ClinVar annotation or gnomAD frequency data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.295083	Structured	0.293667	Uncertain	0.894	0.260	0.250											-14.336	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	2.11	Destabilizing	0.8	1.29	Ambiguous	1.70	Ambiguous	1.14	Destabilizing	0.796	Likely Pathogenic	-4.92	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	5.89	Benign	0.01	Affected			0.3057	0.3881		0	-1	3.7	-69.11
c.772C>G	R258G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R258G is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining twelve tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the variant as pathogenic; premPS remains uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No prediction is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.295083	Structured	0.293667	Uncertain	0.894	0.260	0.250											-14.239	Likely Pathogenic	0.980	Likely Pathogenic	Likely Pathogenic	2.42	Destabilizing	0.5	2.33	Destabilizing	2.38	Destabilizing	0.94	Ambiguous	0.788	Likely Pathogenic	-5.83	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	5.78	Benign	0.04	Affected			0.3166	0.3447		-3	-2	4.1	-99.14
c.772C>T	R258C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R258C missense variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33437677‑C‑T). Prediction tools that agree on a benign effect include only FATHMM. All other evaluated predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—indicate a pathogenic or likely pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.295083	Structured	0.293667	Uncertain	0.894	0.260	0.250					Uncertain		1	6-33437677-C-T	1	6.20e-7	-10.285	Likely Pathogenic	0.790	Likely Pathogenic	Ambiguous	1.17	Ambiguous	0.4	1.76	Ambiguous	1.47	Ambiguous	0.87	Ambiguous	0.771	Likely Pathogenic	-6.79	Deleterious	1.000	Probably Damaging	0.993	Probably Damaging	5.77	Benign	0.00	Affected	3.39	15	0.3307	0.3411		-3	-4	7.0	-53.05
c.773G>A	R258H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R258H is listed as Benign in ClinVar (ID 949697.0) and is present in gnomAD (6‑33437678‑G‑A). Prediction tools that agree on a benign effect include FATHMM and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain calls come from FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. The high‑accuracy consensus (SGM) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic verdict. AlphaMissense‑Optimized remains benign, while Foldetta is inconclusive. Overall, the majority of evidence points to a pathogenic impact, which contradicts the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.295083	Structured	0.293667	Uncertain	0.894	0.260	0.250					Benign/Likely benign		3	6-33437678-G-A	10	6.20e-6	-10.533	Likely Pathogenic	0.525	Ambiguous	Likely Benign	1.60	Ambiguous	0.6	1.00	Ambiguous	1.30	Ambiguous	1.47	Destabilizing	0.830	Likely Pathogenic	-4.06	Deleterious	1.000	Probably Damaging	0.991	Probably Damaging	5.77	Benign	0.01	Affected	3.39	15	0.2925	0.1980		2	0	1.3	-19.05	212.5	81.8	0.1	0.0	-0.5	0.2		X						Potentially Pathogenic	The guanidinium group of Arg258, located at the end of an α-β loop connecting the PH domain to the C2 domain (res. Lys251-Arg258), forms hydrogen bonds with the carboxamide groups of Asn727 and Asn729 side chains, as well as with the backbone carbonyl groups of Ala724, Leu725, and Asn727 in the WT simulations. Although the imidazole group of His258 can act as a hydrogen bond donor/acceptor, the swapped residue is unable to maintain an equally well-coordinated hydrogen bond network for linking the C2 and GAP domains in the variant simulations.
c.773G>C	R258P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R258P is not reported in ClinVar and has no entries in gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only FATHMM predicts a benign outcome. Predictions of uncertain status come from FoldX, Rosetta, and Foldetta. High‑accuracy tools reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta remains inconclusive. Overall, the preponderance of evidence supports a pathogenic classification for R258P, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.295083	Structured	0.293667	Uncertain	0.894	0.260	0.250											-14.293	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	1.26	Ambiguous	0.4	0.92	Ambiguous	1.09	Ambiguous	1.00	Destabilizing	0.924	Likely Pathogenic	-5.83	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	5.79	Benign	0.01	Affected			0.2148	0.4557		0	-2	2.9	-59.07
c.773G>T	R258L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R258L is not reported in ClinVar and is present in gnomAD (ID 6‑33437678‑G‑T). Prediction tools that agree on a benign effect include FoldX, Rosetta, FATHMM, and the combined Foldetta stability method. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Two tools give inconclusive results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.295083	Structured	0.293667	Uncertain	0.894	0.260	0.250								6-33437678-G-T	1	6.20e-7	-13.302	Likely Pathogenic	0.905	Likely Pathogenic	Ambiguous	0.14	Likely Benign	0.2	0.10	Likely Benign	0.12	Likely Benign	0.52	Ambiguous	0.908	Likely Pathogenic	-5.90	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	5.84	Benign	0.01	Affected	3.39	15	0.1606	0.4602		-2	-3	8.3	-43.03
c.775C>G	R259G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas the remaining 13 tools—including SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The high‑accuracy subset reinforces this assessment: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. Rosetta alone is uncertain and is treated as unavailable. Overall, the consensus of available predictions indicates that R259G is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.338208	Uncertain	0.885	0.255	0.250											-15.389	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	3.17	Destabilizing	0.6	1.53	Ambiguous	2.35	Destabilizing	1.14	Destabilizing	0.762	Likely Pathogenic	-6.43	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	5.78	Benign	0.00	Affected			0.3342	0.4139		-3	-2	4.1	-99.14
c.775C>T	R259W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R259W is listed in ClinVar with an uncertain significance (ClinVar ID 2014570.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, remains inconclusive. Overall, the preponderance of evidence indicates that R259W is most likely pathogenic, a conclusion that does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.338208	Uncertain	0.885	0.255	0.250					Uncertain		1				-12.186	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	1.95	Ambiguous	0.8	0.51	Ambiguous	1.23	Ambiguous	0.51	Ambiguous	0.691	Likely Pathogenic	-7.35	Deleterious	1.000	Probably Damaging	0.993	Probably Damaging	5.76	Benign	0.00	Affected	3.39	15	0.1221	0.4269		2	-3	3.6	30.03	254.0	40.0	0.2	0.2	0.2	0.4	X	X					X	Potentially Pathogenic	The guanidinium group of Arg259, located at the beginning of an anti-parallel β sheet strand (res. Arg259-Arg272), forms salt bridges with the carboxylate groups of Asp684 at the end of an α helix (res. Ile683-Gln702, GAP domain) and Asp261 on the same β strand. The Arg259 side chain also frequently forms hydrogen bonds with the backbone carbonyl groups of Ser257, Asn256, and Asp255. In the variant simulations, the indole ring of the Trp259 side chain cannot form salt bridges or maintain hydrogen bonding with the carboxylate group of Asp684 or other nearby residues. Notably, the amino group of the Lys254 side chain maintains a salt bridge with Asp684 and Glu244 throughout the variant simulations, while it forms a cation-π bond with the indole ring of Trp259 in the variant. This salt bridge is not maintained in the WT simulations. Additionally, the partially or loosely α helical conformation of a lysine-containing loop (res. Lys251-Ser257), which extends to a nearby α helix (res. Met414-Asn426), could be stabilized due to the residue swap. Moreover, the bulky size of the Trp259 side chain requires nearby residues to adjust their positioning to accommodate the introduced residue, weakening the tertiary structure assembly between the C2, PH, and GAP domains. The residue swap potentially causes more severe effects during protein folding or for the SynGAP-membrane interaction than the solvent-only simulations imply.
c.776G>A	R259Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259Q is catalogued in gnomAD (6‑33437681‑G‑A) but has no entry in ClinVar. In silico assessment shows a consensus of pathogenicity: 9 of 11 evaluated tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a deleterious effect, while only FATHMM indicates a benign outcome. Predictions of protein‑stability change are inconclusive, with FoldX, Rosetta and the combined Foldetta method returning uncertain results. High‑accuracy predictors reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies the variant as likely pathogenic; Foldetta remains uncertain. Overall, the computational evidence strongly favors a pathogenic interpretation, and this is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.338208	Uncertain	0.885	0.255	0.250								6-33437681-G-A	1	6.20e-7	-12.598	Likely Pathogenic	0.966	Likely Pathogenic	Likely Pathogenic	1.19	Ambiguous	0.3	1.30	Ambiguous	1.25	Ambiguous	1.40	Destabilizing	0.851	Likely Pathogenic	-3.68	Deleterious	0.999	Probably Damaging	0.978	Probably Damaging	5.81	Benign	0.01	Affected	3.39	15	0.3329	0.2703		1	1	1.0	-28.06	258.7	52.8	0.1	0.1	-0.3	0.4	X	X						Potentially Pathogenic	The guanidinium group of Arg259, located at the beginning of an anti-parallel β sheet strand (res. Arg259-Arg272), forms salt bridges with the carboxylate groups of Asp684 at the end of an α helix (res. Ile683-Gln702, GAP domain) and Asp261 on the same β strand. The Arg259 side chain also frequently forms hydrogen bonds with the backbone carbonyl groups of Ser257, Asn256, and Asp255. In the variant simulations, the carboxamide group of the Gln259 side chain cannot form salt bridges or maintain hydrogen bonding with the carboxylate group of Asp684, which could affect the tertiary structure assembly between the C2 and GAP domains. Notably, the amino group of the Lys254 side chain maintains a salt bridge with Asp684 and Glu244 throughout the variant simulations, but this interaction is not maintained in the WT simulations. Thus, the partially or loosely α helical conformation of a lysine-containing loop (res. Lys251-Ser257), which extends to a nearby α helix (res. Met414-Asn426), could be stabilized due to the residue swap.
c.776G>C	R259P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods further support this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.338208	Uncertain	0.885	0.255	0.250											-14.876	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	6.34	Destabilizing	1.6	3.78	Destabilizing	5.06	Destabilizing	1.16	Destabilizing	0.902	Likely Pathogenic	-6.43	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	5.84	Benign	0.00	Affected			0.2051	0.5249		0	-2	2.9	-59.07
c.776G>T	R259L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259L is not reported in ClinVar and is absent from gnomAD. Among the available in‑silico predictors, the benign‑predicted tools are Rosetta and FATHMM, while the pathogenic‑predicted tools include SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Foldetta and premPS are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of predictions support a pathogenic effect, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.338208	Uncertain	0.885	0.255	0.250											-14.185	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	2.84	Destabilizing	1.1	0.16	Likely Benign	1.50	Ambiguous	0.64	Ambiguous	0.894	Likely Pathogenic	-6.43	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	5.87	Benign	0.00	Affected			0.1934	0.5499		-3	-2	8.3	-43.03
c.778G>A	V260I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V260I missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome, while ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts benign. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.254060	Structured	0.382651	Uncertain	0.888	0.259	0.250											-7.525	In-Between	0.104	Likely Benign	Likely Benign	-0.16	Likely Benign	0.1	0.27	Likely Benign	0.06	Likely Benign	-0.14	Likely Benign	0.404	Likely Benign	-0.85	Neutral	0.994	Probably Damaging	0.970	Probably Damaging	5.83	Benign	0.19	Tolerated			0.0559	0.3704		4	3	0.3	14.03
c.778G>C	V260L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V260L missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, polyPhen‑2 (HumDiv and HumVar) and ESM1b. The high‑accuracy assessment shows AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, and Foldetta predicts a benign effect on protein stability. No prediction is missing or inconclusive. Overall, the evidence points to a benign effect for V260L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.254060	Structured	0.382651	Uncertain	0.888	0.259	0.250											-8.785	Likely Pathogenic	0.416	Ambiguous	Likely Benign	-0.26	Likely Benign	0.1	0.15	Likely Benign	-0.06	Likely Benign	0.25	Likely Benign	0.532	Likely Pathogenic	-1.84	Neutral	0.994	Probably Damaging	0.970	Probably Damaging	5.90	Benign	0.11	Tolerated			0.0730	0.4360		2	1	-0.4	14.03
c.778G>T	V260L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V260L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the variant is most likely benign based on the aggregate predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.254060	Structured	0.382651	Uncertain	0.888	0.259	0.250											-8.785	Likely Pathogenic	0.416	Ambiguous	Likely Benign	-0.26	Likely Benign	0.1	0.15	Likely Benign	-0.06	Likely Benign	0.25	Likely Benign	0.532	Likely Pathogenic	-1.84	Neutral	0.994	Probably Damaging	0.970	Probably Damaging	5.90	Benign	0.11	Tolerated			0.0730	0.4360		2	1	-0.4	14.03
c.779T>A	V260E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V260E is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign impact on protein stability. Overall, the majority of computational evidence points toward a pathogenic interpretation, and this conclusion is not contradicted by the ClinVar status. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.254060	Structured	0.382651	Uncertain	0.888	0.259	0.250											-9.516	Likely Pathogenic	0.667	Likely Pathogenic	Likely Benign	-0.02	Likely Benign	0.1	0.32	Likely Benign	0.15	Likely Benign	1.10	Destabilizing	0.848	Likely Pathogenic	-3.66	Deleterious	0.999	Probably Damaging	0.991	Probably Damaging	5.79	Benign	0.09	Tolerated			0.0846	0.1636		-2	-2	-7.7	29.98
c.779T>C	V260A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V260A missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, the SGM‑Consensus (majority vote), and Foldetta. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Two tools (premPS and AlphaMissense‑Default) give uncertain results. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta—all indicate a benign outcome. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.254060	Structured	0.382651	Uncertain	0.888	0.259	0.250											-3.271	Likely Benign	0.407	Ambiguous	Likely Benign	0.38	Likely Benign	0.0	0.02	Likely Benign	0.20	Likely Benign	0.81	Ambiguous	0.487	Likely Benign	-1.41	Neutral	0.994	Probably Damaging	0.970	Probably Damaging	5.87	Benign	0.33	Tolerated			0.2676	0.1903		0	0	-2.4	-28.05
c.779T>G	V260G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V260G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FATHMM and AlphaMissense‑Optimized, while the majority of tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. FoldX, Rosetta, and Foldetta are uncertain and therefore not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (3 pathogenic vs. 1 benign). Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for V260G, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.254060	Structured	0.382651	Uncertain	0.888	0.259	0.250											-9.300	Likely Pathogenic	0.644	Likely Pathogenic	Likely Benign	1.00	Ambiguous	0.3	1.86	Ambiguous	1.43	Ambiguous	1.40	Destabilizing	0.817	Likely Pathogenic	-4.20	Deleterious	0.991	Probably Damaging	0.999	Probably Damaging	5.76	Benign	0.00	Affected			0.1844	0.1949		-1	-3	-4.6	-42.08
c.77G>A	G26E 2D AIThe SynGAP1 missense variant G26E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.486429	Structured	0.438291	Uncertain	0.351	0.878	0.375											-3.966	Likely Benign	0.481	Ambiguous	Likely Benign										0.199	Likely Benign	-2.08	Neutral	0.994	Probably Damaging	0.986	Probably Damaging	3.90	Benign	0.00	Affected			0.1623	0.4238		0	-2	-3.1	72.06
c.77G>C	G26A 2D AIThe SynGAP1 missense variant G26A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G26A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.486429	Structured	0.438291	Uncertain	0.351	0.878	0.375											-3.308	Likely Benign	0.135	Likely Benign	Likely Benign										0.062	Likely Benign	-1.25	Neutral	0.953	Possibly Damaging	0.952	Probably Damaging	4.02	Benign	0.00	Affected			0.4093	0.5251		1	0	2.2	14.03
c.77G>T	G26V 2D AIThe SynGAP1 missense variant G26V is reported in gnomAD (variant ID 6‑33423486‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: the benign‑predicted set includes REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the pathogenic‑predicted set contains polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” No Foldetta stability result is available, so it does not influence the conclusion. Overall, the majority of evidence points to a benign effect for G26V, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.486429	Structured	0.438291	Uncertain	0.351	0.878	0.375								6-33423486-G-T	1	6.20e-7	-3.499	Likely Benign	0.165	Likely Benign	Likely Benign										0.197	Likely Benign	-2.34	Neutral	0.994	Probably Damaging	0.990	Probably Damaging	3.89	Benign	0.00	Affected	4.32	1	0.1344	0.4333		-3	-1	4.6	42.08
c.781G>A	D261N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261N is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include premPS, FATHMM, and AlphaMissense‑Optimized, while the majority of tools predict a pathogenic outcome: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.422514	Uncertain	0.883	0.264	0.125											-11.804	Likely Pathogenic	0.746	Likely Pathogenic	Likely Benign	1.58	Ambiguous	0.7	1.28	Ambiguous	1.43	Ambiguous	0.23	Likely Benign	0.579	Likely Pathogenic	-2.94	Deleterious	0.997	Probably Damaging	0.989	Probably Damaging	5.82	Benign	0.02	Affected			0.0767	0.4745		2	1	0.0	-0.98
c.781G>C	D261H 2D AIThe SynGAP1 missense variant D261H is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are premPS and FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; Rosetta is uncertain and is treated as unavailable. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic (3 pathogenic vs. 1 benign); and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.422514	Uncertain	0.883	0.264	0.125											-13.688	Likely Pathogenic	0.961	Likely Pathogenic	Likely Pathogenic	4.33	Destabilizing	3.2	0.93	Ambiguous	2.63	Destabilizing	0.33	Likely Benign	0.780	Likely Pathogenic	-3.67	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	6.04	Benign	0.01	Affected			0.0937	0.5465		1	-1	0.3	22.05
c.781G>T	D261Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D261Y missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are premPS and FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect; and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No prediction or folding stability result is missing or inconclusive beyond the stated uncertainties. Overall, the preponderance of evidence points to a pathogenic effect for D261Y, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.422514	Uncertain	0.883	0.264	0.125											-14.961	Likely Pathogenic	0.955	Likely Pathogenic	Ambiguous	2.93	Destabilizing	2.1	0.81	Ambiguous	1.87	Ambiguous	-0.12	Likely Benign	0.886	Likely Pathogenic	-5.50	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	5.73	Benign	0.01	Affected			0.0474	0.5476		-4	-3	2.2	48.09
c.782A>C	D261A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D261A missense variant is not reported in ClinVar (status: None) and has no entries in gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, while the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Given the preponderance of pathogenic predictions and the lack of conflicting evidence, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.422514	Uncertain	0.883	0.264	0.125											-11.426	Likely Pathogenic	0.913	Likely Pathogenic	Ambiguous	1.70	Ambiguous	0.3	1.46	Ambiguous	1.58	Ambiguous	0.04	Likely Benign	0.839	Likely Pathogenic	-4.59	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	5.80	Benign	0.04	Affected			0.2785	0.4577		0	-2	5.3	-44.01
c.782A>G	D261G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261G is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include premPS and FATHMM, while the remaining tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Based on the aggregate predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.422514	Uncertain	0.883	0.264	0.125											-10.847	Likely Pathogenic	0.945	Likely Pathogenic	Ambiguous	2.81	Destabilizing	0.5	2.96	Destabilizing	2.89	Destabilizing	0.21	Likely Benign	0.850	Likely Pathogenic	-4.77	Deleterious	0.997	Probably Damaging	0.989	Probably Damaging	5.81	Benign	0.02	Affected			0.2924	0.4562		1	-1	3.1	-58.04
c.782A>T	D261V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, and FATHMM, while those that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.422514	Uncertain	0.883	0.264	0.125											-12.138	Likely Pathogenic	0.923	Likely Pathogenic	Ambiguous	1.72	Ambiguous	0.6	-0.68	Ambiguous	0.52	Ambiguous	-0.01	Likely Benign	0.869	Likely Pathogenic	-5.50	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	5.73	Benign	0.08	Tolerated			0.0553	0.4734		-2	-3	7.7	-15.96
c.783C>A	D261E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The high‑accuracy consensus from AlphaMissense‑Optimized and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) both indicate a benign outcome, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is inconclusive. Overall, the majority of evidence points to a benign impact. This assessment is consistent with the absence of ClinVar annotation and does not contradict any existing database status. Based on the predictions, the variant is most likely benign, and this does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.284882	Structured	0.422514	Uncertain	0.883	0.264	0.125											-2.646	Likely Benign	0.268	Likely Benign	Likely Benign	1.44	Ambiguous	0.8	0.79	Ambiguous	1.12	Ambiguous	-0.03	Likely Benign	0.377	Likely Benign	0.20	Neutral	0.994	Probably Damaging	0.978	Probably Damaging	5.88	Benign	1.00	Tolerated			0.0963	0.4359		3	2	0.0	14.03
c.783C>G	D261E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Protein‑stability calculations from FoldX and Rosetta are uncertain. Overall, the majority of evidence points to a benign impact, which is consistent with the absence of a ClinVar claim and gnomAD observation. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.284882	Structured	0.422514	Uncertain	0.883	0.264	0.125											-2.646	Likely Benign	0.268	Likely Benign	Likely Benign	1.44	Ambiguous	0.8	0.79	Ambiguous	1.12	Ambiguous	-0.03	Likely Benign	0.377	Likely Benign	0.20	Neutral	0.994	Probably Damaging	0.978	Probably Damaging	5.88	Benign	1.00	Tolerated			0.0963	0.4359		3	2	0.0	14.03
c.784A>C	N262H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Rosetta, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. FoldX and Foldetta results are uncertain, providing no clear direction. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.284882	Structured	0.399879	Uncertain	0.912	0.240	0.000											-6.932	Likely Benign	0.154	Likely Benign	Likely Benign	1.82	Ambiguous	0.5	0.41	Likely Benign	1.12	Ambiguous	0.33	Likely Benign	0.694	Likely Pathogenic	-3.44	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	5.81	Benign	0.41	Tolerated			0.1122	0.4860		2	1	0.3	23.04
c.784A>G	N262D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N262D is reported in gnomAD (ID 6‑33437689‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from FoldX, Rosetta, Foldetta, and FATHMM; pathogenic predictions from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is Uncertain, SGM‑Consensus remains Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.399879	Uncertain	0.912	0.240	0.000								6-33437689-A-G	1	6.20e-7	-13.363	Likely Pathogenic	0.848	Likely Pathogenic	Ambiguous	0.27	Likely Benign	0.1	0.36	Likely Benign	0.32	Likely Benign	1.16	Destabilizing	0.820	Likely Pathogenic	-4.31	Deleterious	0.997	Probably Damaging	0.980	Probably Damaging	5.85	Benign	0.05	Affected	3.40	14	0.1696	0.2586		1	2	0.0	0.98
c.784A>T	N262Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (seven pathogenic vs. three benign) lean toward a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.284882	Structured	0.399879	Uncertain	0.912	0.240	0.000											-12.177	Likely Pathogenic	0.490	Ambiguous	Likely Benign	1.86	Ambiguous	0.5	0.52	Ambiguous	1.19	Ambiguous	0.36	Likely Benign	0.858	Likely Pathogenic	-6.48	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	5.85	Benign	0.01	Affected			0.0445	0.3877		-2	-2	2.2	49.07
c.785A>C	N262T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262T has no ClinVar record and is not reported in gnomAD. Functional prediction tools cluster into three groups: benign predictions come from SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b; the remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta’s stability analysis is uncertain. Overall, the balance of evidence leans toward pathogenicity, with no conflict with ClinVar status (which is absent). Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.284882	Structured	0.399879	Uncertain	0.912	0.240	0.000											-11.478	Likely Pathogenic	0.544	Ambiguous	Likely Benign	1.40	Ambiguous	0.3	1.44	Ambiguous	1.42	Ambiguous	0.74	Ambiguous	0.723	Likely Pathogenic	-5.23	Deleterious	0.997	Probably Damaging	0.980	Probably Damaging	5.88	Benign	0.19	Tolerated			0.1055	0.5164		0	0	2.8	-13.00
c.785A>G	N262S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N262S is not listed in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools cluster into two groups: benign predictions come from SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is uncertain. Consequently, the overall evidence is mixed, with a slight tilt toward pathogenicity because five tools predict pathogenic while four predict benign. The variant is most likely pathogenic based on the current predictions, and this assessment does not contradict ClinVar status, as the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.284882	Structured	0.399879	Uncertain	0.912	0.240	0.000											-8.841	Likely Pathogenic	0.182	Likely Benign	Likely Benign	0.91	Ambiguous	0.2	0.90	Ambiguous	0.91	Ambiguous	0.69	Ambiguous	0.638	Likely Pathogenic	-4.31	Deleterious	0.997	Probably Damaging	0.970	Probably Damaging	5.84	Benign	0.16	Tolerated			0.3101	0.5158		1	1	2.7	-27.03
c.785A>T	N262I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262I is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include premPS and FATHMM, whereas the majority of tools predict a pathogenic outcome: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are uncertain and therefore treated as unavailable. High‑accuracy methods give an uncertain result for AlphaMissense‑Optimized, a pathogenic consensus from SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain result for Foldetta. Overall, the evidence points to a pathogenic effect for the variant, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.399879	Uncertain	0.912	0.240	0.000											-15.203	Likely Pathogenic	0.868	Likely Pathogenic	Ambiguous	1.21	Ambiguous	0.4	0.54	Ambiguous	0.88	Ambiguous	0.09	Likely Benign	0.777	Likely Pathogenic	-7.79	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	5.88	Benign	0.01	Affected			0.0449	0.4638		-2	-3	8.0	-0.94
c.786T>A	N262K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262K has no ClinVar entry and is not present in gnomAD. Prediction tools that indicate a benign effect include FoldX, premPS, and FATHMM. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic impact for N262K. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.399879	Uncertain	0.912	0.240	0.000											-12.512	Likely Pathogenic	0.962	Likely Pathogenic	Likely Pathogenic	0.47	Likely Benign	0.2	1.00	Ambiguous	0.74	Ambiguous	0.33	Likely Benign	0.531	Likely Pathogenic	-5.13	Deleterious	0.997	Probably Damaging	0.986	Probably Damaging	5.84	Benign	0.02	Affected			0.1799	0.3413		1	0	-0.4	14.07
c.786T>G	N262K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262K has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely disagree: benign predictions come from FoldX, premPS, and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and Foldetta. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Taken together, the majority of evidence points to a pathogenic effect for N262K. This conclusion is consistent with the absence of a ClinVar classification, as there is no existing report to contradict the prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.399879	Uncertain	0.912	0.240	0.000											-12.512	Likely Pathogenic	0.962	Likely Pathogenic	Likely Pathogenic	0.47	Likely Benign	0.2	1.00	Ambiguous	0.74	Ambiguous	0.33	Likely Benign	0.532	Likely Pathogenic	-5.13	Deleterious	0.997	Probably Damaging	0.986	Probably Damaging	5.84	Benign	0.02	Affected			0.1799	0.3413		1	0	-0.4	14.07
c.787G>A	V263M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Benign. No conflicting evidence is present. **Based on the aggregate predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.268042	Structured	0.356141	Uncertain	0.918	0.257	0.000											-5.956	Likely Benign	0.218	Likely Benign	Likely Benign	0.20	Likely Benign	0.1	-0.24	Likely Benign	-0.02	Likely Benign	0.43	Likely Benign	0.444	Likely Benign	-0.95	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	5.84	Benign	0.03	Affected			0.0665	0.3545		2	1	-2.3	32.06
c.787G>C	V263L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are inconclusive are Rosetta (Uncertain) and premPS (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.268042	Structured	0.356141	Uncertain	0.918	0.257	0.000											-6.599	Likely Benign	0.275	Likely Benign	Likely Benign	-0.16	Likely Benign	0.1	-0.63	Ambiguous	-0.40	Likely Benign	0.66	Ambiguous	0.453	Likely Benign	-1.26	Neutral	0.994	Probably Damaging	0.970	Probably Damaging	5.85	Benign	0.18	Tolerated			0.0759	0.3950		2	1	-0.4	14.03
c.787G>T	V263L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are inconclusive are Rosetta (Uncertain) and premPS (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.268042	Structured	0.356141	Uncertain	0.918	0.257	0.000											-6.599	Likely Benign	0.275	Likely Benign	Likely Benign	-0.16	Likely Benign	0.1	-0.63	Ambiguous	-0.40	Likely Benign	0.66	Ambiguous	0.453	Likely Benign	-1.26	Neutral	0.994	Probably Damaging	0.970	Probably Damaging	5.85	Benign	0.18	Tolerated			0.0759	0.3950		2	1	-0.4	14.03
c.788T>A	V263E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V263E missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools largely agree on a deleterious effect: FATHMM predicts the variant as benign, while the remaining twelve tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—classify it as pathogenic. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized remains uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Overall, the preponderance of evidence points to a pathogenic impact for V263E, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.268042	Structured	0.356141	Uncertain	0.918	0.257	0.000											-13.498	Likely Pathogenic	0.809	Likely Pathogenic	Ambiguous	2.04	Destabilizing	0.3	2.18	Destabilizing	2.11	Destabilizing	1.99	Destabilizing	0.862	Likely Pathogenic	-3.84	Deleterious	0.999	Probably Damaging	0.991	Probably Damaging	5.96	Benign	0.01	Affected			0.0886	0.1436		-2	-2	-7.7	29.98
c.788T>C	V263A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Rosetta, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), and SIFT. Predictions marked “Uncertain” include FoldX, Foldetta, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of evidence points to a benign effect. Thus, the variant is most likely benign based on current predictions, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.268042	Structured	0.356141	Uncertain	0.918	0.257	0.000											-6.877	Likely Benign	0.530	Ambiguous	Likely Benign	1.40	Ambiguous	0.1	0.00	Likely Benign	0.70	Ambiguous	1.26	Destabilizing	0.622	Likely Pathogenic	-2.17	Neutral	0.994	Probably Damaging	0.970	Probably Damaging	5.97	Benign	0.04	Affected			0.2565	0.1822		0	0	-2.4	-28.05
c.788T>G	V263G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V263G missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized; those that agree on a pathogenic effect are REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta’s stability prediction is uncertain. Overall, the preponderance of evidence points to a pathogenic impact for V263G, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.268042	Structured	0.356141	Uncertain	0.918	0.257	0.000											-10.388	Likely Pathogenic	0.669	Likely Pathogenic	Likely Benign	2.27	Destabilizing	0.2	1.63	Ambiguous	1.95	Ambiguous	1.88	Destabilizing	0.820	Likely Pathogenic	-4.59	Deleterious	0.991	Probably Damaging	0.999	Probably Damaging	6.07	Benign	0.01	Affected			0.1790	0.1868		-1	-3	-4.6	-42.08
c.790C>A	L264I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L264I is not reported in ClinVar and is present in gnomAD (ID 6‑33437695‑C‑A). Prediction tools that indicate a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the balance of evidence—six pathogenic versus three benign predictions, a pathogenic SGM Consensus, and an uncertain Foldetta—suggests that the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.185198	Structured	0.323473	Uncertain	0.939	0.264	0.000								6-33437695-C-A	1	6.20e-7	-10.945	Likely Pathogenic	0.638	Likely Pathogenic	Likely Benign	1.90	Ambiguous	0.5	0.84	Ambiguous	1.37	Ambiguous	0.95	Ambiguous	0.418	Likely Benign	-1.84	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	0.66	Pathogenic	0.02	Affected	3.38	18	0.0764	0.2630		2	2	0.7	0.00
c.790C>G	L264V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and AlphaMissense‑Optimized; all other evaluated algorithms (SGM‑Consensus, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic or likely pathogenic outcome, while Rosetta remains uncertain. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies the variant as Pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for L264V, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.185198	Structured	0.323473	Uncertain	0.939	0.264	0.000											-10.621	Likely Pathogenic	0.630	Likely Pathogenic	Likely Benign	2.55	Destabilizing	0.1	1.62	Ambiguous	2.09	Destabilizing	1.24	Destabilizing	0.444	Likely Benign	-2.76	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	0.73	Pathogenic	0.01	Affected			0.1280	0.2289		2	1	0.4	-14.03
c.791T>A	L264Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264Q is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.185198	Structured	0.323473	Uncertain	0.939	0.264	0.000					Uncertain		1				-15.729	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	3.43	Destabilizing	0.1	2.41	Destabilizing	2.92	Destabilizing	2.48	Destabilizing	0.678	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.49	Pathogenic	0.00	Affected	3.38	18	0.0942	0.0558		-2	-2	-7.3	14.97	254.7	-7.6	0.0	0.0	0.0	0.3	X		X				X	Potentially Pathogenic	The iso-butyl branched hydrocarbon side chain of Leu264, located at the end of an anti-parallel β sheet strand (res. Arg259-Arg272), packs against multiple hydrophobic residues such as Leu266, Phe314, Leu317, and Leu323 in the WT simulations. In the variant simulations, the hydrophilic carboxamide group of the Gln264 side chain is not suitable for the hydrophobic niche, causing the hydrophobic residues to make room for the swapped residue. Additionally, the carboxamide group of Gln264 forms hydrogen bonds with the backbone amide groups of Arg405 and Lys256 in the β sheet and the carbonyl group of Val350 in an α helical section of a nearby loop (res. Pro359-Phe358). The residue swap disrupts the packing of the C2 domain, which could adversely affect the C2 domain structure during folding. This disruption could potentially weaken the stability of the SynGAP-membrane association.
c.791T>C	L264P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset reports a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.185198	Structured	0.323473	Uncertain	0.939	0.264	0.000					Uncertain		1				-12.285	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	5.73	Destabilizing	0.3	6.57	Destabilizing	6.15	Destabilizing	2.65	Destabilizing	0.767	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.49	Pathogenic	0.00	Affected			0.3239	0.1053		-3	-3	-5.4	-16.04
c.791T>G	L264R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264R is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.185198	Structured	0.323473	Uncertain	0.939	0.264	0.000											-16.976	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.25	Destabilizing	0.3	3.37	Destabilizing	3.81	Destabilizing	2.28	Destabilizing	0.742	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.49	Pathogenic	0.00	Affected			0.1132	0.0558		-3	-2	-8.3	43.03
c.793A>C	K265Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K265Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Among standard in‑silico predictors, five tools (REVEL, FoldX, PROVEAN, AlphaMissense‑Optimized, Foldetta) predict a benign effect, while five (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM) predict pathogenicity. Three tools (premPS, AlphaMissense‑Default, Rosetta) are inconclusive. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a pathogenic consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and a benign outcome from Foldetta. Overall, the predictions are mixed; the balance of evidence, including the two high‑confidence benign calls, suggests the variant is more likely benign, and this does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.209395	Structured	0.309758	Uncertain	0.936	0.275	0.000											-8.533	Likely Pathogenic	0.505	Ambiguous	Likely Benign	0.35	Likely Benign	0.1	-1.15	Ambiguous	-0.40	Likely Benign	0.80	Ambiguous	0.386	Likely Benign	-2.46	Neutral	1.000	Probably Damaging	0.998	Probably Damaging	1.85	Pathogenic	0.05	Affected			0.4401	0.1062		1	1	0.4	-0.04
c.793A>G	K265E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265E missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and Foldetta. Those that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are AlphaMissense‑Optimized, FoldX, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evaluated tools (eight pathogenic vs. three benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.209395	Structured	0.309758	Uncertain	0.936	0.275	0.000											-12.163	Likely Pathogenic	0.952	Likely Pathogenic	Ambiguous	0.63	Ambiguous	0.2	0.00	Likely Benign	0.32	Likely Benign	0.95	Ambiguous	0.461	Likely Benign	-2.79	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.94	Pathogenic	0.05	Affected			0.3801	0.0882		0	1	0.4	0.94
c.794A>C	K265T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265T missense variant is reported in gnomAD (ID 6‑33437699‑A‑C) but has no ClinVar entry. Prediction tools that classify the variant as benign include REVEL, SIFT, and Rosetta. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Four tools give uncertain results: FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.209395	Structured	0.309758	Uncertain	0.936	0.275	0.000								6-33437699-A-C	1	6.20e-7	-9.425	Likely Pathogenic	0.839	Likely Pathogenic	Ambiguous	0.99	Ambiguous	0.1	0.37	Likely Benign	0.68	Ambiguous	0.83	Ambiguous	0.441	Likely Benign	-3.75	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.91	Pathogenic	0.07	Tolerated	3.38	18	0.2042	0.3178		-1	0	3.2	-27.07
c.794A>G	K265R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K265R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster into two groups: benign predictions include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. No prediction or stability result is missing or inconclusive. Based on the aggregate evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.209395	Structured	0.309758	Uncertain	0.936	0.275	0.000											-3.366	Likely Benign	0.136	Likely Benign	Likely Benign	0.04	Likely Benign	0.1	-0.44	Likely Benign	-0.20	Likely Benign	0.30	Likely Benign	0.223	Likely Benign	-1.08	Neutral	0.999	Probably Damaging	0.995	Probably Damaging	1.90	Pathogenic	0.36	Tolerated			0.4713	0.0976		3	2	-0.6	28.01
c.794A>T	K265M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265M missense variant is not reported in ClinVar and has no entries in gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify it as damaging. Benign predictions are limited to FoldX, Foldetta, and premPS. Uncertain results come from Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this view: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, while Foldetta predicts a benign folding‑stability change. Overall, the preponderance of evidence supports a pathogenic classification for K265M, and this conclusion is not contradicted by the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.209395	Structured	0.309758	Uncertain	0.936	0.275	0.000											-10.885	Likely Pathogenic	0.904	Likely Pathogenic	Ambiguous	-0.22	Likely Benign	0.2	-0.63	Ambiguous	-0.43	Likely Benign	0.19	Likely Benign	0.516	Likely Pathogenic	-3.78	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.79	Pathogenic	0.01	Affected			0.1005	0.3695		0	-1	5.8	3.02
c.795G>C	K265N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and Rosetta, whereas the majority of algorithms predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.209395	Structured	0.309758	Uncertain	0.936	0.275	0.000											-8.759	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	0.98	Ambiguous	0.1	0.16	Likely Benign	0.57	Ambiguous	0.85	Ambiguous	0.350	Likely Benign	-3.26	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.86	Pathogenic	0.03	Affected			0.3691	0.1158		1	0	0.4	-14.07
c.795G>T	K265N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and Rosetta, while the majority of algorithms predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain or inconclusive results are reported only for FoldX, Foldetta, and premPS, and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.209395	Structured	0.309758	Uncertain	0.936	0.275	0.000											-8.759	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	0.98	Ambiguous	0.1	0.16	Likely Benign	0.57	Ambiguous	0.85	Ambiguous	0.351	Likely Benign	-3.26	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.86	Pathogenic	0.03	Affected			0.3691	0.1158		1	0	0.4	-14.07
c.796C>A	L266M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools remain uncertain: premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of tools (six benign vs. four pathogenic, with two uncertain) lean toward a benign classification, and this conclusion is not contradicted by ClinVar status. Thus, the variant is most likely benign based on the collective predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.232838	Structured	0.297157	Uncertain	0.948	0.264	0.000											-9.740	Likely Pathogenic	0.362	Ambiguous	Likely Benign	0.07	Likely Benign	0.1	-0.47	Likely Benign	-0.20	Likely Benign	0.95	Ambiguous	0.288	Likely Benign	-1.66	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.55	Pathogenic	0.07	Tolerated			0.0581	0.2853		4	2	-1.9	18.03
c.796C>G	L266V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L266V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. FoldX, Rosetta, and Foldetta give uncertain results and are therefore considered unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic) and Foldetta is also inconclusive. Consequently, the variant is most likely benign based on the current predictions, and this assessment does not contradict ClinVar, which has no reported status for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.232838	Structured	0.297157	Uncertain	0.948	0.264	0.000											-8.586	Likely Pathogenic	0.153	Likely Benign	Likely Benign	1.71	Ambiguous	0.1	0.97	Ambiguous	1.34	Ambiguous	1.32	Destabilizing	0.193	Likely Benign	-2.20	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	2.37	Pathogenic	0.11	Tolerated			0.1152	0.2456		2	1	0.4	-14.03
c.797T>A	L266Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L266Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect: none. Tools that agree on a pathogenic effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The only tool with an uncertain outcome is Rosetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.232838	Structured	0.297157	Uncertain	0.948	0.264	0.000											-16.672	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	2.92	Destabilizing	0.1	1.49	Ambiguous	2.21	Destabilizing	2.21	Destabilizing	0.563	Likely Pathogenic	-5.25	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.53	Pathogenic	0.00	Affected			0.0815	0.0558		-2	-2	-7.3	14.97
c.797T>C	L266P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No conflicting benign evidence is present. Therefore, the variant is most likely pathogenic, and this conclusion is consistent with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.232838	Structured	0.297157	Uncertain	0.948	0.264	0.000											-15.752	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	7.08	Destabilizing	0.1	4.02	Destabilizing	5.55	Destabilizing	2.31	Destabilizing	0.654	Likely Pathogenic	-6.06	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.53	Pathogenic	0.00	Affected			0.3158	0.1021		-3	-3	-5.4	-16.04
c.797T>G	L266R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect, so the benign‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.232838	Structured	0.297157	Uncertain	0.948	0.264	0.000											-17.131	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	3.97	Destabilizing	0.2	2.76	Destabilizing	3.37	Destabilizing	2.04	Destabilizing	0.574	Likely Pathogenic	-5.32	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.53	Pathogenic	0.00	Affected			0.1059	0.0558		-3	-2	-8.3	43.03
c.799T>A	W267R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267R has no ClinVar entry and is not reported in gnomAD. Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic or likely pathogenic scores. Tools that are inconclusive (FoldX and premPS) are noted as uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No benign predictions are present. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.298060	Uncertain	0.943	0.274	0.000											-13.868	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.94	Ambiguous	0.1	2.47	Destabilizing	2.21	Destabilizing	0.51	Ambiguous	0.672	Likely Pathogenic	-12.87	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.00	Pathogenic	0.01	Affected			0.3763	0.0571		2	-3	-3.6	-30.03
c.799T>C	W267R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267R is not reported in ClinVar (ClinVar status: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tools predict a benign outcome. Uncertain predictions are provided by FoldX and premPS. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts Likely Pathogenic; and Foldetta predicts Pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.298060	Uncertain	0.943	0.274	0.000											-13.868	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.94	Ambiguous	0.1	2.47	Destabilizing	2.21	Destabilizing	0.51	Ambiguous	0.672	Likely Pathogenic	-12.87	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.00	Pathogenic	0.01	Affected			0.3763	0.0571		2	-3	-3.6	-30.03
c.799T>G	W267G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy methods corroborate this: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic, with no contradiction to its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.298060	Uncertain	0.943	0.274	0.000											-15.020	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	4.40	Destabilizing	0.2	3.99	Destabilizing	4.20	Destabilizing	1.20	Destabilizing	0.678	Likely Pathogenic	-11.95	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.96	Pathogenic	0.03	Affected			0.4049	0.1481		-7	-2	0.5	-129.16
c.79C>A	P27T 2D AIThe SynGAP1 missense variant P27T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including high‑accuracy tools, points to a benign effect for P27T, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.517562	Disordered	0.437871	Uncertain	0.430	0.881	0.375											-3.612	Likely Benign	0.103	Likely Benign	Likely Benign										0.106	Likely Benign	-2.07	Neutral	0.909	Possibly Damaging	0.901	Possibly Damaging	3.85	Benign	0.00	Affected			0.2430	0.5923		0	-1	0.9	3.99
c.79C>G	P27A 2D AIThe SynGAP1 missense variant P27A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including high‑accuracy tools, points to a benign effect for P27A, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.517562	Disordered	0.437871	Uncertain	0.430	0.881	0.375											-3.409	Likely Benign	0.079	Likely Benign	Likely Benign										0.077	Likely Benign	-1.98	Neutral	0.805	Possibly Damaging	0.857	Possibly Damaging	3.90	Benign	0.00	Affected			0.4041	0.5219		1	-1	3.4	-26.04
c.79C>T	P27S 2D AIThe SynGAP1 missense variant P27S is reported in gnomAD (ID 6‑33423488‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign, and the SGM‑Consensus (derived from the majority of these high‑accuracy predictors) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign. Foldetta stability analysis is unavailable. Overall, the preponderance of evidence indicates that P27S is most likely benign, and this assessment does not contradict any ClinVar classification, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.517562	Disordered	0.437871	Uncertain	0.430	0.881	0.375								6-33423488-C-T	1	6.20e-7	-2.891	Likely Benign	0.098	Likely Benign	Likely Benign										0.063	Likely Benign	-2.01	Neutral	0.909	Possibly Damaging	0.901	Possibly Damaging	3.91	Benign	0.00	Affected	4.32	1	0.3916	0.5443		-1	1	0.8	-10.04
c.7A>G	R3G 2D AIThe SynGAP1 missense variant R3G is reported in gnomAD (ID 6‑33420271‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign; Foldetta results are unavailable. Taken together, the preponderance of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.550331	Binding	0.358	0.920	0.875								6-33420271-A-G			-3.093	Likely Benign	0.160	Likely Benign	Likely Benign										0.099	Likely Benign	-0.20	Neutral	0.115	Benign	0.018	Benign	3.99	Benign	0.00	Affected	4.32	1	0.3559	0.4114		-2	-3	4.1	-99.14
c.7A>T	R3W 2D AIThe SynGAP1 missense variant R3W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R3W, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.550331	Binding	0.358	0.920	0.875											-5.023	Likely Benign	0.591	Likely Pathogenic	Likely Benign										0.122	Likely Benign	0.08	Neutral	0.962	Probably Damaging	0.363	Benign	3.94	Benign	0.00	Affected			0.1407	0.4634		2	-3	3.6	30.03
c.800G>C	W267S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267S is not listed in ClinVar and has no allele in gnomAD. Functional prediction tools largely agree on a deleterious effect: SIFT is the sole benign predictor, whereas the remaining 12 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all report pathogenicity; premPS is uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.298060	Uncertain	0.943	0.274	0.000											-12.833	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	3.42	Destabilizing	0.3	3.20	Destabilizing	3.31	Destabilizing	0.87	Ambiguous	0.593	Likely Pathogenic	-12.87	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.03	Pathogenic	0.09	Tolerated			0.3809	0.1415		-2	-3	0.1	-99.14
c.800G>T	W267L 2D AIThe SynGAP1 missense variant W267L is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign effect. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS, which are treated as unavailable evidence. High‑accuracy assessments further support a damaging effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” while Foldetta’s stability prediction is uncertain. Overall, the evidence strongly indicates that W267L is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.298060	Uncertain	0.943	0.274	0.000											-13.670	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	1.19	Ambiguous	0.7	1.31	Ambiguous	1.25	Ambiguous	0.75	Ambiguous	0.628	Likely Pathogenic	-11.95	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.93	Pathogenic	0.01	Affected			0.2122	0.2843		-2	-2	4.7	-73.05
c.801G>C	W267C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267C is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic based on the consensus of all predictions, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.298060	Uncertain	0.943	0.274	0.000											-12.351	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	2.81	Destabilizing	0.2	2.20	Destabilizing	2.51	Destabilizing	1.00	Destabilizing	0.705	Likely Pathogenic	-11.95	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.90	Pathogenic	0.01	Affected			0.3573	0.1700		-8	-2	3.4	-83.07
c.801G>T	W267C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267C is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic based on the consensus of all predictions, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.298060	Uncertain	0.943	0.274	0.000											-12.351	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	2.81	Destabilizing	0.2	2.20	Destabilizing	2.51	Destabilizing	1.00	Destabilizing	0.705	Likely Pathogenic	-11.95	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.90	Pathogenic	0.01	Affected			0.3573	0.1700		-8	-2	3.4	-83.07
c.802A>C	I268L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Two tools give uncertain results: premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta indicates a benign folding‑stability outcome. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.216401	Structured	0.314336	Uncertain	0.951	0.264	0.000											-6.544	Likely Benign	0.402	Ambiguous	Likely Benign	0.37	Likely Benign	0.1	-0.07	Likely Benign	0.15	Likely Benign	0.96	Ambiguous	0.390	Likely Benign	-1.84	Neutral	0.981	Probably Damaging	0.970	Probably Damaging	1.65	Pathogenic	0.03	Affected			0.0635	0.3037		2	2	-0.7	0.00
c.802A>G	I268V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign, while Foldetta’s stability analysis is uncertain. Overall, the majority of reliable predictors indicate a benign impact, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.216401	Structured	0.314336	Uncertain	0.951	0.264	0.000											-4.553	Likely Benign	0.147	Likely Benign	Likely Benign	1.46	Ambiguous	0.0	0.95	Ambiguous	1.21	Ambiguous	0.71	Ambiguous	0.139	Likely Benign	-0.56	Neutral	0.958	Probably Damaging	0.970	Probably Damaging	2.15	Pathogenic	0.71	Tolerated			0.0845	0.2489		4	3	-0.3	-14.03
c.802A>T	I268F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome; only Rosetta and Foldetta are uncertain. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) remains uncertain. Overall, the consensus of available predictions strongly supports a pathogenic classification for I268F, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.314336	Uncertain	0.951	0.264	0.000											-11.426	Likely Pathogenic	0.968	Likely Pathogenic	Likely Pathogenic	2.85	Destabilizing	0.7	0.59	Ambiguous	1.72	Ambiguous	1.00	Destabilizing	0.685	Likely Pathogenic	-3.68	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.53	Pathogenic	0.00	Affected			0.0427	0.2158		1	0	-1.7	34.02
c.803T>A	I268N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.314336	Uncertain	0.951	0.264	0.000											-13.664	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	3.48	Destabilizing	0.1	3.17	Destabilizing	3.33	Destabilizing	2.21	Destabilizing	0.812	Likely Pathogenic	-6.26	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.51	Pathogenic	0.00	Affected			0.0708	0.0142		-2	-3	-8.0	0.94
c.803T>C	I268T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268T is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on pathogenicity include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a destabilizing, pathogenic effect. All available predictions are concordant and point to a deleterious impact. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.314336	Uncertain	0.951	0.264	0.000											-10.753	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	3.44	Destabilizing	0.1	3.19	Destabilizing	3.32	Destabilizing	1.93	Destabilizing	0.828	Likely Pathogenic	-4.24	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.53	Pathogenic	0.00	Affected			0.0882	0.0638		0	-1	-5.2	-12.05
c.803T>G	I268S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.314336	Uncertain	0.951	0.264	0.000											-13.032	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	4.93	Destabilizing	0.1	4.54	Destabilizing	4.74	Destabilizing	2.10	Destabilizing	0.841	Likely Pathogenic	-5.34	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.53	Pathogenic	0.00	Affected			0.2037	0.0530		-1	-2	-5.3	-26.08
c.804C>G	I268M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I268M missense variant is catalogued in gnomAD (ID 6‑33437709‑C‑G) but has no ClinVar entry. Functional prediction tools largely disagree: benign predictions come from FoldX and AlphaMissense‑Optimized, whereas the remaining evaluated algorithms (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all indicate pathogenicity. Rosetta and Foldetta provide inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it as likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the preponderance of evidence from the majority of prediction tools points to a pathogenic effect, which is consistent with the lack of a ClinVar classification but does not contradict any existing ClinVar status (none). Thus, the variant is most likely pathogenic, and this prediction does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.314336	Uncertain	0.951	0.264	0.000								6-33437709-C-G	1	6.20e-7	-9.721	Likely Pathogenic	0.739	Likely Pathogenic	Likely Benign	0.12	Likely Benign	0.2	0.95	Ambiguous	0.54	Ambiguous	1.32	Destabilizing	0.622	Likely Pathogenic	-2.58	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.52	Pathogenic	0.01	Affected	3.38	19	0.0579	0.2145		1	2	-2.6	18.03
c.805A>C	I269L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I269L missense variant is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors shows a predominance of benign calls: REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized all predict benign. Pathogenicity is suggested by polyPhen‑2 (HumDiv and HumVar) and FATHMM, while ESM1b and AlphaMissense‑Default remain uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, Foldetta predicts benign stability, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to an equal split between benign and pathogenic signals. Overall, the balance of evidence favors a benign effect for I269L, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.216401	Structured	0.343787	Uncertain	0.937	0.244	0.125											-7.588	In-Between	0.470	Ambiguous	Likely Benign	0.00	Likely Benign	0.0	0.19	Likely Benign	0.10	Likely Benign	0.47	Likely Benign	0.348	Likely Benign	-1.47	Neutral	0.981	Probably Damaging	0.970	Probably Damaging	1.88	Pathogenic	0.28	Tolerated			0.0662	0.2817		2	2	-0.7	0.00
c.805A>G	I269V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I269V missense variant has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that are uncertain or inconclusive are FoldX, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools lean toward a benign interpretation, but the high‑accuracy consensus indicates a pathogenic signal, leaving the variant’s clinical significance uncertain. This assessment does not contradict any existing ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.216401	Structured	0.343787	Uncertain	0.937	0.244	0.125											-8.748	Likely Pathogenic	0.344	Ambiguous	Likely Benign	0.95	Ambiguous	0.0	0.49	Likely Benign	0.72	Ambiguous	0.71	Ambiguous	0.393	Likely Benign	-0.72	Neutral	0.958	Probably Damaging	0.970	Probably Damaging	1.87	Pathogenic	0.10	Tolerated			0.0844	0.2859		4	3	-0.3	-14.03
c.805A>T	I269L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: eight tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Optimized) predict a benign effect, while three tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM) predict pathogenicity. Two tools (ESM1b, AlphaMissense‑Default) return uncertain results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized classifies the variant as benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign impact. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields no clear majority and is therefore unavailable as evidence. Overall, the preponderance of evidence supports a benign classification, which is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.216401	Structured	0.343787	Uncertain	0.937	0.244	0.125											-7.588	In-Between	0.470	Ambiguous	Likely Benign	0.00	Likely Benign	0.0	0.19	Likely Benign	0.10	Likely Benign	0.47	Likely Benign	0.348	Likely Benign	-1.47	Neutral	0.981	Probably Damaging	0.970	Probably Damaging	1.88	Pathogenic	0.28	Tolerated			0.0662	0.2817		2	2	-0.7	0.00
c.806T>A	I269K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools largely agree on a deleterious effect: SIFT is the sole benign predictor, whereas the remaining methods—SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. FoldX and Rosetta individually report uncertain effects, and Foldetta remains unavailable. Overall, the consensus of the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.343787	Uncertain	0.937	0.244	0.125											-14.609	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	1.45	Ambiguous	0.1	1.86	Ambiguous	1.66	Ambiguous	1.55	Destabilizing	0.763	Likely Pathogenic	-5.10	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.76	Pathogenic	0.06	Tolerated			0.0878	0.0713		-2	-3	-8.4	15.01
c.806T>C	I269T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269T is not reported in ClinVar (no ClinVar entry) but is present in gnomAD (variant ID 6‑33437711‑T‑C). Among general in‑silico predictors, only SIFT classifies the change as benign, whereas the remaining tools that provide a definitive call (REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. High‑accuracy assessments give a more nuanced view: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a pathogenic effect. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.343787	Uncertain	0.937	0.244	0.125								6-33437711-T-C	2	1.24e-6	-9.376	Likely Pathogenic	0.887	Likely Pathogenic	Ambiguous	1.97	Ambiguous	0.1	2.10	Destabilizing	2.04	Destabilizing	1.38	Destabilizing	0.727	Likely Pathogenic	-3.70	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.72	Pathogenic	0.09	Tolerated	3.38	19	0.0833	0.0808		-1	0	-5.2	-12.05
c.806T>G	I269R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: the benign group contains only SIFT, whereas the pathogenic group includes SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta give uncertain results, and Foldetta is also uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as unavailable. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.343787	Uncertain	0.937	0.244	0.125											-14.567	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	1.34	Ambiguous	0.1	1.99	Ambiguous	1.67	Ambiguous	1.50	Destabilizing	0.765	Likely Pathogenic	-5.23	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.69	Pathogenic	0.07	Tolerated			0.1108	0.0870		-2	-3	-9.0	43.03
c.807A>G	I269M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269M is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include PROVEAN and AlphaMissense‑Optimized, whereas REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default predict it to be pathogenic. Five tools (FoldX, Rosetta, Foldetta, premPS, and ESM1b) give uncertain results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized reports a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta remains uncertain. Overall, the majority of predictions support a pathogenic impact, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.216401	Structured	0.343787	Uncertain	0.937	0.244	0.125											-7.863	In-Between	0.715	Likely Pathogenic	Likely Benign	0.91	Ambiguous	0.1	1.66	Ambiguous	1.29	Ambiguous	0.94	Ambiguous	0.507	Likely Pathogenic	-2.19	Neutral	0.999	Probably Damaging	0.998	Probably Damaging	1.75	Pathogenic	0.05	Affected			0.0580	0.2283		2	1	-2.6	18.03
c.808G>A	E270K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E270K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FoldX, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give uncertain results: Foldetta (a combined FoldX‑MD/Rosetta stability assessment) and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta remains uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, which is consistent with the lack of ClinVar reporting and gnomAD absence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.382573	Uncertain	0.938	0.231	0.125											-14.466	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	-0.06	Likely Benign	0.2	2.26	Destabilizing	1.10	Ambiguous	0.71	Ambiguous	0.530	Likely Pathogenic	-3.68	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.68	Pathogenic	0.01	Affected			0.2296	0.4251		0	1	-0.4	-0.94
c.808G>C	E270Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E270Q missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, and premPS, whereas the majority of tools predict pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates several high‑accuracy predictors, classifies the variant as Likely Pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized is Uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is Uncertain. Rosetta alone is Uncertain, and Foldetta’s uncertainty reflects limited stability change evidence. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.382573	Uncertain	0.938	0.231	0.125											-11.096	Likely Pathogenic	0.886	Likely Pathogenic	Ambiguous	0.00	Likely Benign	0.2	1.00	Ambiguous	0.50	Ambiguous	0.46	Likely Benign	0.418	Likely Benign	-2.76	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.65	Pathogenic	0.03	Affected			0.1044	0.4015		2	2	0.0	-0.98
c.809A>C	E270A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E270A missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools cluster into three groups: benign predictions are made only by premPS; pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; and three tools (FoldX, Rosetta, Foldetta) give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points to a deleterious effect. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.382573	Uncertain	0.938	0.231	0.125											-13.618	Likely Pathogenic	0.956	Likely Pathogenic	Likely Pathogenic	0.64	Ambiguous	0.2	0.77	Ambiguous	0.71	Ambiguous	0.41	Likely Benign	0.547	Likely Pathogenic	-5.52	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.61	Pathogenic	0.01	Affected			0.4122	0.3951		0	-1	5.3	-58.04
c.809A>G	E270G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E270G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic. Rosetta also predicts pathogenicity, while FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. No tool predicts a benign effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.382573	Uncertain	0.938	0.231	0.125											-13.759	Likely Pathogenic	0.968	Likely Pathogenic	Likely Pathogenic	1.23	Ambiguous	0.2	2.37	Destabilizing	1.80	Ambiguous	0.61	Ambiguous	0.576	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	1.63	Pathogenic	0.00	Affected			0.3254	0.3876		0	-2	3.1	-72.06
c.809A>T	E270V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E270V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess sequence conservation and structural impact uniformly classify the substitution as pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic scores. No tool predicts a benign effect. Uncertain results are reported only by FoldX, Rosetta, Foldetta, and premPS, which are not considered evidence for or against pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic”; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is inconclusive. Overall, the consensus of available predictions indicates that E270V is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.382573	Uncertain	0.938	0.231	0.125											-15.969	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	1.38	Ambiguous	0.6	1.88	Ambiguous	1.63	Ambiguous	-0.52	Ambiguous	0.574	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.53	Pathogenic	0.00	Affected			0.0672	0.4498		-2	-2	7.7	-29.98
c.80C>A	P27H 2D AIThe SynGAP1 missense variant P27H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for P27H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.517562	Disordered	0.437871	Uncertain	0.430	0.881	0.375											-4.116	Likely Benign	0.177	Likely Benign	Likely Benign										0.128	Likely Benign	-2.46	Neutral	0.992	Probably Damaging	0.977	Probably Damaging	3.79	Benign	0.00	Affected			0.2384	0.5290		0	-2	-1.6	40.02
c.80C>G	P27R 2D AIThe SynGAP1 missense variant P27R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for P27R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.517562	Disordered	0.437871	Uncertain	0.430	0.881	0.375											-3.260	Likely Benign	0.268	Likely Benign	Likely Benign										0.146	Likely Benign	-2.28	Neutral	0.972	Probably Damaging	0.954	Probably Damaging	3.82	Benign	0.00	Affected			0.1744	0.4203		0	-2	-2.9	59.07
c.80C>T	P27L 2D AIThe SynGAP1 missense variant P27L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The predictions do not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.517562	Disordered	0.437871	Uncertain	0.430	0.881	0.375											-3.297	Likely Benign	0.161	Likely Benign	Likely Benign										0.174	Likely Benign	-2.59	Deleterious	0.909	Possibly Damaging	0.927	Probably Damaging	3.82	Benign	0.00	Affected			0.2684	0.6161		-3	-3	5.4	16.04
c.810G>C	E270D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E270D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. The majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Rosetta. Tools with inconclusive results—FoldX, Foldetta, and premPS—are listed as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.382573	Uncertain	0.938	0.231	0.125											-11.954	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	1.52	Ambiguous	0.1	2.15	Destabilizing	1.84	Ambiguous	0.91	Ambiguous	0.379	Likely Benign	-2.76	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.60	Pathogenic	0.02	Affected			0.1908	0.2540		3	2	0.0	-14.03
c.810G>T	E270D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E270D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. The majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Rosetta, and the SGM‑Consensus (which is “Likely Pathogenic”). Predictions that are inconclusive or uncertain are FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also indicating a likely pathogenic outcome, while Foldetta’s stability analysis is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E270D, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.382573	Uncertain	0.938	0.231	0.125											-11.954	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	1.52	Ambiguous	0.1	2.15	Destabilizing	1.84	Ambiguous	0.91	Ambiguous	0.383	Likely Benign	-2.76	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.60	Pathogenic	0.02	Affected			0.1908	0.2540		3	2	0.0	-14.03
c.811G>A	A271T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining evidence—premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—consistently predict pathogenicity. FoldX, Rosetta, and Foldetta are inconclusive, and AlphaMissense‑Optimized also yields an uncertain result. High‑accuracy assessments show that the SGM‑Consensus (majority vote) predicts pathogenicity, while AlphaMissense‑Optimized and Foldetta remain unavailable. Taken together, the overwhelming majority of reliable predictors classify the variant as pathogenic, and this conclusion does not conflict with the ClinVar status, which currently has no entry for A271T. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.413873	Uncertain	0.939	0.220	0.125											-9.564	Likely Pathogenic	0.934	Likely Pathogenic	Ambiguous	0.59	Ambiguous	0.1	0.54	Ambiguous	0.57	Ambiguous	1.00	Destabilizing	0.498	Likely Benign	-3.68	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	0.66	Pathogenic	0.01	Affected			0.1076	0.4691		1	0	-2.5	30.03
c.811G>C	A271P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (integrating FoldX‑MD and Rosetta outputs) also reports a pathogenic effect. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.413873	Uncertain	0.939	0.220	0.125											-14.699	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.06	Destabilizing	0.2	2.97	Destabilizing	3.52	Destabilizing	1.15	Destabilizing	0.680	Likely Pathogenic	-4.60	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.62	Pathogenic	0.01	Affected			0.1705	0.3267		1	-1	-3.4	26.04
c.811G>T	A271S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic impact. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.413873	Uncertain	0.939	0.220	0.125											-9.552	Likely Pathogenic	0.629	Likely Pathogenic	Likely Benign	0.19	Likely Benign	0.1	1.47	Ambiguous	0.83	Ambiguous	1.14	Destabilizing	0.453	Likely Benign	-2.76	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	0.64	Pathogenic	0.03	Affected			0.2260	0.3312		1	1	-2.6	16.00
c.812C>A	A271D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271D is listed in ClinVar as Pathogenic (ClinVar ID 2019732.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.413873	Uncertain	0.939	0.220	0.125					Pathogenic		1				-18.590	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.71	Destabilizing	0.4	2.67	Destabilizing	3.69	Destabilizing	1.59	Destabilizing	0.706	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.62	Pathogenic	0.00	Affected	3.38	19	0.1565	0.1541		0	-2	-5.3	44.01	226.2	-63.4	0.0	0.0	0.9	0.1	X		X	X			X	Potentially Pathogenic	The methyl group of Ala271, located near the end of an anti-parallel β sheet strand (res. Arg259-Arg272), packs against multiple hydrophobic residues such as Val400, Val306, and Leu274 in the WT simulations. In the variant simulations, the carboxylate group of Asp271 is not suitable for the hydrophobic niche, causing the hydrophobic residues to make room for the swapped residue. Additionally, the carboxylate group of the Asp271 side chain forms hydrogen bonds with the backbone amide groups of Arg272 and Ala399 in the β sheet, or even forms a salt bridge with the amino group of the Lys394 side chain. This directly affects the integrity of the anti-parallel β sheet at the end. In short, the residue swap disrupts the C2 domain packing during folding, which could weaken the stability of the SynGAP-membrane association.
c.812C>G	A271G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or unavailable stability results and are not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as unavailable. Overall, the balance of evidence (seven pathogenic versus three benign predictions) indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.413873	Uncertain	0.939	0.220	0.125											-9.508	Likely Pathogenic	0.183	Likely Benign	Likely Benign	1.73	Ambiguous	0.1	1.43	Ambiguous	1.58	Ambiguous	1.31	Destabilizing	0.434	Likely Benign	-3.68	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	0.89	Pathogenic	0.01	Affected			0.1869	0.2388		1	0	-2.2	-14.03
c.812C>T	A271V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, and Foldetta, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains inconclusive; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.413873	Uncertain	0.939	0.220	0.125											-8.185	Likely Pathogenic	0.940	Likely Pathogenic	Ambiguous	-0.22	Likely Benign	0.2	0.78	Ambiguous	0.28	Likely Benign	0.37	Likely Benign	0.466	Likely Benign	-3.68	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	0.69	Pathogenic	0.02	Affected			0.0986	0.4409		0	0	2.4	28.05
c.814C>G	R272G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R272G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions are limited to REVEL, whereas pathogenic predictions are made by FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results come from Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this assessment is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.071867	Structured	0.425620	Uncertain	0.925	0.215	0.125											-11.540	Likely Pathogenic	0.831	Likely Pathogenic	Ambiguous	3.40	Destabilizing	0.0	1.94	Ambiguous	2.67	Destabilizing	1.06	Destabilizing	0.479	Likely Benign	-4.57	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.75	Pathogenic	0.01	Affected			0.3082	0.3062		-3	-2	4.1	-99.14
c.814C>T	R272W 2D AISynGAP1 missense variant R272W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a predominance of pathogenic calls: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict deleterious effects, while the consensus SGM tool (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely pathogenic outcome. Benign predictions are limited to REVEL, Rosetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the balance of evidence favors a pathogenic impact for R272W, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.071867	Structured	0.425620	Uncertain	0.925	0.215	0.125											-12.145	Likely Pathogenic	0.863	Likely Pathogenic	Ambiguous	2.98	Destabilizing	1.6	0.12	Likely Benign	1.55	Ambiguous	0.19	Likely Benign	0.461	Likely Benign	-5.49	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.72	Pathogenic	0.00	Affected			0.1460	0.3643		2	-3	3.6	30.03
c.815G>A	R272Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R272Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437720‑G‑A). Prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, AlphaMissense‑Default, AlphaMissense‑Optimized, and PROVEAN. Those that predict pathogenicity are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive; and Foldetta predicts benign. With the majority of high‑accuracy tools supporting a benign effect, the variant is most likely benign, which does not contradict its current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.071867	Structured	0.425620	Uncertain	0.925	0.215	0.125					Uncertain		2	6-33437720-G-A	14	8.67e-6	-9.559	Likely Pathogenic	0.286	Likely Benign	Likely Benign	0.73	Ambiguous	0.1	0.15	Likely Benign	0.44	Likely Benign	1.00	Destabilizing	0.321	Likely Benign	-1.81	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	1.88	Pathogenic	0.03	Affected	3.38	19	0.2966	0.1973		1	1	1.0	-28.06	255.7	52.9	0.0	0.0	-0.2	0.1				X				Uncertain	The guanidinium group of Arg272, located at the end of an anti-parallel β sheet strand (res. Arg259-Arg272), is stably maintained in an upright and outward position via stacking with the indole ring of the Trp362 side chain in another β strand (res. Thr359-Pro364). In the WT simulations, Arg272 forms hydrogen bonds with the glycine-rich Ω loop residues (res. Val365-Pro398, e.g., Gly380) and creates a salt bridge with the carboxylate group of the Asp304 side chain.In the variant simulations, the carboxamide group of the Gln272 side chain does not stack with the indole ring of Trp362 as stably as the guanidinium group of Arg272 in the WT. Consequently, the Gln272 side chain is freer to interact with the loop residues than Arg272, potentially negatively affecting the dynamic SynGAP-membrane association. Additionally, Arg272 faces the RasGTPase interface, so the residue swap could impact the SynGAP-Ras complex formation and GTPase activation.
c.815G>C	R272P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R272P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the single uncertain call (premPS) does not alter the overall consensus. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.071867	Structured	0.425620	Uncertain	0.925	0.215	0.125											-11.812	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	5.64	Destabilizing	0.2	3.99	Destabilizing	4.82	Destabilizing	0.80	Ambiguous	0.561	Likely Pathogenic	-3.95	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.74	Pathogenic	0.01	Affected			0.2057	0.4102		0	-2	2.9	-59.07
c.815G>T	R272L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R272L missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and premPS. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the majority of evaluated tools predict a pathogenic impact. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.071867	Structured	0.425620	Uncertain	0.925	0.215	0.125											-10.796	Likely Pathogenic	0.796	Likely Pathogenic	Ambiguous	1.66	Ambiguous	0.3	-0.46	Likely Benign	0.60	Ambiguous	0.41	Likely Benign	0.470	Likely Benign	-4.57	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.75	Pathogenic	0.01	Affected			0.1691	0.4230		-3	-2	8.3	-43.03
c.817G>A	E273K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E273K is not reported in ClinVar and is present in gnomAD (ID 6‑33437722‑G‑A). Functional prediction tools that agree on benign impact include REVEL, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, and SIFT. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions marked uncertain are FoldX and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools lean toward a benign effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.071867	Structured	0.398918	Uncertain	0.863	0.196	0.125								6-33437722-G-A	1	6.20e-7	-12.690	Likely Pathogenic	0.917	Likely Pathogenic	Ambiguous	-0.57	Ambiguous	0.3	-0.38	Likely Benign	-0.48	Likely Benign	0.23	Likely Benign	0.205	Likely Benign	-2.66	Deleterious	0.896	Possibly Damaging	0.415	Benign	1.77	Pathogenic	0.12	Tolerated	3.38	18	0.2312	0.2996		1	0	-0.4	-0.94
c.817G>C	E273Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E273Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of individual predictors (seven benign vs. five pathogenic) lean toward a benign classification, while the SGM Consensus and AlphaMissense‑Optimized provide conflicting signals. Thus, the variant is most likely benign based on the aggregate predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.071867	Structured	0.398918	Uncertain	0.863	0.196	0.125											-9.865	Likely Pathogenic	0.503	Ambiguous	Likely Benign	-0.29	Likely Benign	0.1	-0.29	Likely Benign	-0.29	Likely Benign	-0.01	Likely Benign	0.168	Likely Benign	-1.84	Neutral	0.946	Possibly Damaging	0.671	Possibly Damaging	1.77	Pathogenic	0.04	Affected			0.1220	0.3130		2	2	0.0	-0.98
c.818A>C	E273A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E273A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, whereas AlphaMissense‑Optimized predicts Benign and Foldetta (combining FoldX‑MD and Rosetta) predicts Benign. Overall, the majority of individual tools are split evenly, but the two high‑accuracy methods favor a benign effect. Thus, the variant is most likely benign based on current computational predictions, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.071867	Structured	0.398918	Uncertain	0.863	0.196	0.125											-8.851	Likely Pathogenic	0.422	Ambiguous	Likely Benign	0.29	Likely Benign	0.2	-0.29	Likely Benign	0.00	Likely Benign	0.16	Likely Benign	0.240	Likely Benign	-3.61	Deleterious	0.896	Possibly Damaging	0.492	Possibly Damaging	1.73	Pathogenic	0.04	Affected			0.3160	0.3615		0	-1	5.3	-58.04
c.818A>G	E273G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E273G missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, premPS, SIFT, and ESM1b; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Four tools (FoldX, Rosetta, AlphaMissense‑Default, Foldetta) returned uncertain results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it pathogenic; Foldetta remains uncertain. Given the split between benign and pathogenic signals and the lack of a ClinVar classification, the variant is best described as of uncertain significance, with a slight inclination toward benign based on the most reliable single‑tool prediction. This assessment does not contradict any existing ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.071867	Structured	0.398918	Uncertain	0.863	0.196	0.125											-4.784	Likely Benign	0.373	Ambiguous	Likely Benign	-0.65	Ambiguous	0.2	-0.93	Ambiguous	-0.79	Ambiguous	-0.46	Likely Benign	0.225	Likely Benign	-2.71	Deleterious	0.896	Possibly Damaging	0.519	Possibly Damaging	1.95	Pathogenic	0.26	Tolerated			0.2763	0.3341		0	-2	3.1	-72.06
c.818A>T	E273V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E273V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL and premPS. The majority of tools predict a pathogenic impact: Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, SGM‑Consensus (Likely Pathogenic), and Foldetta. Two tools give inconclusive results: AlphaMissense‑Optimized (Uncertain) and FoldX (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as Pathogenic. Overall, the consensus of pathogenic‑predicting tools outweighs the benign predictions, indicating that E273V is most likely pathogenic; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.071867	Structured	0.398918	Uncertain	0.863	0.196	0.125											-11.671	Likely Pathogenic	0.814	Likely Pathogenic	Ambiguous	1.93	Ambiguous	0.3	3.31	Destabilizing	2.62	Destabilizing	0.17	Likely Benign	0.361	Likely Benign	-4.66	Deleterious	0.984	Probably Damaging	0.825	Possibly Damaging	1.70	Pathogenic	0.01	Affected			0.0811	0.3813		-2	-2	7.7	-29.98
c.819G>C	E273D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E273D missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or likely benign. Only FATHMM predicts a pathogenic outcome, while premPS remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of evidence supports a benign impact for E273D, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.071867	Structured	0.398918	Uncertain	0.863	0.196	0.125											-1.811	Likely Benign	0.058	Likely Benign	Likely Benign	0.26	Likely Benign	0.1	-0.48	Likely Benign	-0.11	Likely Benign	-0.63	Ambiguous	0.094	Likely Benign	1.99	Neutral	0.004	Benign	0.010	Benign	2.00	Pathogenic	1.00	Tolerated	3.38	18	0.1711	0.1859		3	2	0.0	-14.03	223.1	22.1	0.2	0.0	0.0	0.1						X		Potentially Benign	The negatively charged residue Glu273, located in a β hairpin loop (res. Glu273-Lys278) that connects two anti-parallel β sheet strands, is replaced with another negatively charged residue, aspartate. Because the C2 domain loop faces the membrane surface, the potentially crucial role of the carboxylate group of Glu273 or Asp273 on SynGAP-membrane association cannot be fully explored via solvent-only simulations.As a minor note, the neighboring residue Arg272, which stacks with the indole ring of the Trp362 side chain and directly faces RasGTPase, forms a salt bridge more often with Asp273 than with the non-mutated Glu273 in the simulations. Regardless, due to the similar physicochemical properties of the WT and variant residues at the membrane interface, the residue swap is likely to be well tolerated.
c.819G>T	E273D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E273D is listed in ClinVar as Benign (ClinVar ID 1471608.0) and is present in gnomAD (variant ID 6‑33437724‑G‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while premPS is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Benign. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No prediction contradicts the ClinVar benign status; overall, the evidence strongly supports that E273D is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.071867	Structured	0.398918	Uncertain	0.863	0.196	0.125					Benign		1	6-33437724-G-T	2	1.24e-6	-1.811	Likely Benign	0.058	Likely Benign	Likely Benign	0.26	Likely Benign	0.1	-0.48	Likely Benign	-0.11	Likely Benign	-0.63	Ambiguous	0.092	Likely Benign	1.99	Neutral	0.004	Benign	0.010	Benign	2.00	Pathogenic	1.00	Tolerated	3.38	18	0.1711	0.1859		3	2	0.0	-14.03	223.1	22.1	0.2	0.0	0.0	0.1						X		Potentially Benign	The negatively charged residue Glu273, located in a β hairpin loop (res. Glu273-Lys278) that connects two anti-parallel β sheet strands, is replaced with another negatively charged residue, aspartate. Because the C2 domain loop faces the membrane surface, the potentially crucial role of the carboxylate group of Glu273 or Asp273 on SynGAP-membrane association cannot be fully explored via solvent-only simulations.As a minor note, the neighboring residue Arg272, which stacks with the indole ring of the Trp362 side chain and directly faces RasGTPase, forms a salt bridge more often with Asp273 than with the non-mutated Glu273 in the simulations. Regardless, due to the similar physicochemical properties of the WT and variant residues at the membrane interface, the residue swap is likely to be well tolerated.
c.820C>A	L274M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, PROVEAN, and AlphaMissense‑Optimized, whereas those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Three tools (Rosetta, premPS, and ESM1b) returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting benign. Overall, the majority of predictions (seven pathogenic vs. four benign) and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.066181	Structured	0.377483	Uncertain	0.866	0.195	0.250											-7.386	In-Between	0.658	Likely Pathogenic	Likely Benign	0.24	Likely Benign	0.2	0.74	Ambiguous	0.49	Likely Benign	0.81	Ambiguous	0.512	Likely Pathogenic	-1.77	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	0.04	Pathogenic	0.01	Affected			0.0810	0.2202		4	2	-1.9	18.03
c.820C>G	L274V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while both the SGM‑Consensus and Foldetta (combining FoldX‑MD and Rosetta outputs) predict pathogenicity. No predictions are missing or inconclusive. Overall, the preponderance of evidence from multiple independent tools points to a pathogenic impact for L274V. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.066181	Structured	0.377483	Uncertain	0.866	0.195	0.250											-5.634	Likely Benign	0.593	Likely Pathogenic	Likely Benign	2.13	Destabilizing	0.6	2.22	Destabilizing	2.18	Destabilizing	0.99	Ambiguous	0.378	Likely Benign	-2.56	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	0.10	Pathogenic	0.02	Affected			0.1448	0.1860		2	1	0.4	-14.03
c.821T>A	L274Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274Q is reported in ClinVar with an uncertain significance (ClinVar ID 1810279.0) and is not found in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while Rosetta remains inconclusive. No tool predicts a benign outcome. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.066181	Structured	0.377483	Uncertain	0.866	0.195	0.250					Uncertain		1				-15.518	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	2.54	Destabilizing	0.3	1.74	Ambiguous	2.14	Destabilizing	1.97	Destabilizing	0.774	Likely Pathogenic	-5.42	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.00	Pathogenic	0.00	Affected	3.38	19	0.1128	0.0688		-2	-2	-7.3	14.97	245.9	1.8	0.0	0.0	0.1	0.2	X		X				X	Potentially Pathogenic	The aliphatic side chain of Leu274, located in a β hairpin loop (res. Glu273-Lys278) connecting two anti-parallel β sheet strands, packs against multiple hydrophobic residues facing the β sheet (e.g., Ala271, Leu327, Tyr280, Val306). The hydrophilic carboxamide group of the Gln274 side chain is not suitable for this hydrophobic niche, causing nearby residues to adjust to make room for the hydrophilic glutamine. Additionally, a new hydrogen bond forms with the backbone carboxyl group of Arg272 in another β strand (res. Glu273-Arg259).As a result, the backbone amide group of Ala399 and the carbonyl group of Arg272, which connect two β strands at the β sheet end, form fewer hydrogen bonds in the variant than in the WT simulations. Although no major secondary structure disruption is observed in the variant simulations, the residue swap could profoundly affect the C2 domain folding, as the hydrophobic packing of Leu274 is crucial for maintaining the loop's contact with the rest of the C2 domain. Lastly, because the Leu274-containing loop faces the membrane surface, the residue swap could also negatively impact the SynGAP-membrane association.
c.821T>C	L274P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool in the dataset predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.066181	Structured	0.377483	Uncertain	0.866	0.195	0.250											-14.667	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	5.62	Destabilizing	1.5	4.49	Destabilizing	5.06	Destabilizing	1.66	Destabilizing	0.804	Likely Pathogenic	-6.30	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.00	Pathogenic	0.00	Affected			0.3535	0.0625		-3	-3	-5.4	-16.04
c.821T>G	L274R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274R is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. All available predictions and stability analyses are concordant and indicate a likely pathogenic impact. Thus, based on the current computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.066181	Structured	0.377483	Uncertain	0.866	0.195	0.250											-17.691	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	3.61	Destabilizing	0.8	3.15	Destabilizing	3.38	Destabilizing	1.56	Destabilizing	0.807	Likely Pathogenic	-5.45	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.00	Pathogenic	0.00	Affected			0.1404	0.0488		-3	-2	-8.3	43.03
c.823C>A	P275T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P275T is reported in gnomAD (ID 6‑33437728‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain and therefore not considered evidence. No other tools provide conclusive results. Overall, the majority of predictions, including the SGM‑Consensus, indicate a pathogenic effect, and this assessment does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.059222	Structured	0.353469	Uncertain	0.811	0.208	0.250								6-33437728-C-A	3	1.86e-6	-8.708	Likely Pathogenic	0.309	Likely Benign	Likely Benign	2.44	Destabilizing	0.3	1.15	Ambiguous	1.80	Ambiguous	0.69	Ambiguous	0.425	Likely Benign	-5.38	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.75	Pathogenic	0.01	Affected	3.38	19	0.1808	0.4000		-1	0	0.9	3.99
c.823C>G	P275A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275A is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437728‑C‑G). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments are less decisive: AlphaMissense‑Optimized reports a benign outcome, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is uncertain. Consequently, the overall evidence leans toward a benign interpretation, with no ClinVar record to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.059222	Structured	0.353469	Uncertain	0.811	0.208	0.250								6-33437728-C-G	1	6.20e-7	-6.137	Likely Benign	0.133	Likely Benign	Likely Benign	1.87	Ambiguous	0.2	1.11	Ambiguous	1.49	Ambiguous	0.50	Likely Benign	0.410	Likely Benign	-4.95	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.79	Pathogenic	0.32	Tolerated	3.38	19	0.3475	0.3243		-1	1	3.4	-26.04
c.823C>T	P275S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275S is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437728‑C‑T). Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for P275S, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.059222	Structured	0.353469	Uncertain	0.811	0.208	0.250								6-33437728-C-T	1	6.20e-7	-7.886	In-Between	0.312	Likely Benign	Likely Benign	2.11	Destabilizing	0.3	1.28	Ambiguous	1.70	Ambiguous	0.77	Ambiguous	0.388	Likely Benign	-5.24	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.78	Pathogenic	0.03	Affected	3.38	19	0.3489	0.3339		-1	1	0.8	-10.04
c.824C>A	P275H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a deleterious effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default, all of which classify the change as pathogenic. Tools that are inconclusive or uncertain are Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Taken together, the majority of evidence points to a pathogenic impact, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.059222	Structured	0.353469	Uncertain	0.811	0.208	0.250											-13.157	Likely Pathogenic	0.804	Likely Pathogenic	Ambiguous	2.34	Destabilizing	0.8	0.87	Ambiguous	1.61	Ambiguous	0.88	Ambiguous	0.585	Likely Pathogenic	-6.54	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.73	Pathogenic	0.01	Affected			0.2069	0.3074		0	-2	-1.6	40.02
c.824C>G	P275R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments further support this view: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. AlphaMissense‑Optimized remains uncertain, but its result does not counter the overall consensus. Consequently, the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.059222	Structured	0.353469	Uncertain	0.811	0.208	0.250											-13.557	Likely Pathogenic	0.915	Likely Pathogenic	Ambiguous	2.10	Destabilizing	0.6	2.11	Destabilizing	2.11	Destabilizing	0.82	Ambiguous	0.645	Likely Pathogenic	-6.36	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.75	Pathogenic	0.01	Affected			0.1637	0.3039		0	-2	-2.9	59.07
c.824C>T	P275L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275L is not reported in ClinVar and is absent from gnomAD. In silico predictions cluster into two groups: benign predictions come from REVEL, premPS, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Overall, the majority of tools predict pathogenicity, and the high‑accuracy consensus supports a likely pathogenic classification. This prediction does not contradict any ClinVar status, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.059222	Structured	0.353469	Uncertain	0.811	0.208	0.250											-9.785	Likely Pathogenic	0.304	Likely Benign	Likely Benign	1.63	Ambiguous	0.2	1.22	Ambiguous	1.43	Ambiguous	0.29	Likely Benign	0.430	Likely Benign	-6.81	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.83	Pathogenic	0.00	Affected			0.2139	0.5056		-3	-3	5.4	16.04
c.826C>A	P276T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P276T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign, two pathogenic), and Foldetta is uncertain. Overall, the majority of tools (six pathogenic vs. four benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.037156	Structured	0.338937	Uncertain	0.724	0.230	0.250											-5.793	Likely Benign	0.146	Likely Benign	Likely Benign	2.61	Destabilizing	0.1	0.75	Ambiguous	1.68	Ambiguous	0.63	Ambiguous	0.293	Likely Benign	-3.53	Deleterious	0.961	Probably Damaging	0.721	Possibly Damaging	1.87	Pathogenic	0.03	Affected			0.1601	0.4676		0	-1	0.9	3.99
c.826C>G	P276A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P276A is reported in gnomAD (variant ID 6‑33437731‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The high‑accuracy consensus methods give a benign signal: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status (none is available). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.037156	Structured	0.338937	Uncertain	0.724	0.230	0.250								6-33437731-C-G	5	3.10e-6	-3.414	Likely Benign	0.058	Likely Benign	Likely Benign	1.42	Ambiguous	0.1	1.01	Ambiguous	1.22	Ambiguous	0.50	Likely Benign	0.187	Likely Benign	-2.31	Neutral	0.044	Benign	0.030	Benign	1.98	Pathogenic	0.57	Tolerated	3.38	19	0.3149	0.3669		-1	1	3.4	-26.04
c.826C>T	P276S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P276S missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign calls from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic calls from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Four tools predict benign while five predict pathogenic, and four additional methods (FoldX, Rosetta, Foldetta, premPS) return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive; Foldetta also reports an uncertain stability change. Taken together, the preponderance of evidence leans toward a pathogenic effect, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.037156	Structured	0.338937	Uncertain	0.724	0.230	0.250											-5.946	Likely Benign	0.142	Likely Benign	Likely Benign	1.78	Ambiguous	0.2	0.96	Ambiguous	1.37	Ambiguous	0.65	Ambiguous	0.205	Likely Benign	-3.25	Deleterious	0.835	Possibly Damaging	0.468	Possibly Damaging	1.92	Pathogenic	0.05	Affected			0.3191	0.3736		1	-1	0.8	-10.04
c.827C>A	P276H 2D 3DClick to see structure in 3D Viewer AISynGAP1 P276H is reported in gnomAD (ID 6‑33437732‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the variant as pathogenic, while only AlphaMissense‑Optimized predicts a benign outcome. Uncertain results are provided by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.037156	Structured	0.338937	Uncertain	0.724	0.230	0.250								6-33437732-C-A	1	6.20e-7	-10.469	Likely Pathogenic	0.575	Likely Pathogenic	Likely Benign	1.98	Ambiguous	0.1	1.09	Ambiguous	1.54	Ambiguous	0.85	Ambiguous	0.534	Likely Pathogenic	-4.80	Deleterious	1.000	Probably Damaging	0.961	Probably Damaging	1.84	Pathogenic	0.00	Affected	3.38	19	0.1739	0.3439		-2	0	-1.6	40.02
c.827C>G	P276R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P276R missense variant is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (gnomAD ID 6‑33437732‑C‑G). Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Stability‑based predictors (FoldX, Rosetta, premPS, Foldetta) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.037156	Structured	0.338937	Uncertain	0.724	0.230	0.250								6-33437732-C-G	7	4.34e-6	-10.983	Likely Pathogenic	0.714	Likely Pathogenic	Likely Benign	1.78	Ambiguous	0.2	1.02	Ambiguous	1.40	Ambiguous	0.78	Ambiguous	0.498	Likely Benign	-4.52	Deleterious	0.994	Probably Damaging	0.892	Possibly Damaging	1.89	Pathogenic	0.01	Affected	3.38	19	0.1445	0.2828		-2	0	-2.9	59.07
c.827C>T	P276L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P276L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. FoldX, Rosetta, and Foldetta provide uncertain or unavailable stability results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta remains unavailable. Overall, the predictions are mixed, with an equal split between benign and pathogenic calls, and the high‑accuracy tools do not yield a definitive verdict. Consequently, the variant is most likely benign based on the current evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.037156	Structured	0.338937	Uncertain	0.724	0.230	0.250											-6.687	Likely Benign	0.196	Likely Benign	Likely Benign	1.64	Ambiguous	0.1	0.87	Ambiguous	1.26	Ambiguous	0.33	Likely Benign	0.439	Likely Benign	-4.92	Deleterious	0.961	Probably Damaging	0.655	Possibly Damaging	1.87	Pathogenic	0.01	Affected			0.2179	0.5650		-3	-3	5.4	16.04
c.829A>C	K277Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K277Q is reported in gnomAD (ID 6‑33437734‑A‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from FoldX, Foldetta, and premPS; pathogenic predictions from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic effect, with only a minority of tools indicating benign or uncertain outcomes. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.061840	Structured	0.321811	Uncertain	0.649	0.247	0.250								6-33437734-A-C	1	6.20e-7	-12.547	Likely Pathogenic	0.904	Likely Pathogenic	Ambiguous	0.03	Likely Benign	0.1	0.63	Ambiguous	0.33	Likely Benign	0.42	Likely Benign	0.655	Likely Pathogenic	-3.68	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.83	Pathogenic	0.02	Affected	3.38	19	0.4000	0.0672		1	1	0.4	-0.04
c.829A>G	K277E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K277E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, and Foldetta. Tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No predictions are missing or inconclusive. Overall, the majority of tools (10/13) predict pathogenicity, whereas only three predict benign. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.061840	Structured	0.321811	Uncertain	0.649	0.247	0.250											-14.886	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	-0.14	Likely Benign	0.1	0.18	Likely Benign	0.02	Likely Benign	0.51	Ambiguous	0.694	Likely Pathogenic	-3.68	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.85	Pathogenic	0.01	Affected			0.3462	0.0492		0	1	0.4	0.94
c.82T>A	S28T 2D AIThe SynGAP1 missense variant S28T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.545602	Disordered	0.438157	Uncertain	0.354	0.884	0.125											-3.810	Likely Benign	0.081	Likely Benign	Likely Benign										0.054	Likely Benign	-0.21	Neutral	0.000	Benign	0.000	Benign	4.20	Benign	0.64	Tolerated			0.1874	0.6140		1	1	0.1	14.03
c.82T>C	S28P 2D AIThe SynGAP1 missense variant S28P is listed in ClinVar (ID 1500161.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only SIFT indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta stability analysis is unavailable. Overall, the collective evidence points to a benign classification for S28P, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.545602	Disordered	0.438157	Uncertain	0.354	0.884	0.125					Uncertain		1				-3.309	Likely Benign	0.051	Likely Benign	Likely Benign										0.047	Likely Benign	1.37	Neutral	0.000	Benign	0.000	Benign	4.53	Benign	0.00	Affected	4.32	1	0.2432	0.5499		1	-1	-0.8	10.04
c.82T>G	S28A 2D AIThe SynGAP1 missense variant S28A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.545602	Disordered	0.438157	Uncertain	0.354	0.884	0.125											-3.517	Likely Benign	0.063	Likely Benign	Likely Benign										0.039	Likely Benign	0.09	Neutral	0.000	Benign	0.000	Benign	4.27	Benign	1.00	Tolerated			0.5194	0.4958	Weaken	1	1	2.6	-16.00
c.830A>C	K277T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K277T missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect are Rosetta and premPS, while the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict pathogenicity. FoldX and Foldetta return uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that K277T is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.061840	Structured	0.321811	Uncertain	0.649	0.247	0.250											-11.688	Likely Pathogenic	0.981	Likely Pathogenic	Likely Pathogenic	1.46	Ambiguous	0.1	0.14	Likely Benign	0.80	Ambiguous	0.17	Likely Benign	0.573	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	2.02	Pathogenic	0.01	Affected			0.1837	0.2220		0	-1	3.2	-27.07
c.830A>G	K277R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K277R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Rosetta gives an uncertain result. High‑accuracy methods give a benign prediction from AlphaMissense‑Optimized and from Foldetta; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it is a 2‑vs‑2 split. Overall, the majority of evidence (7 benign vs. 5 pathogenic) supports a benign classification. This consensus does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.061840	Structured	0.321811	Uncertain	0.649	0.247	0.250											-6.652	Likely Benign	0.156	Likely Benign	Likely Benign	-0.01	Likely Benign	0.1	0.53	Ambiguous	0.26	Likely Benign	0.06	Likely Benign	0.518	Likely Pathogenic	-2.76	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.83	Pathogenic	0.06	Tolerated			0.4232	0.0678		3	2	-0.6	28.01
c.830A>T	K277M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K277M missense variant is not reported in ClinVar and has no entries in gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX and premPS, while the majority of tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label the change as pathogenic. High‑accuracy methods reinforce this trend: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.061840	Structured	0.321811	Uncertain	0.649	0.247	0.250											-13.918	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.18	Likely Benign	0.0	1.14	Ambiguous	0.66	Ambiguous	0.15	Likely Benign	0.712	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.80	Pathogenic	0.00	Affected			0.0945	0.2584		0	-1	5.8	3.02
c.831G>C	K277N 2D AIThe SynGAP1 missense variant K277N is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and premPS. Tools that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as Benign. No predictions are missing or inconclusive. Overall, the majority of tools (10/14) predict pathogenicity, whereas four tools predict benign. Therefore, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.061840	Structured	0.321811	Uncertain	0.649	0.247	0.250											-9.646	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	-0.07	Likely Benign	0.4	0.08	Likely Benign	0.01	Likely Benign	0.46	Likely Benign	0.572	Likely Pathogenic	-4.60	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.83	Pathogenic	0.03	Affected			0.3265	0.0568		1	0	0.4	-14.07
c.831G>T	K277N 2D AIThe SynGAP1 missense variant K277N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, and premPS. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also likely pathogenic; Foldetta, a protein‑folding stability predictor, reports a benign effect. Overall, the preponderance of evidence (10 pathogenic vs. 4 benign predictions) points to a pathogenic classification. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.061840	Structured	0.321811	Uncertain	0.649	0.247	0.250											-9.646	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	-0.07	Likely Benign	0.4	0.08	Likely Benign	0.01	Likely Benign	0.46	Likely Benign	0.572	Likely Pathogenic	-4.60	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.83	Pathogenic	0.03	Affected			0.3265	0.0568		1	0	0.4	-14.07
c.832A>C	K278Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts a likely pathogenic outcome, whereas Foldetta (combining FoldX‑MD and Rosetta stability outputs) predicts a benign effect, and AlphaMissense‑Optimized remains uncertain. Overall, the majority of evidence points to a pathogenic impact for K278Q, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.120615	Structured	0.310130	Uncertain	0.748	0.253	0.125											-11.107	Likely Pathogenic	0.902	Likely Pathogenic	Ambiguous	0.23	Likely Benign	0.1	0.25	Likely Benign	0.24	Likely Benign	0.73	Ambiguous	0.387	Likely Benign	-3.63	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.71	Pathogenic	0.05	Affected			0.3770	0.0672		1	1	0.4	-0.04
c.832A>G	K278E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and SIFT, all of which score the substitution as tolerated. In contrast, a majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as damaging. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely pathogenic verdict. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, predicts a benign effect. premPS is inconclusive and therefore not considered evidence. High‑accuracy assessments therefore show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as pathogenic, and Foldetta as benign. Overall, the preponderance of evidence from multiple independent predictors indicates that K278E is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.120615	Structured	0.310130	Uncertain	0.748	0.253	0.125											-14.047	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.40	Likely Benign	0.1	0.39	Likely Benign	0.40	Likely Benign	0.68	Ambiguous	0.463	Likely Benign	-3.64	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.76	Pathogenic	0.06	Tolerated			0.3189	0.0492		0	1	0.4	0.94
c.833A>C	K278T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278T is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, Rosetta, Foldetta, and premPS. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict any ClinVar annotation because the variant is not yet classified in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.120615	Structured	0.310130	Uncertain	0.748	0.253	0.125											-11.227	Likely Pathogenic	0.978	Likely Pathogenic	Likely Pathogenic	0.85	Ambiguous	0.2	-0.08	Likely Benign	0.39	Likely Benign	0.46	Likely Benign	0.484	Likely Benign	-5.40	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.70	Pathogenic	0.04	Affected			0.1775	0.2220		0	-1	3.2	-27.07
c.833A>G	K278R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields an equal split of benign and pathogenic calls. Overall, the majority of evidence points to a benign impact. Thus, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.120615	Structured	0.310130	Uncertain	0.748	0.253	0.125											-5.313	Likely Benign	0.216	Likely Benign	Likely Benign	-0.05	Likely Benign	0.0	0.18	Likely Benign	0.07	Likely Benign	0.13	Likely Benign	0.282	Likely Benign	-2.66	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.73	Pathogenic	0.10	Tolerated			0.3926	0.0489		3	2	-0.6	28.01
c.833A>T	K278M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278M is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that indicate a benign effect include FoldX, Foldetta, and premPS, whereas the majority of tools predict a pathogenic effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic impact for K278M, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.120615	Structured	0.310130	Uncertain	0.748	0.253	0.125											-12.861	Likely Pathogenic	0.989	Likely Pathogenic	Likely Pathogenic	-0.15	Likely Benign	0.1	-0.59	Ambiguous	-0.37	Likely Benign	0.25	Likely Benign	0.526	Likely Pathogenic	-5.47	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.67	Pathogenic	0.01	Affected			0.0975	0.2584		0	-1	5.8	3.02
c.834G>C	K278N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278N is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, premPS, and SIFT, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign. Overall, the majority of tools support a pathogenic effect, so the variant is most likely pathogenic; this is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.120615	Structured	0.310130	Uncertain	0.748	0.253	0.125											-10.611	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.40	Likely Benign	0.0	0.05	Likely Benign	0.23	Likely Benign	0.44	Likely Benign	0.255	Likely Benign	-4.51	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.81	Pathogenic	0.07	Tolerated			0.3071	0.0568		1	0	0.4	-14.07
c.834G>T	K278N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K278N is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, premPS, and SIFT, whereas tools that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With a majority of evidence pointing to deleterious effects and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.120615	Structured	0.310130	Uncertain	0.748	0.253	0.125											-10.611	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.40	Likely Benign	0.0	0.05	Likely Benign	0.23	Likely Benign	0.44	Likely Benign	0.255	Likely Benign	-4.51	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.81	Pathogenic	0.07	Tolerated			0.3071	0.0568		1	0	0.4	-14.07
c.835C>G	R279G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote) which labels it “Likely Pathogenic.” AlphaMissense‑Optimized is uncertain, providing no definitive evidence. High‑accuracy assessments further support pathogenicity: the SGM‑Consensus remains “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the overwhelming majority of predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.155435	Structured	0.309382	Uncertain	0.887	0.257	0.125											-9.941	Likely Pathogenic	0.920	Likely Pathogenic	Ambiguous	3.10	Destabilizing	0.7	2.85	Destabilizing	2.98	Destabilizing	1.11	Destabilizing	0.442	Likely Benign	-5.37	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.92	Pathogenic	0.02	Affected			0.2961	0.2209		-3	-2	4.1	-99.14
c.835C>T	R279W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279W is listed in ClinVar with an uncertain significance (ClinVar ID 1204186.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining pathogenic‑predicating tools—FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—consistently predict a deleterious impact. Uncertain or inconclusive results come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R279W, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.155435	Structured	0.309382	Uncertain	0.887	0.257	0.125					Uncertain		1				-11.417	Likely Pathogenic	0.942	Likely Pathogenic	Ambiguous	2.00	Destabilizing	0.8	1.47	Ambiguous	1.74	Ambiguous	0.80	Ambiguous	0.485	Likely Benign	-6.29	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.88	Pathogenic	0.00	Affected	3.39	18	0.1200	0.2519		2	-3	3.6	30.03	270.0	38.3	0.1	0.0	0.3	0.0								Uncertain	The guanidinium group of Arg279, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), can form hydrogen bond with the backbone carbonyl groups of nearby loop residues (e.g., Ser296, Ser331, and As332) and form salt bridges with the carboxylate groups of Asp330 and Asp332. In the WT simulations, Arg279 sporadically forms a salt bridge even with the carboxylate group of Glu613, loosely connecting the C2 domain and GAP domain. Meanwhile, the indole ring of the Trp279 side chain is unable to hydrogen bond with the loop residues in the variant simulations. The lack of hydrogen bond or salt bridge formation with the loop residues could be significant, as Arg279 and the loops face the polar head group region of the membrane. Thus, although Trp279 could interact with the membrane surface as a “lipid anchor,” any changes to the wider loop dynamics could still adversely affect the formation of a stable SynGAP-membrane association. However, no definite conclusions on the effect of the residue swap on the SynGAP-membrane association can be drawn from solvent-only simulations.
c.836G>A	R279Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279Q is reported in gnomAD (ID 6‑33437741‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect are SIFT and AlphaMissense‑Optimized; those that agree on a pathogenic effect are SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of reliable predictors (nine pathogenic vs two benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.155435	Structured	0.309382	Uncertain	0.887	0.257	0.125								6-33437741-G-A	6	3.72e-6	-8.730	Likely Pathogenic	0.761	Likely Pathogenic	Likely Benign	1.37	Ambiguous	0.1	0.88	Ambiguous	1.13	Ambiguous	1.35	Destabilizing	0.554	Likely Pathogenic	-2.61	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	1.94	Pathogenic	0.06	Tolerated	3.39	18	0.2680	0.1792		1	1	1.0	-28.06
c.836G>C	R279P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. No tool predicts a benign effect. FoldX reports an uncertain outcome, but Rosetta, Foldetta, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all predict pathogenicity. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus, based on a majority vote of the aforementioned predictors, is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.155435	Structured	0.309382	Uncertain	0.887	0.257	0.125											-14.926	Likely Pathogenic	0.971	Likely Pathogenic	Likely Pathogenic	1.42	Ambiguous	0.9	4.27	Destabilizing	2.85	Destabilizing	1.21	Destabilizing	0.626	Likely Pathogenic	-5.01	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.90	Pathogenic	0.02	Affected			0.2179	0.3281		0	-2	2.9	-59.07
c.836G>T	R279L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R279L is reported in gnomAD (ID 6‑33437741‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a unanimous majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.155435	Structured	0.309382	Uncertain	0.887	0.257	0.125								6-33437741-G-T	1	6.20e-7	-12.390	Likely Pathogenic	0.926	Likely Pathogenic	Ambiguous	0.01	Likely Benign	0.2	0.14	Likely Benign	0.08	Likely Benign	0.39	Likely Benign	0.576	Likely Pathogenic	-5.37	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.91	Pathogenic	0.03	Affected	3.39	18	0.1682	0.3266		-2	-3	8.3	-43.03
c.838T>A	Y280N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only SIFT, whereas all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the overwhelming consensus of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for Y280N. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.161087	Structured	0.321243	Uncertain	0.917	0.248	0.125											-13.090	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	4.26	Destabilizing	0.2	4.18	Destabilizing	4.22	Destabilizing	1.82	Destabilizing	0.589	Likely Pathogenic	-8.27	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.95	Pathogenic	0.06	Tolerated			0.1902	0.0212		-2	-2	-2.2	-49.07
c.838T>C	Y280H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280H is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Among the available in‑silico predictors, none indicate a benign effect; all 14 tools that produced a classification predict pathogenicity: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are inconclusive or missing. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.161087	Structured	0.321243	Uncertain	0.917	0.248	0.125											-9.970	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	3.01	Destabilizing	0.3	2.58	Destabilizing	2.80	Destabilizing	1.95	Destabilizing	0.588	Likely Pathogenic	-4.60	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.94	Pathogenic	0.01	Affected			0.2021	0.0212		0	2	-1.9	-26.03
c.838T>G	Y280D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280D is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.161087	Structured	0.321243	Uncertain	0.917	0.248	0.125											-16.885	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	5.91	Destabilizing	0.2	5.89	Destabilizing	5.90	Destabilizing	2.00	Destabilizing	0.580	Likely Pathogenic	-9.19	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.94	Pathogenic	0.02	Affected			0.3593	0.0212		-4	-3	-2.2	-48.09
c.839A>C	Y280S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the substitution as pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (integrating FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is consistent with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.161087	Structured	0.321243	Uncertain	0.917	0.248	0.125											-13.491	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	4.63	Destabilizing	0.3	4.80	Destabilizing	4.72	Destabilizing	2.03	Destabilizing	0.635	Likely Pathogenic	-8.27	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	2.00	Pathogenic	0.05	Affected			0.3993	0.1227		-3	-2	0.5	-76.10
c.839A>G	Y280C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic or likely pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a pathogenic effect on protein stability. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.161087	Structured	0.321243	Uncertain	0.917	0.248	0.125											-10.645	Likely Pathogenic	0.982	Likely Pathogenic	Likely Pathogenic	3.85	Destabilizing	0.2	4.45	Destabilizing	4.15	Destabilizing	1.68	Destabilizing	0.629	Likely Pathogenic	-8.24	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.96	Pathogenic	0.01	Affected			0.2877	0.1296		0	-2	3.8	-60.04
c.839A>T	Y280F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—premPS, ESM1b, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive and therefore unavailable. Overall, the majority of available predictions favor a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.161087	Structured	0.321243	Uncertain	0.917	0.248	0.125											-7.844	In-Between	0.414	Ambiguous	Likely Benign	0.49	Likely Benign	0.2	0.03	Likely Benign	0.26	Likely Benign	0.87	Ambiguous	0.544	Likely Pathogenic	-3.68	Deleterious	0.999	Probably Damaging	0.992	Probably Damaging	1.98	Pathogenic	0.02	Affected			0.2263	0.2398		7	3	4.1	-16.00
c.83C>A	S28Y 2D AIThe SynGAP1 missense variant S28Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. There is no conflict with ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.545602	Disordered	0.438157	Uncertain	0.354	0.884	0.125											-4.521	Likely Benign	0.270	Likely Benign	Likely Benign										0.041	Likely Benign	-0.94	Neutral	0.009	Benign	0.001	Benign	4.13	Benign	0.05	Affected			0.0895	0.5067		-3	-2	-0.5	76.10
c.83C>G	S28C 2D AIThe SynGAP1 missense variant S28C is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.545602	Disordered	0.438157	Uncertain	0.354	0.884	0.125											-4.800	Likely Benign	0.107	Likely Benign	Likely Benign										0.021	Likely Benign	-0.26	Neutral	0.022	Benign	0.004	Benign	4.13	Benign	0.11	Tolerated			0.1387	0.5741		0	-1	3.3	16.06
c.83C>T	S28F 2D AIThe SynGAP1 missense variant S28F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.545602	Disordered	0.438157	Uncertain	0.354	0.884	0.125											-4.548	Likely Benign	0.255	Likely Benign	Likely Benign										0.045	Likely Benign	-1.13	Neutral	0.009	Benign	0.002	Benign	4.13	Benign	0.05	Affected			0.0748	0.5340		-3	-2	3.6	60.10
c.841T>A	Y281N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281N is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions are provided only by SIFT, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized remains inconclusive, SGM‑Consensus is labeled Likely Pathogenic, and Foldetta predicts a destabilizing, pathogenic outcome. Overall, the collective evidence indicates that Y281N is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.337647	Uncertain	0.927	0.254	0.000											-11.620	Likely Pathogenic	0.941	Likely Pathogenic	Ambiguous	3.29	Destabilizing	0.2	2.49	Destabilizing	2.89	Destabilizing	1.71	Destabilizing	0.713	Likely Pathogenic	-6.20	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.99	Pathogenic	0.09	Tolerated			0.2494	0.1503		-2	-2	-2.2	-49.07
c.841T>C	Y281H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SIFT classifies it as benign, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict pathogenicity. High‑accuracy methods provide a clearer picture: AlphaMissense‑Optimized is uncertain, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic folding instability. With the overwhelming consensus from most predictors and the high‑accuracy tools supporting a damaging effect, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.337647	Uncertain	0.927	0.254	0.000											-8.522	Likely Pathogenic	0.884	Likely Pathogenic	Ambiguous	2.65	Destabilizing	0.2	2.05	Destabilizing	2.35	Destabilizing	1.63	Destabilizing	0.717	Likely Pathogenic	-3.82	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.99	Pathogenic	0.16	Tolerated			0.2651	0.1503		0	2	-1.9	-26.03
c.841T>G	Y281D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SIFT classifies it as benign, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict it to be pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. No tool yields an inconclusive result. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.337647	Uncertain	0.927	0.254	0.000											-15.506	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	4.27	Destabilizing	0.0	4.53	Destabilizing	4.40	Destabilizing	1.48	Destabilizing	0.813	Likely Pathogenic	-6.73	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.98	Pathogenic	0.06	Tolerated			0.4173	0.1175		-4	-3	-2.2	-48.09
c.842A>C	Y281S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools cluster into two groups: the single benign prediction comes from SIFT, while the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. With the overwhelming majority of evidence indicating pathogenicity and no ClinVar annotation to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.337647	Uncertain	0.927	0.254	0.000											-9.541	Likely Pathogenic	0.847	Likely Pathogenic	Ambiguous	3.24	Destabilizing	0.3	3.02	Destabilizing	3.13	Destabilizing	1.59	Destabilizing	0.642	Likely Pathogenic	-5.68	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.02	Pathogenic	0.12	Tolerated			0.4203	0.2543		-3	-2	0.5	-76.10
c.842A>G	Y281C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized indicates a benign outcome, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. Consequently, the variant is most likely pathogenic based on the overwhelming majority of predictions, and this assessment does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.337647	Uncertain	0.927	0.254	0.000											-8.528	Likely Pathogenic	0.752	Likely Pathogenic	Likely Benign	3.00	Destabilizing	0.1	2.71	Destabilizing	2.86	Destabilizing	1.48	Destabilizing	0.615	Likely Pathogenic	-5.55	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.99	Pathogenic	0.05	Affected			0.2949	0.2176		0	-2	3.8	-60.04
c.842A>T	Y281F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. No evidence from the uncertain FoldX result is considered. Overall, the consensus of high‑confidence tools points to a benign classification, which is consistent with the absence of ClinVar evidence and gnomAD data. Thus, the variant is most likely benign, and this conclusion does not contradict ClinVar status, which has no reported pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.098513	Structured	0.337647	Uncertain	0.927	0.254	0.000											-3.991	Likely Benign	0.146	Likely Benign	Likely Benign	0.75	Ambiguous	0.2	-0.26	Likely Benign	0.25	Likely Benign	-0.37	Likely Benign	0.372	Likely Benign	-0.32	Neutral	0.999	Probably Damaging	0.992	Probably Damaging	1.17	Pathogenic	0.54	Tolerated			0.2380	0.3885		7	3	4.1	-16.00
c.844T>A	C282S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, whereas the majority of other in‑silico predictors (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all classify the variant as pathogenic. Stability‑based methods (FoldX, Rosetta, and Foldetta) return uncertain results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.348535	Uncertain	0.942	0.250	0.000					Uncertain		1				-11.846	Likely Pathogenic	0.958	Likely Pathogenic	Likely Pathogenic	1.55	Ambiguous	0.1	1.23	Ambiguous	1.39	Ambiguous	1.62	Destabilizing	0.460	Likely Benign	-9.19	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.64	Pathogenic	0.03	Affected	3.39	18	0.5009	0.1286	Weaken	0	-1	-3.3	-16.06	233.2	14.8	-0.1	0.0	-0.2	0.3						X		Potentially Benign	The thiol-containing side chain of Cys282, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), packs against multiple hydrophobic residues (e.g., Ile268, Leu284, Trp308, Leu327). In the variant simulations, the hydroxyl-containing side chain of Ser282 is more hydrophilic and, hence, not as favorable as Cys282 for this hydrophobic niche. Due to this polarity difference, the residue swap could potentially weaken the hydrophobic packing of the C2 domain during the folding process.Moreover, because the C2 domain interacts with the membrane, there could also be a negative effect on the stability of the SynGAP-membrane association. However, no large-scale structural changes were observed during the variant simulations. The hydroxyl group of Ser282 forms a hydrogen bond with the backbone carbonyl group of His326 in another β strand (res. Ala322-Arg329), which competes directly with the backbone amide group of Glu283 within the secondary structure element.
c.844T>C	C282R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282R is listed in ClinVar as Pathogenic (ClinVar ID 635755.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to REVEL, which scores the variant as benign. All other evaluated algorithms predict a pathogenic outcome: FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Rosetta’s output is uncertain and is therefore not counted as evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) also predicts pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, which aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.348535	Uncertain	0.942	0.250	0.000					Pathogenic		2				-16.378	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	3.13	Destabilizing	0.6	1.58	Ambiguous	2.36	Destabilizing	1.70	Destabilizing	0.466	Likely Benign	-11.03	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.63	Pathogenic	0.00	Affected	3.39	18	0.1696	0.1557		-4	-3	-7.0	53.05	297.4	-98.2	-0.1	0.1	0.5	0.0	X		X				X	Potentially Pathogenic	The thiol-containing side chain of Cys282, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), is packed against multiple hydrophobic residues (e.g., Ile268, Leu284, Trp308, Leu327). In the variant simulations, the bulky side chain of Arg282 with its positively charged guanidinium group is not suitable for this hydrophobic niche. Consequently, the hydrophobic residues must either make room to accommodate Arg282 or it must escape the hydrophobic C2 domain core.As a result, new hydrogen bonds are formed with the backbone carbonyl groups of the surrounding β sheet residues Ala399, Leu325, and His326, which decreases the unity of the secondary structure elements. Notably, it is likely that the residue swap causes major problems during the C2 domain folding that are not visible in the variant simulations. In fact, even increased lability in the C2 domain could adversely affect the establishment of a stable SynGAP-membrane association.
c.844T>G	C282G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The high‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; SGM‑Consensus is pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among pathogenic predictors and the high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.348535	Uncertain	0.942	0.250	0.000											-15.830	Likely Pathogenic	0.837	Likely Pathogenic	Ambiguous	2.60	Destabilizing	0.1	2.83	Destabilizing	2.72	Destabilizing	1.60	Destabilizing	0.482	Likely Benign	-11.03	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.64	Pathogenic	0.04	Affected			0.3229	0.2238		-3	-3	-2.9	-46.09
c.845G>A	C282Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282Y resides in the C2 domain. ClinVar has no entry for this variant, and it is not listed in gnomAD. Prediction tools that indicate a benign effect are REVEL and premPS. All other evaluated algorithms—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.348535	Uncertain	0.942	0.250	0.000											-13.438	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	8.50	Destabilizing	1.1	2.91	Destabilizing	5.71	Destabilizing	0.41	Likely Benign	0.419	Likely Benign	-10.11	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.63	Pathogenic	0.00	Affected			0.1069	0.3089		0	-2	-3.8	60.04
c.845G>C	C282S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions from FoldX, Rosetta, and Foldetta are inconclusive and are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, while Foldetta remains uncertain. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.348535	Uncertain	0.942	0.250	0.000											-11.846	Likely Pathogenic	0.958	Likely Pathogenic	Likely Pathogenic	1.55	Ambiguous	0.1	1.23	Ambiguous	1.39	Ambiguous	1.62	Destabilizing	0.436	Likely Benign	-9.19	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.64	Pathogenic	0.03	Affected	3.39	18	0.5009	0.1286	Weaken	0	-1	-3.3	-16.06	233.2	14.8	-0.1	0.0	-0.2	0.3						X		Potentially Benign	The thiol-containing side chain of Cys282, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), packs against multiple hydrophobic residues (e.g., Ile268, Leu284, Trp308, Leu327). In the variant simulations, the hydroxyl-containing side chain of Ser282 is more hydrophilic and, hence, not as favorable as Cys282 for this hydrophobic niche. Due to this polarity difference, the residue swap could potentially weaken the hydrophobic packing of the C2 domain during the folding process.Moreover, because the C2 domain interacts with the membrane, there could also be a negative effect on the stability of the SynGAP-membrane association. However, no large-scale structural changes were observed during the variant simulations. The hydroxyl group of Ser282 forms a hydrogen bond with the backbone carbonyl group of His326 in another β strand (res. Ala322-Arg329), which competes directly with the backbone amide group of Glu283 within the secondary structure element.
c.845G>T	C282F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282F is not listed in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are provided by REVEL and premPS, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic outcome. Taken together, the overwhelming majority of evidence points to a pathogenic impact for C282F. This conclusion is consistent with the absence of a ClinVar entry, which does not contradict the prediction. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.348535	Uncertain	0.942	0.250	0.000											-13.288	Likely Pathogenic	0.983	Likely Pathogenic	Likely Pathogenic	6.22	Destabilizing	1.4	2.38	Destabilizing	4.30	Destabilizing	0.42	Likely Benign	0.430	Likely Benign	-10.11	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.65	Pathogenic	0.00	Affected			0.1267	0.3607		-4	-2	0.3	44.04
c.846T>G	C282W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change C282W is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to REVEL, which scores the variant as benign. All other evaluated predictors—FoldX, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. Uncertain results come only from premPS and Rosetta, which are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic status; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. **Thus, the variant is most likely pathogenic based on the collective predictions, and this conclusion is not contradicted by any ClinVar annotation.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.348535	Uncertain	0.942	0.250	0.000											-15.392	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	10.69	Destabilizing	1.7	-1.05	Ambiguous	4.82	Destabilizing	0.70	Ambiguous	0.418	Likely Benign	-10.11	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.63	Pathogenic	0.03	Affected			0.1457	0.2978		-8	-2	-3.4	83.07
c.847G>A	E283K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E283K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL and FoldX, whereas the majority of algorithms predict it to be pathogenic: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.358602	Uncertain	0.950	0.249	0.000											-14.350	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.30	Likely Benign	0.1	0.82	Ambiguous	0.56	Ambiguous	0.62	Ambiguous	0.443	Likely Benign	-3.68	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.92	Pathogenic	0.01	Affected			0.2989	0.5714		0	1	-0.4	-0.94
c.847G>C	E283Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E283Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The premPS score is uncertain and does not contribute to the consensus. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of tools (nine pathogenic vs. four benign) predict a pathogenic impact. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.358602	Uncertain	0.950	0.249	0.000											-10.650	Likely Pathogenic	0.978	Likely Pathogenic	Likely Pathogenic	0.48	Likely Benign	0.1	-0.01	Likely Benign	0.24	Likely Benign	0.61	Ambiguous	0.372	Likely Benign	-2.76	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.67	Pathogenic	0.01	Affected			0.1432	0.5389		2	2	0.0	-0.98
c.848A>C	E283A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E283A is reported in gnomAD (ID 6‑33437753‑A‑C) but has no ClinVar entry. Functional prediction tools that agree on a deleterious effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, all labeling the change as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. Predictions that are inconclusive or unavailable—FoldX, Rosetta, Foldetta, and premPS—do not provide evidence for or against pathogenicity. High‑accuracy assessments confirm the deleterious nature: AlphaMissense‑Optimized predicts pathogenic, SGM Consensus indicates Likely Pathogenic, while Foldetta remains uncertain. Taken together, the overwhelming majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.358602	Uncertain	0.950	0.249	0.000								6-33437753-A-C	2	1.24e-6	-12.547	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	1.26	Ambiguous	0.1	1.19	Ambiguous	1.23	Ambiguous	0.53	Ambiguous	0.529	Likely Pathogenic	-5.52	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.67	Pathogenic	0.01	Affected	3.38	19	0.4104	0.5807		-1	0	5.3	-58.04
c.848A>G	E283G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E283G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the single uncertain call from premPS is treated as unavailable. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.358602	Uncertain	0.950	0.249	0.000											-13.937	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	3.13	Destabilizing	0.1	2.74	Destabilizing	2.94	Destabilizing	0.55	Ambiguous	0.559	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	1.63	Pathogenic	0.01	Affected			0.3123	0.4842		0	-2	3.1	-72.06
c.848A>T	E283V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E283V missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are FoldX and premPS, while the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give inconclusive results: Rosetta (Uncertain) and Foldetta (Uncertain). High‑accuracy methods specifically indicate that AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely pathogenic, whereas Foldetta’s stability assessment is uncertain. Taken together, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic effect for E283V. This conclusion is consistent with the absence of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.358602	Uncertain	0.950	0.249	0.000											-13.602	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.44	Likely Benign	0.2	0.56	Ambiguous	0.50	Ambiguous	0.36	Likely Benign	0.558	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.83	Pathogenic	0.00	Affected			0.0874	0.6011		-2	-2	7.7	-29.98
c.849G>C	E283D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E283D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL and SIFT, whereas pathogenic predictions are made by AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and FoldX. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a pathogenic change, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic. The Foldetta stability analysis is inconclusive and therefore treated as unavailable. Overall, the majority of evidence points to a pathogenic effect for E283D, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.358602	Uncertain	0.950	0.249	0.000											-10.190	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	2.25	Destabilizing	0.2	0.94	Ambiguous	1.60	Ambiguous	0.60	Ambiguous	0.280	Likely Benign	-2.76	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.63	Pathogenic	0.06	Tolerated			0.2008	0.3480		3	2	0.0	-14.03
c.849G>T	E283D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E283D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and SIFT, whereas a majority of tools predict a pathogenic impact: AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and FoldX. Predictions that remain inconclusive are Foldetta, Rosetta, and premPS. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta’s stability analysis is uncertain. Overall, the preponderance of evidence indicates that E283D is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.358602	Uncertain	0.950	0.249	0.000											-10.190	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	2.25	Destabilizing	0.2	0.94	Ambiguous	1.60	Ambiguous	0.60	Ambiguous	0.280	Likely Benign	-2.76	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.63	Pathogenic	0.06	Tolerated			0.2008	0.3480		3	2	0.0	-14.03
c.850C>A	L284I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L284I missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Overall, the majority of predictions, including the high‑accuracy methods, support a benign classification. This consensus does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.094817	Structured	0.371601	Uncertain	0.950	0.255	0.000											-5.853	Likely Benign	0.293	Likely Benign	Likely Benign	0.50	Ambiguous	0.0	1.22	Ambiguous	0.86	Ambiguous	0.49	Likely Benign	0.364	Likely Benign	-1.51	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	1.88	Pathogenic	0.13	Tolerated			0.0738	0.3006		2	2	0.7	0.00
c.850C>G	L284V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L284V missense variant has no ClinVar entry and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Predictions that are uncertain or inconclusive are FoldX, AlphaMissense‑Default, and Foldetta. High‑accuracy methods give a benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta remains uncertain. Overall, the balance of evidence leans toward a pathogenic effect, and this assessment does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.094817	Structured	0.371601	Uncertain	0.950	0.255	0.000											-6.726	Likely Benign	0.347	Ambiguous	Likely Benign	1.65	Ambiguous	0.2	2.08	Destabilizing	1.87	Ambiguous	1.38	Destabilizing	0.248	Likely Benign	-2.32	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	2.18	Pathogenic	0.03	Affected			0.1259	0.2456		2	1	0.4	-14.03
c.850C>T	L284F 2D AIThe SynGAP1 missense variant L284F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Taken together, the overwhelming majority of evidence indicates that the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.094817	Structured	0.371601	Uncertain	0.950	0.255	0.000											-11.656	Likely Pathogenic	0.970	Likely Pathogenic	Likely Pathogenic	2.04	Destabilizing	1.9	1.05	Ambiguous	1.55	Ambiguous	0.62	Ambiguous	0.654	Likely Pathogenic	-3.51	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.69	Pathogenic	0.01	Affected			0.0515	0.2779		2	0	-1.0	34.02
c.851T>A	L284H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L284H is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a pathogenic impact. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.094817	Structured	0.371601	Uncertain	0.950	0.255	0.000											-16.581	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.26	Destabilizing	0.1	3.06	Destabilizing	3.16	Destabilizing	2.57	Destabilizing	0.772	Likely Pathogenic	-6.22	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.65	Pathogenic	0.00	Affected			0.0954	0.0726		-2	-3	-7.0	23.98
c.851T>C	L284P 2D AIThe SynGAP1 missense variant L284P is listed in ClinVar as Pathogenic (ClinVar ID 3344808.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.094817	Structured	0.371601	Uncertain	0.950	0.255	0.000					Likely Pathogenic		1				-15.588	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	5.83	Destabilizing	0.2	5.81	Destabilizing	5.82	Destabilizing	1.89	Destabilizing	0.794	Likely Pathogenic	-6.17	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.64	Pathogenic	0.00	Affected			0.3540	0.1021		-3	-3	-5.4	-16.04
c.851T>G	L284R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L284R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.094817	Structured	0.371601	Uncertain	0.950	0.255	0.000											-17.698	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	5.05	Destabilizing	0.5	4.29	Destabilizing	4.67	Destabilizing	2.14	Destabilizing	0.797	Likely Pathogenic	-5.38	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.65	Pathogenic	0.00	Affected			0.1175	0.0600		-3	-2	-8.3	43.03
c.853T>A	C285S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285S has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas a majority of the remaining predictors (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default) indicate a pathogenic impact. The remaining tools (FoldX, Rosetta, Foldetta, ESM1b, AlphaMissense‑Optimized) return uncertain results, which are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.375400	Uncertain	0.946	0.250	0.000											-7.149	In-Between	0.868	Likely Pathogenic	Ambiguous	0.73	Ambiguous	0.1	0.75	Ambiguous	0.74	Ambiguous	1.20	Destabilizing	0.507	Likely Pathogenic	-8.09	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.90	Pathogenic	0.08	Tolerated			0.5210	0.2038	Weaken	0	-1	-3.3	-16.06
c.853T>C	C285R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FoldX, which scores the variant as benign. All other evaluated predictors—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms a likely pathogenic status, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Consequently, the preponderance of evidence points to a pathogenic effect for C285R, and this conclusion does not contradict any existing ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.375400	Uncertain	0.946	0.250	0.000											-9.127	Likely Pathogenic	0.981	Likely Pathogenic	Likely Pathogenic	-0.47	Likely Benign	0.2	-0.63	Ambiguous	-0.55	Ambiguous	1.53	Destabilizing	0.583	Likely Pathogenic	-9.66	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.83	Pathogenic	0.04	Affected			0.1947	0.1453		-4	-3	-7.0	53.05
c.853T>G	C285G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a pathogenic interpretation: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict deleterious effects. Tools that assess protein stability (FoldX, Rosetta, Foldetta) and AlphaMissense‑Optimized return uncertain results, providing no clear evidence for or against pathogenicity. High‑accuracy assessments further support a likely pathogenic verdict: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta remain inconclusive. Overall, the consensus of the majority of predictors indicates that the variant is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.375400	Uncertain	0.946	0.250	0.000											-9.937	Likely Pathogenic	0.859	Likely Pathogenic	Ambiguous	1.26	Ambiguous	0.0	1.57	Ambiguous	1.42	Ambiguous	1.50	Destabilizing	0.564	Likely Pathogenic	-9.86	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.78	Pathogenic	0.04	Affected			0.3509	0.2922		-3	-3	-2.9	-46.09
c.854G>A	C285Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and Rosetta. Those that agree on a pathogenic effect include SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for C285Y. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.375400	Uncertain	0.946	0.250	0.000											-7.210	In-Between	0.895	Likely Pathogenic	Ambiguous	3.66	Destabilizing	1.1	-2.33	Stabilizing	0.67	Ambiguous	0.53	Ambiguous	0.484	Likely Benign	-8.67	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.88	Pathogenic	0.18	Tolerated			0.1413	0.3689		0	-2	-3.8	60.04
c.854G>C	C285S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and SIFT, whereas premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. Predictions from FoldX, Rosetta, ESM1b, AlphaMissense‑Optimized, and Foldetta are inconclusive. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic classification; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for C285S, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.375400	Uncertain	0.946	0.250	0.000											-7.149	In-Between	0.868	Likely Pathogenic	Ambiguous	0.73	Ambiguous	0.1	0.75	Ambiguous	0.74	Ambiguous	1.20	Destabilizing	0.499	Likely Benign	-8.09	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.90	Pathogenic	0.08	Tolerated			0.5210	0.2038	Weaken	0	-1	-3.3	-16.06
c.854G>T	C285F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome; Foldetta is uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence (12 pathogenic vs. 3 benign predictions) indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.375400	Uncertain	0.946	0.250	0.000											-9.397	Likely Pathogenic	0.716	Likely Pathogenic	Likely Benign	3.27	Destabilizing	1.1	-1.72	Ambiguous	0.78	Ambiguous	0.35	Likely Benign	0.500	Likely Pathogenic	-8.84	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.81	Pathogenic	0.12	Tolerated			0.1626	0.4007		-4	-2	0.3	44.04
c.855C>G	C285W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant C285W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and Rosetta, whereas pathogenic predictions are made by SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy subset confirms this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta remains uncertain. No prediction tool is missing or inconclusive enough to alter the overall assessment. Consequently, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.375400	Uncertain	0.946	0.250	0.000											-9.017	Likely Pathogenic	0.969	Likely Pathogenic	Likely Pathogenic	3.35	Destabilizing	1.1	-2.28	Stabilizing	0.54	Ambiguous	0.61	Ambiguous	0.327	Likely Benign	-8.97	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.78	Pathogenic	0.11	Tolerated			0.1934	0.3697		-8	-2	-3.4	83.07
c.856C>A	L286M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L286M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, PROVEAN, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Two tools (premPS and ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions (seven pathogenic vs. five benign) and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.122885	Structured	0.385647	Uncertain	0.932	0.260	0.000											-7.998	In-Between	0.781	Likely Pathogenic	Likely Benign	-0.06	Likely Benign	0.1	0.17	Likely Benign	0.06	Likely Benign	0.98	Ambiguous	0.663	Likely Pathogenic	-1.84	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.54	Pathogenic	0.02	Affected			0.0789	0.3371		4	2	-1.9	18.03
c.856C>G	L286V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L286V is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—consistently predict a pathogenic impact; AlphaMissense‑Default and Rosetta are uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized indicates benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.122885	Structured	0.385647	Uncertain	0.932	0.260	0.000											-9.986	Likely Pathogenic	0.500	Ambiguous	Likely Benign	2.44	Destabilizing	0.5	1.63	Ambiguous	2.04	Destabilizing	1.26	Destabilizing	0.676	Likely Pathogenic	-2.76	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	1.71	Pathogenic	0.01	Affected			0.1492	0.3007		2	1	0.4	-14.03
c.857T>A	L286Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L286Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect. No tool predicts a benign outcome. Two tools, Rosetta and Foldetta, return uncertain results. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts pathogenic; SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.122885	Structured	0.385647	Uncertain	0.932	0.260	0.000											-13.056	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	2.37	Destabilizing	0.3	1.42	Ambiguous	1.90	Ambiguous	2.06	Destabilizing	0.852	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.48	Pathogenic	0.00	Affected			0.1123	0.0958		-2	-2	-7.3	14.97
c.857T>C	L286P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L286P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.122885	Structured	0.385647	Uncertain	0.932	0.260	0.000											-14.982	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	5.43	Destabilizing	0.9	6.38	Destabilizing	5.91	Destabilizing	2.10	Destabilizing	0.878	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.47	Pathogenic	0.00	Affected			0.3719	0.1182		-3	-3	-5.4	-16.04
c.857T>G	L286R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L286R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while Rosetta remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely pathogenic outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity; the SGM‑Consensus (majority vote) is likely pathogenic; and Foldetta, which integrates FoldX‑MD (pathogenic) and Rosetta (uncertain), reports a pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.122885	Structured	0.385647	Uncertain	0.932	0.260	0.000											-15.563	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	2.90	Destabilizing	0.3	1.80	Ambiguous	2.35	Destabilizing	1.97	Destabilizing	0.868	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.49	Pathogenic	0.00	Affected			0.1370	0.0600		-3	-2	-8.3	43.03
c.859G>A	D287N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D287N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions (REVEL, FoldX, premPS, SIFT) and pathogenic predictions (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default). Two tools give uncertain results (Rosetta, AlphaMissense‑Optimized). High‑accuracy assessments further separate the evidence: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign impact. Overall, the majority of conventional predictors lean toward pathogenicity, while the most accurate stability‑based method suggests benign. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000											-10.167	Likely Pathogenic	0.944	Likely Pathogenic	Ambiguous	0.16	Likely Benign	0.3	-0.54	Ambiguous	-0.19	Likely Benign	0.05	Likely Benign	0.372	Likely Benign	-4.60	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.62	Pathogenic	0.06	Tolerated			0.1338	0.8194		2	1	0.0	-0.98
c.859G>C	D287H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D287H missense variant is listed in ClinVar as Pathogenic (ClinVar ID 1700054.0) and is not reported in gnomAD. Functional prediction tools that assess the variant’s effect on protein function largely agree on a deleterious outcome. Benign predictions come from FoldX, Rosetta, and Foldetta, whereas pathogenic predictions are reported by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS remains uncertain. High‑accuracy assessments further support a pathogenic classification: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of evidence points to a pathogenic effect, consistent with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000					Likely Pathogenic		1				-14.518	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.48	Likely Benign	0.3	0.32	Likely Benign	0.40	Likely Benign	0.63	Ambiguous	0.589	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.51	Pathogenic	0.00	Affected	3.38	23	0.1620	0.8487		1	-1	0.3	22.05	235.6	3.8	0.1	1.2	0.1	0.1	X	X						Potentially Pathogenic	The carboxylate group of Asp287, located at the beginning of a β hairpin loop connecting two anti-parallel β sheet strands (res. Arg279-Leu286, res. Met289-Pro298), maintains a salt bridge with the guanidinium group of Arg324 in the β sheet during the WT simulations. In the variant simulations, the imidazole ring of the His287 side chain is unable to form a salt bridge with Arg324 or establish any other stable compensatory interactions, which could weaken the beta sandwich assembly of the C2 domain. This destabilization of the C2 domain could adversely affect the stability of the SynGAP-membrane association.
c.859G>T	D287Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D287Y missense variant is reported in ClinVar as Pathogenic (ClinVar ID 2263930.0) and is not found in gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, and premPS, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. High‑accuracy assessments give a pathogenic verdict from AlphaMissense‑Optimized, a Likely Pathogenic consensus from SGM, and a benign outcome from Foldetta. Overall, the majority of evidence points to a deleterious effect. Therefore, the variant is most likely pathogenic, in agreement with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000					Likely Pathogenic		1				-12.877	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.21	Likely Benign	0.2	0.48	Likely Benign	0.35	Likely Benign	0.27	Likely Benign	0.663	Likely Pathogenic	-8.27	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.51	Pathogenic	0.00	Affected	3.38	23	0.0597	0.7361		-4	-3	2.2	48.09	257.8	-44.4	-0.6	1.6	0.2	0.3	X	X						Potentially Pathogenic	The carboxylate group of Asp287, located at the beginning of a β hairpin loop linking two anti-parallel β sheet strands (res. Arg279-Leu286, res. Met289-Pro298), maintains a salt bridge with the guanidinium group of Arg324 in the β sheet during the WT simulations. In the variant simulations, the phenol group of the Tyr287 side chain is unable to form a salt bridge with the guanidinium group of Arg324, which could weaken the tertiary structure assembly of the C2 domain. However, the phenol group of Tyr287 frequently stacks with the Arg324 guanidinium side chain, which could help maintain the tertiary structure, especially compared to the D287H variant. The destabilization of the C2 domain could adversely affect the stability of the SynGAP-membrane association.
c.85A>C	M29L 2D AIThe SynGAP1 missense variant M29L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250											-1.633	Likely Benign	0.079	Likely Benign	Likely Benign										0.200	Likely Benign	-0.49	Neutral	0.006	Benign	0.039	Benign	4.27	Benign	0.00	Affected			0.1984	0.5336		4	2	1.9	-18.03
c.85A>G	M29V 2D AIThe SynGAP1 missense variant M29V is reported in gnomAD (ID 6‑33423494‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, representing the sole discordant signal. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for M29V, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250								6-33423494-A-G	1	6.20e-7	-1.841	Likely Benign	0.057	Likely Benign	Likely Benign										0.209	Likely Benign	-0.39	Neutral	0.006	Benign	0.091	Benign	4.27	Benign	0.00	Affected	4.32	1	0.4022	0.4433		1	2	2.3	-32.06
c.85A>T	M29L 2D AIThe SynGAP1 missense variant M29L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; there is no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250											-1.633	Likely Benign	0.079	Likely Benign	Likely Benign										0.200	Likely Benign	-0.49	Neutral	0.006	Benign	0.039	Benign	4.27	Benign	0.00	Affected			0.1984	0.5336		4	2	1.9	-18.03
c.860A>C	D287A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D287A is listed in ClinVar with an Uncertain significance status and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, FoldX, Rosetta, Foldetta, and premPS, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta) as benign. The overall tally favors pathogenicity (8 tools vs 5 benign), but the conflicting high‑accuracy results leave uncertainty. Thus, the variant is most likely pathogenic according to the majority of predictions, which does not contradict its ClinVar Uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000					Uncertain		1				-14.686	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.30	Likely Benign	0.1	-0.04	Likely Benign	0.13	Likely Benign	0.40	Likely Benign	0.484	Likely Benign	-7.35	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.58	Pathogenic	0.01	Affected	3.38	23	0.4448	0.7431		-2	0	5.3	-44.01
c.860A>G	D287G 2D AIThe SynGAP1 missense variant D287G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Foldetta, premPS, and Rosetta, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict it to be pathogenic; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of predictions indicates a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000											-13.558	Likely Pathogenic	0.967	Likely Pathogenic	Likely Pathogenic	0.61	Ambiguous	1.1	0.31	Likely Benign	0.46	Likely Benign	0.38	Likely Benign	0.521	Likely Pathogenic	-6.43	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.59	Pathogenic	0.01	Affected			0.4688	0.7390		1	-1	3.1	-58.04
c.860A>T	D287V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D287V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS; all other evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, while FoldX is uncertain and thus not counted as evidence. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000											-14.418	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.71	Ambiguous	0.4	3.94	Destabilizing	2.83	Destabilizing	0.25	Likely Benign	0.516	Likely Pathogenic	-8.27	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.57	Pathogenic	0.01	Affected			0.0884	0.7788		-2	-3	7.7	-15.96
c.861T>A	D287E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D287E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, ESM1b, and the protein‑folding stability method Foldetta; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic), also reports it as pathogenic. In contrast, Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect on protein stability. No evidence is available from Rosetta alone. Overall, the majority of predictions, including the high‑accuracy methods, indicate a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000											-5.250	Likely Benign	0.990	Likely Pathogenic	Likely Pathogenic	0.35	Likely Benign	0.2	0.54	Ambiguous	0.45	Likely Benign	0.50	Likely Benign	0.416	Likely Benign	-3.68	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.54	Pathogenic	0.01	Affected			0.1541	0.7833		3	2	0.0	14.03
c.861T>G	D287E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D287E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, ESM1b, and the protein‑folding stability method Foldetta; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic), also reports it as pathogenic. In contrast, Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect on protein stability. No evidence is available from Rosetta alone. Overall, the majority of predictions, including the high‑accuracy methods, indicate a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000											-5.250	Likely Benign	0.990	Likely Pathogenic	Likely Pathogenic	0.35	Likely Benign	0.2	0.54	Ambiguous	0.45	Likely Benign	0.50	Likely Benign	0.416	Likely Benign	-3.68	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.54	Pathogenic	0.01	Affected			0.1541	0.7833		3	2	0.0	14.03
c.862G>A	D288N 2D 3DClick to see structure in 3D Viewer AISynGAP1 D288N is listed in ClinVar with an uncertain significance (ClinVar ID 2572204.0) and is present in gnomAD (6‑33437767‑G‑A). Computational predictors are divided: benign calls come from REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic. Because the majority of high‑accuracy tools predict benign and the overall split of predictions is even, the variant is most likely benign, which does not contradict the ClinVar status of uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.395525	Uncertain	0.873	0.261	0.000					Uncertain		1	6-33437767-G-A	2	1.24e-6	-10.535	Likely Pathogenic	0.521	Ambiguous	Likely Benign	-0.39	Likely Benign	0.1	0.01	Likely Benign	-0.19	Likely Benign	-0.03	Likely Benign	0.321	Likely Benign	-3.73	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.78	Pathogenic	0.05	Affected	3.38	23	0.1398	0.5770		1	2	0.0	-0.98
c.862G>C	D288H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D288H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, and premPS. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling the variant as Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect on protein folding stability. Overall, the majority of tools (7/12) predict pathogenicity, and the high‑accuracy consensus leans toward pathogenic, with no conflict with ClinVar status. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.395525	Uncertain	0.873	0.261	0.000											-12.589	Likely Pathogenic	0.953	Likely Pathogenic	Ambiguous	0.08	Likely Benign	0.1	0.36	Likely Benign	0.22	Likely Benign	-0.02	Likely Benign	0.460	Likely Benign	-5.40	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.65	Pathogenic	0.01	Affected			0.1639	0.6254		1	-1	0.3	22.05
c.862G>T	D288Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288Y missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, and premPS; pathogenic predictions from SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from the available tools suggests a benign effect. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.395525	Uncertain	0.873	0.261	0.000											-15.269	Likely Pathogenic	0.979	Likely Pathogenic	Likely Pathogenic	0.11	Likely Benign	0.2	1.10	Ambiguous	0.61	Ambiguous	0.10	Likely Benign	0.472	Likely Benign	-7.11	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.64	Pathogenic	0.00	Affected			0.0635	0.5009		-4	-3	2.2	48.09
c.863A>C	D288A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288A missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, and SIFT. Those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized, Foldetta, and Rosetta give uncertain results and are treated as unavailable for pathogenicity inference. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain. Overall, seven tools predict pathogenicity while four predict benign, with no conflicting ClinVar evidence. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.395525	Uncertain	0.873	0.261	0.000											-13.470	Likely Pathogenic	0.908	Likely Pathogenic	Ambiguous	0.34	Likely Benign	0.1	1.27	Ambiguous	0.81	Ambiguous	0.10	Likely Benign	0.451	Likely Benign	-6.09	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.71	Pathogenic	0.07	Tolerated			0.4060	0.5788		0	-2	5.3	-44.01
c.863A>G	D288G 2D 3DClick to see structure in 3D Viewer AISynGAP1 D288G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, premPS, SIFT, AlphaMissense‑Optimized, and Foldetta. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. No folding‑stability result is available from FoldX. Overall, the balance of evidence slightly favors a pathogenic interpretation, with one high‑accuracy tool supporting benignity. The prediction does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.395525	Uncertain	0.873	0.261	0.000											-8.531	Likely Pathogenic	0.739	Likely Pathogenic	Likely Benign	-0.71	Ambiguous	0.4	0.21	Likely Benign	-0.25	Likely Benign	-0.15	Likely Benign	0.436	Likely Benign	-5.03	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	2.05	Pathogenic	0.13	Tolerated			0.4126	0.5934		1	-1	3.1	-58.04
c.863A>T	D288V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are provided by REVEL and premPS, whereas the remaining tools—FoldX (uncertain), Rosetta, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—all indicate a pathogenic effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.395525	Uncertain	0.873	0.261	0.000											-15.812	Likely Pathogenic	0.981	Likely Pathogenic	Likely Pathogenic	1.74	Ambiguous	0.5	5.44	Destabilizing	3.59	Destabilizing	0.13	Likely Benign	0.481	Likely Benign	-7.14	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.63	Pathogenic	0.05	Affected			0.0838	0.5545		-2	-3	7.7	-15.96
c.864C>A	D288E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Two tools give uncertain results: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.125101	Structured	0.395525	Uncertain	0.873	0.261	0.000											-6.685	Likely Benign	0.350	Ambiguous	Likely Benign	0.10	Likely Benign	0.0	0.74	Ambiguous	0.42	Likely Benign	-0.10	Likely Benign	0.203	Likely Benign	-2.84	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.74	Pathogenic	0.13	Tolerated			0.1559	0.5476		3	2	0.0	14.03
c.864C>G	D288E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Two tools give uncertain results: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.125101	Structured	0.395525	Uncertain	0.873	0.261	0.000											-6.685	Likely Benign	0.350	Ambiguous	Likely Benign	0.10	Likely Benign	0.0	0.74	Ambiguous	0.42	Likely Benign	-0.10	Likely Benign	0.203	Likely Benign	-2.84	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.74	Pathogenic	0.13	Tolerated			0.1559	0.5476		3	2	0.0	14.03
c.865A>C	M289L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M289L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only FATHMM predicts a pathogenic outcome. Grouping by consensus, the benign‑predicting tools outnumber the single pathogenic prediction. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a “Likely Benign” verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.127496	Structured	0.403499	Uncertain	0.886	0.276	0.000											-5.778	Likely Benign	0.157	Likely Benign	Likely Benign	0.13	Likely Benign	0.0	-0.10	Likely Benign	0.02	Likely Benign	0.39	Likely Benign	0.070	Likely Benign	-0.95	Neutral	0.136	Benign	0.033	Benign	1.79	Pathogenic	0.27	Tolerated			0.1092	0.3634		4	2	1.9	-18.03
c.865A>G	M289V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M289V is reported in ClinVar as Benign (ClinVar ID 2122760.0) and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus all predict benign, while only FATHMM predicts pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates benign. No prediction or stability result is inconclusive. Overall, the computational evidence strongly supports a benign classification, consistent with the ClinVar status and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.127496	Structured	0.403499	Uncertain	0.886	0.276	0.000					Benign		1				-4.239	Likely Benign	0.117	Likely Benign	Likely Benign	1.09	Ambiguous	0.1	-0.27	Likely Benign	0.41	Likely Benign	0.24	Likely Benign	0.150	Likely Benign	-0.36	Neutral	0.136	Benign	0.054	Benign	1.80	Pathogenic	1.00	Tolerated	3.38	23	0.2280	0.2808		2	1	2.3	-32.06	204.2	51.0	0.0	0.0	0.2	0.0						X		Potentially Benign	The hydrophobic residue Met289, located in a β hairpin linking two anti-parallel β sheet strands (res. Met289-Arg299, res. Arg272-Leu286), is swapped for another hydrophobic residue, valine. In the variant simulations, the branched hydrocarbon side chain of Val289 packs against the phenol group of the Tyr291 side chain but is unable to form methionine-aromatic interactions. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. However, based on the simulations, the residue swap does not cause adverse effects on the structure.
c.865A>T	M289L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M289L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not currently listed in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.127496	Structured	0.403499	Uncertain	0.886	0.276	0.000											-5.778	Likely Benign	0.157	Likely Benign	Likely Benign	0.13	Likely Benign	0.0	-0.10	Likely Benign	0.02	Likely Benign	0.39	Likely Benign	0.070	Likely Benign	-0.95	Neutral	0.136	Benign	0.033	Benign	1.79	Pathogenic	0.27	Tolerated			0.1092	0.3634		4	2	1.9	-18.03
c.866T>A	M289K 2D 3DClick to see structure in 3D Viewer AISynGAP1 M289K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Because the majority of consensus and individual predictors lean toward pathogenicity, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status since none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.127496	Structured	0.403499	Uncertain	0.886	0.276	0.000											-12.192	Likely Pathogenic	0.738	Likely Pathogenic	Likely Benign	0.36	Likely Benign	0.2	0.60	Ambiguous	0.48	Likely Benign	0.94	Ambiguous	0.229	Likely Benign	-2.52	Deleterious	0.891	Possibly Damaging	0.492	Possibly Damaging	1.94	Pathogenic	0.12	Tolerated			0.1271	0.0879		0	-1	-5.8	-3.02
c.866T>C	M289T 2D AIThe SynGAP1 missense variant M289T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a benign effect. Taken together, the majority of evidence indicates that M289T is most likely benign, and this conclusion does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.127496	Structured	0.403499	Uncertain	0.886	0.276	0.000					Uncertain		1				-4.668	Likely Benign	0.238	Likely Benign	Likely Benign	0.73	Ambiguous	0.1	0.17	Likely Benign	0.45	Likely Benign	-0.01	Likely Benign	0.222	Likely Benign	-0.47	Neutral	0.801	Possibly Damaging	0.315	Benign	1.83	Pathogenic	0.57	Tolerated			0.1657	0.1534		-1	-1	-2.6	-30.09
c.866T>G	M289R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M289R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No predictions or stability results are missing or inconclusive. Overall, the majority of tools lean toward a pathogenic effect, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.127496	Structured	0.403499	Uncertain	0.886	0.276	0.000											-11.090	Likely Pathogenic	0.719	Likely Pathogenic	Likely Benign	0.04	Likely Benign	0.1	0.28	Likely Benign	0.16	Likely Benign	1.01	Destabilizing	0.228	Likely Benign	-2.84	Deleterious	0.989	Probably Damaging	0.767	Possibly Damaging	1.84	Pathogenic	0.08	Tolerated			0.1482	0.0828		0	-1	-6.4	24.99
c.867G>A	M289I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M289I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while FoldX and AlphaMissense‑Default are uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign prediction; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the preponderance of evidence indicates that M289I is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.127496	Structured	0.403499	Uncertain	0.886	0.276	0.000											-6.010	Likely Benign	0.505	Ambiguous	Likely Benign	0.62	Ambiguous	0.1	-0.23	Likely Benign	0.20	Likely Benign	0.36	Likely Benign	0.040	Likely Benign	-0.72	Neutral	0.005	Benign	0.018	Benign	1.78	Pathogenic	0.31	Tolerated			0.1001	0.2758		2	1	2.6	-18.03
c.867G>C	M289I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M289I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while FoldX and AlphaMissense‑Default are uncertain. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the preponderance of evidence indicates that M289I is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.127496	Structured	0.403499	Uncertain	0.886	0.276	0.000											-6.010	Likely Benign	0.505	Ambiguous	Likely Benign	0.62	Ambiguous	0.1	-0.23	Likely Benign	0.20	Likely Benign	0.36	Likely Benign	0.040	Likely Benign	-0.72	Neutral	0.005	Benign	0.018	Benign	1.78	Pathogenic	0.31	Tolerated			0.1001	0.2758		2	1	2.6	-18.03
c.867G>T	M289I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M289I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while FoldX and AlphaMissense‑Default are uncertain. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the preponderance of evidence indicates that M289I is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.127496	Structured	0.403499	Uncertain	0.886	0.276	0.000											-6.010	Likely Benign	0.505	Ambiguous	Likely Benign	0.62	Ambiguous	0.1	-0.23	Likely Benign	0.20	Likely Benign	0.36	Likely Benign	0.040	Likely Benign	-0.72	Neutral	0.005	Benign	0.018	Benign	1.78	Pathogenic	0.31	Tolerated			0.1001	0.2758		2	1	2.6	-18.03
c.868C>A	L290M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L290M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, and PROVEAN, whereas pathogenic predictions are reported by polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Tools with uncertain outcomes include Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta. High‑accuracy analyses indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence leans toward a pathogenic effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.127496	Structured	0.399723	Uncertain	0.904	0.255	0.000											-8.393	Likely Pathogenic	0.901	Likely Pathogenic	Ambiguous	0.48	Likely Benign	0.2	0.98	Ambiguous	0.73	Ambiguous	0.59	Ambiguous	0.438	Likely Benign	-1.84	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.92	Pathogenic	0.02	Affected			0.0823	0.4167		4	2	-1.9	18.03
c.868C>G	L290V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L290V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and Rosetta, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, premPS, ESM1b, AlphaMissense‑Optimized, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence from multiple pathogenic‑predicting tools and the SGM Consensus suggests that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.127496	Structured	0.399723	Uncertain	0.904	0.255	0.000											-7.392	In-Between	0.834	Likely Pathogenic	Ambiguous	1.17	Ambiguous	0.1	0.35	Likely Benign	0.76	Ambiguous	0.62	Ambiguous	0.366	Likely Benign	-2.76	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	1.98	Pathogenic	0.05	Affected			0.1574	0.4177		2	1	0.4	-14.03
c.869T>A	L290Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L290Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which itself is “Likely Pathogenic”). Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta’s stability prediction is unavailable. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.127496	Structured	0.399723	Uncertain	0.904	0.255	0.000											-12.776	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	1.12	Ambiguous	0.1	1.38	Ambiguous	1.25	Ambiguous	0.68	Ambiguous	0.697	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.97	Pathogenic	0.06	Tolerated			0.1079	0.1014		-2	-2	-7.3	14.97
c.869T>C	L290P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L290P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously favor a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenicity. No tool in the dataset predicts a benign outcome; the remaining tools (FoldX, Rosetta, Foldetta, premPS) return uncertain results, which are treated as unavailable evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is inconclusive. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.127496	Structured	0.399723	Uncertain	0.904	0.255	0.000											-11.796	Likely Pathogenic	0.973	Likely Pathogenic	Likely Pathogenic	0.79	Ambiguous	0.1	1.10	Ambiguous	0.95	Ambiguous	0.56	Ambiguous	0.727	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.01	Pathogenic	0.03	Affected			0.3646	0.1703		-3	-3	-5.4	-16.04
c.869T>G	L290R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L290R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions are limited to FoldX, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all classify the variant as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. Overall, the consensus of the majority of evidence points to a pathogenic impact. This conclusion is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.127496	Structured	0.399723	Uncertain	0.904	0.255	0.000											-13.938	Likely Pathogenic	0.988	Likely Pathogenic	Likely Pathogenic	0.48	Likely Benign	0.1	0.88	Ambiguous	0.68	Ambiguous	0.89	Ambiguous	0.705	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.03	Pathogenic	0.01	Affected			0.1215	0.1056		-3	-2	-8.3	43.03
c.86T>A	M29K 2D AIThe SynGAP1 missense variant M29K is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency or clinical annotation. Prediction tools that converge on a benign outcome include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective predictions point to a benign effect, and this conclusion does not contradict the absence of a ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250											-2.514	Likely Benign	0.287	Likely Benign	Likely Benign										0.197	Likely Benign	-0.88	Neutral	0.018	Benign	0.184	Benign	4.27	Benign	0.00	Affected			0.2019	0.1312		0	-1	-5.8	-3.02
c.86T>C	M29T 2D AIThe SynGAP1 missense variant M29T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that M29T is most likely benign, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250					Uncertain		1				-2.167	Likely Benign	0.122	Likely Benign	Likely Benign										0.199	Likely Benign	-0.37	Neutral	0.018	Benign	0.184	Benign	4.33	Benign	0.00	Affected	4.32	1	0.2633	0.2716		-1	-1	-2.6	-30.09
c.86T>G	M29R 2D AIThe SynGAP1 missense variant M29R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250											-1.708	Likely Benign	0.241	Likely Benign	Likely Benign										0.211	Likely Benign	-0.92	Neutral	0.042	Benign	0.184	Benign	4.23	Benign	0.00	Affected			0.2076	0.1293		0	-1	-6.4	24.99
c.871T>A	Y291N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291N is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy methods corroborate this: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic effect. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.383842	Uncertain	0.912	0.251	0.000											-13.599	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	2.82	Destabilizing	0.6	3.37	Destabilizing	3.10	Destabilizing	2.16	Destabilizing	0.533	Likely Pathogenic	-7.43	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.76	Pathogenic	0.01	Affected			0.2255	0.0499		-2	-2	-2.2	-49.07
c.871T>C	Y291H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291H is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from REVEL, while all other evaluated algorithms (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a likely pathogenic verdict; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.383842	Uncertain	0.912	0.251	0.000											-8.749	Likely Pathogenic	0.986	Likely Pathogenic	Likely Pathogenic	2.13	Destabilizing	0.2	2.61	Destabilizing	2.37	Destabilizing	1.56	Destabilizing	0.355	Likely Benign	-4.04	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.77	Pathogenic	0.02	Affected			0.2403	0.0499		0	2	-1.9	-26.03
c.871T>G	Y291D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291D is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.383842	Uncertain	0.912	0.251	0.000											-17.570	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	4.13	Destabilizing	0.6	3.86	Destabilizing	4.00	Destabilizing	1.91	Destabilizing	0.650	Likely Pathogenic	-8.19	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.75	Pathogenic	0.01	Affected			0.4300	0.0331		-4	-3	-2.2	-48.09
c.872A>C	Y291S 2D AIThe SynGAP1 missense variant Y291S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in silico predictors classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.383842	Uncertain	0.912	0.251	0.000											-11.928	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	3.47	Destabilizing	0.8	4.47	Destabilizing	3.97	Destabilizing	2.01	Destabilizing	0.588	Likely Pathogenic	-7.31	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.83	Pathogenic	0.02	Affected			0.4850	0.2079		-3	-2	0.5	-76.10
c.872A>G	Y291C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291C is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.383842	Uncertain	0.912	0.251	0.000					Uncertain		1				-8.997	Likely Pathogenic	0.967	Likely Pathogenic	Likely Pathogenic	2.90	Destabilizing	0.4	3.51	Destabilizing	3.21	Destabilizing	1.35	Destabilizing	0.505	Likely Pathogenic	-7.37	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.76	Pathogenic	0.01	Affected	3.38	23	0.3053	0.2527		0	-2	3.8	-60.04	205.2	66.1	0.1	0.0	-0.4	0.4	X						X	Potentially Pathogenic	The phenol group of the Tyr291 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), packs against hydrophobic residues of the C2 and PH domains (e.g., Leu317, Leu286, Leu284, Pro208, Val209). The phenol ring of Tyr291 also forms favorable Met-aromatic stacking with the methyl group of Met289. In the variant simulation, the thiol group of the Cys291 side chain is not as suitable for the hydrophobic inter-domain space as the phenol ring of Tyr291. Consequently, the structural unity of the PH domain is weakened and ultimately unfolds in the second simulation. Moreover, the residue swap might result in severe detrimental effects on the C2 domain structure and the C2-PH domain tertiary structure assembly during folding.
c.872A>T	Y291F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all predict a neutral impact. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic effect, while premPS remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the majority of evidence supports a benign classification, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.173081	Structured	0.383842	Uncertain	0.912	0.251	0.000											-4.095	Likely Benign	0.305	Likely Benign	Likely Benign	-0.43	Likely Benign	0.1	-0.10	Likely Benign	-0.27	Likely Benign	0.71	Ambiguous	0.148	Likely Benign	-2.31	Neutral	0.999	Probably Damaging	0.992	Probably Damaging	1.77	Pathogenic	0.27	Tolerated			0.2362	0.3441		7	3	4.1	-16.00
c.874G>A	A292T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely converge on a deleterious effect: only REVEL classifies it as benign, whereas FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a destabilizing, pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.247041	Structured	0.362042	Uncertain	0.929	0.256	0.000											-11.039	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	2.16	Destabilizing	0.7	3.42	Destabilizing	2.79	Destabilizing	1.08	Destabilizing	0.457	Likely Benign	-3.68	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.68	Pathogenic	0.01	Affected			0.1691	0.7377		1	0	-2.5	30.03
c.874G>C	A292P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely converge on a deleterious effect: only REVEL classifies it as benign, whereas FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a destabilizing, pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.247041	Structured	0.362042	Uncertain	0.929	0.256	0.000											-16.897	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.37	Destabilizing	0.3	9.80	Destabilizing	7.09	Destabilizing	1.23	Destabilizing	0.471	Likely Benign	-4.60	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.67	Pathogenic	0.01	Affected			0.2101	0.5988		1	-1	-3.4	26.04
c.874G>T	A292S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292S is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FoldX, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and PROVEAN. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. No prediction or folding‑stability result is missing; uncertain outcomes are treated as unavailable. Overall, the balance of evidence favors a pathogenic classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.247041	Structured	0.362042	Uncertain	0.929	0.256	0.000											-8.514	Likely Pathogenic	0.804	Likely Pathogenic	Ambiguous	0.40	Likely Benign	0.2	2.13	Destabilizing	1.27	Ambiguous	0.70	Ambiguous	0.364	Likely Benign	-2.76	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.69	Pathogenic	0.03	Affected			0.2850	0.6389		1	1	-2.6	16.00
c.875C>A	A292E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292E is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for A292E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.247041	Structured	0.362042	Uncertain	0.929	0.256	0.000											-14.282	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	6.07	Destabilizing	1.2	3.82	Destabilizing	4.95	Destabilizing	1.54	Destabilizing	0.475	Likely Benign	-4.60	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.69	Pathogenic	0.02	Affected			0.1444	0.2205		0	-1	-5.3	58.04
c.875C>G	A292G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A292G is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, whereas the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain, and individual FoldX and Rosetta predictions are also inconclusive. Overall, the majority of evidence points to a pathogenic impact, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.247041	Structured	0.362042	Uncertain	0.929	0.256	0.000											-9.692	Likely Pathogenic	0.713	Likely Pathogenic	Likely Benign	0.88	Ambiguous	0.1	1.83	Ambiguous	1.36	Ambiguous	1.05	Destabilizing	0.323	Likely Benign	-3.68	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.74	Pathogenic	0.10	Tolerated			0.2187	0.5054		1	0	-2.2	-14.03
c.875C>T	A292V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.247041	Structured	0.362042	Uncertain	0.929	0.256	0.000											-11.170	Likely Pathogenic	0.987	Likely Pathogenic	Likely Pathogenic	2.04	Destabilizing	0.5	4.60	Destabilizing	3.32	Destabilizing	0.85	Ambiguous	0.430	Likely Benign	-3.68	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.75	Pathogenic	0.03	Affected			0.1272	0.6253		0	0	2.4	28.05
c.877C>A	R293S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R293S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a deleterious effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that are inconclusive or uncertain are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus indicating a likely pathogenic outcome, while Foldetta’s stability analysis remains uncertain. Taken together, the overwhelming majority of evidence points to a pathogenic impact for R293S. This conclusion is consistent with the lack of ClinVar annotation, as there is no conflicting status to contradict the prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.338192	Uncertain	0.924	0.269	0.125											-14.103	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	2.66	Destabilizing	0.2	1.30	Ambiguous	1.98	Ambiguous	0.71	Ambiguous	0.561	Likely Pathogenic	-5.52	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.51	Pathogenic	0.01	Affected			0.2794	0.5045		0	-1	3.7	-69.11
c.877C>G	R293G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R293G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains uncertain. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic outcome, and Foldetta (integrating FoldX‑MD and Rosetta stability outputs) also indicates pathogenicity. No tool suggests a benign effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.338192	Uncertain	0.924	0.269	0.125											-15.861	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	3.70	Destabilizing	0.2	2.35	Destabilizing	3.03	Destabilizing	0.57	Ambiguous	0.604	Likely Pathogenic	-6.43	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.45	Pathogenic	0.02	Affected			0.3235	0.3738		-3	-2	4.1	-99.14
c.877C>T	R293C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R293C is listed in ClinVar with an uncertain significance (ClinVar ID 2500611.0) and is present in gnomAD (6‑33437782‑C‑T). Prediction tools that classify the variant as benign include premPS, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Consequently, the overwhelming majority of computational evidence indicates a pathogenic impact for R293C. This prediction aligns with the ClinVar designation of uncertain significance, not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.338192	Uncertain	0.924	0.269	0.125					Uncertain		1	6-33437782-C-T	3	1.86e-6	-12.844	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	1.38	Ambiguous	0.1	0.62	Ambiguous	1.00	Ambiguous	0.02	Likely Benign	0.579	Likely Pathogenic	-7.35	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.46	Pathogenic	0.00	Affected	3.38	23	0.3031	0.4363		-4	-3	7.0	-53.05	226.0	96.5	0.0	0.0	0.1	0.1		X		X			X	Potentially Pathogenic	The guanidinium group of the Arg293 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), packs against the phenol ring of the Tyr281 side chain or forms a salt bridge with the carboxylate group of Glu283 on the outer side of the C2 domain. The positively charged guanidinium side chain of arginine is on the outside surface of the hydrophobic C2 domain, resulting in a twist in the β strand. Although this twist is maintained in the variant simulations, replacing the positively charged residue with a more hydrophobic one, such as cysteine, could remove the twist during protein folding.Because Arg293 is positioned at the C2 and PH domain interface, the residue swap could significantly impact the tertiary structure assembly. Notably, Arg293 is located at the SynGAP-Ras interface, and its role in complex formation cannot be fully understood through solvent-only simulations.
c.878G>A	R293H 2D AISynGAP1 missense variant R293H is listed in ClinVar with an uncertain significance (ClinVar ID 3901513.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL and premPS, whereas the remaining 13 tools—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, classifies the variant as pathogenic. Overall, the preponderance of evidence indicates that R293H is most likely pathogenic, a conclusion that does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.338192	Uncertain	0.924	0.269	0.125					Uncertain		1				-13.009	Likely Pathogenic	0.973	Likely Pathogenic	Likely Pathogenic	4.45	Destabilizing	2.3	2.12	Destabilizing	3.29	Destabilizing	0.32	Likely Benign	0.438	Likely Benign	-4.60	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.45	Pathogenic	0.04	Affected			0.3120	0.2573		2	0	1.3	-19.05
c.878G>C	R293P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R293P is listed in ClinVar as Pathogenic (ClinVar ID 571092.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL and premPS, whereas the remaining tools—FoldX, Rosetta, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as Pathogenic; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, classifies it as Pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is concordant with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.338192	Uncertain	0.924	0.269	0.125					Likely Pathogenic		1				-16.275	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	3.62	Destabilizing	0.4	9.06	Destabilizing	6.34	Destabilizing	0.47	Likely Benign	0.497	Likely Benign	-6.43	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.45	Pathogenic	0.01	Affected	3.38	23	0.2162	0.4778		0	-2	2.9	-59.07	202.3	132.0	0.1	0.0	0.1	0.1	X	X		X				Potentially Pathogenic	The guanidinium group of the Arg293 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), packs against the phenol ring of the Tyr281 side chain or forms a salt bridge with the carboxylate group of Glu283 on the outer side of the C2 domain. In the WT simulations, the positively charged side chain of arginine remains outside the hydrophobic C2 domain, resulting in a twist in the β strand. The backbone amide bond of Arg293 potentially maintains this twist by forming a hydrogen bond with the carbonyl group of His210 or the hydroxyl group of Ser211 in the anti-parallel β sheet.Although this twist is also maintained in the variant simulations, replacing the positively charged residue with proline, which lacks the backbone amide group altogether, causes the β strand to unfold. Because Arg293 is positioned at the C2 and PH domain interface, the residue swap could significantly impact the tertiary structure assembly. Notably, Arg293 is located at the SynGAP-Ras interface, and its role in complex formation cannot be fully understood through solvent-only simulations.
c.878G>T	R293L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R293L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by REVEL and premPS, while the remaining evaluated tools (SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict pathogenicity. Uncertain results from FoldX, Rosetta, and Foldetta are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta provides no definitive stability change. Consequently, the variant is most likely pathogenic based on the consensus of predictive tools, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.338192	Uncertain	0.924	0.269	0.125											-15.502	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	1.56	Ambiguous	0.2	0.93	Ambiguous	1.25	Ambiguous	0.08	Likely Benign	0.493	Likely Benign	-6.43	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.46	Pathogenic	0.01	Affected			0.1815	0.4987		-3	-2	8.3	-43.03
c.87G>A	M29I 2D AIThe SynGAP1 missense variant M29I is catalogued in gnomAD (6-33423496‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes, while the single pathogenic signal comes from SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign likelihood. Foldetta stability analysis is unavailable for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250								6-33423496-G-A	6	3.72e-6	-2.425	Likely Benign	0.185	Likely Benign	Likely Benign										0.067	Likely Benign	-0.51	Neutral	0.006	Benign	0.091	Benign	4.26	Benign	0.00	Affected	4.32	1	0.1680	0.4385		1	2	2.6	-18.03
c.87G>C	M29I 2D AIThe SynGAP1 missense variant M29I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250											-2.425	Likely Benign	0.185	Likely Benign	Likely Benign										0.067	Likely Benign	-0.51	Neutral	0.006	Benign	0.091	Benign	4.26	Benign	0.00	Affected	4.32	1	0.1680	0.4385		1	2	2.6	-18.03
c.87G>T	M29I 2D AIThe SynGAP1 missense variant M29I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250											-2.425	Likely Benign	0.185	Likely Benign	Likely Benign										0.067	Likely Benign	-0.51	Neutral	0.006	Benign	0.091	Benign	4.26	Benign	0.00	Affected	4.32	1	0.1680	0.4385		1	2	2.6	-18.03
c.880A>C	T294P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T294P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX (Uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool reports a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.316932	Uncertain	0.919	0.267	0.125											-17.477	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	1.97	Ambiguous	0.3	5.18	Destabilizing	3.58	Destabilizing	1.15	Destabilizing	0.741	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	-0.19	Pathogenic	0.01	Affected			0.1906	0.4479		0	-1	-0.9	-3.99
c.880A>G	T294A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T294A missense variant is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the only tool with an uncertain call is FoldX. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts Likely Pathogenic, and Foldetta predicts Pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.316932	Uncertain	0.919	0.267	0.125											-12.371	Likely Pathogenic	0.971	Likely Pathogenic	Likely Pathogenic	1.87	Ambiguous	0.1	2.27	Destabilizing	2.07	Destabilizing	1.05	Destabilizing	0.719	Likely Pathogenic	-4.60	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	-0.18	Pathogenic	0.03	Affected			0.3687	0.3494		1	0	2.5	-30.03
c.880A>T	T294S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T294S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). In silico predictors that classify the variant as benign are absent; all available tools that provide a definitive call predict a deleterious effect. Pathogenic predictions come from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of pathogenic calls and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which contains no opposing evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.316932	Uncertain	0.919	0.267	0.125											-7.785	In-Between	0.954	Likely Pathogenic	Ambiguous	1.12	Ambiguous	0.2	1.70	Ambiguous	1.41	Ambiguous	1.19	Destabilizing	0.613	Likely Pathogenic	-3.68	Deleterious	0.999	Probably Damaging	0.992	Probably Damaging	0.08	Pathogenic	0.03	Affected			0.2983	0.3396		1	1	-0.1	-14.03
c.881C>A	T294N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T294N is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy methods reinforce this assessment: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status (no report). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.316932	Uncertain	0.919	0.267	0.125											-14.925	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	2.74	Destabilizing	0.2	2.66	Destabilizing	2.70	Destabilizing	1.56	Destabilizing	0.630	Likely Pathogenic	-4.60	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	-0.18	Pathogenic	0.01	Affected			0.1040	0.3239		0	0	-2.8	13.00
c.881C>G	T294S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T294S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). In silico predictors that classify the variant as benign are absent; all available tools that provide a definitive call predict a deleterious effect. Pathogenic predictions come from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of pathogenic calls and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which contains no opposing evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.316932	Uncertain	0.919	0.267	0.125											-7.785	In-Between	0.954	Likely Pathogenic	Ambiguous	1.12	Ambiguous	0.2	1.70	Ambiguous	1.41	Ambiguous	1.19	Destabilizing	0.583	Likely Pathogenic	-3.68	Deleterious	0.999	Probably Damaging	0.992	Probably Damaging	0.08	Pathogenic	0.03	Affected			0.2983	0.3396		1	1	-0.1	-14.03
c.881C>T	T294I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T294I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on pathogenicity include REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results are Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Based on the overwhelming agreement among pathogenic predictions and the high‑accuracy tool results, the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.316932	Uncertain	0.919	0.267	0.125											-15.302	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	4.09	Destabilizing	0.2	1.33	Ambiguous	2.71	Destabilizing	0.54	Ambiguous	0.768	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	-0.19	Pathogenic	0.01	Affected			0.0808	0.5485		0	-1	5.2	12.05
c.883A>C	T295P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX and AlphaMissense‑Optimized, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome. High‑accuracy assessments further show that AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it as likely pathogenic, and Foldetta reports an uncertain stability change. With the majority of evidence pointing to deleterious effects, the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.401658	Structured	0.295548	Uncertain	0.881	0.288	0.125											-9.941	Likely Pathogenic	0.688	Likely Pathogenic	Likely Benign	0.26	Likely Benign	0.2	3.30	Destabilizing	1.78	Ambiguous	0.60	Ambiguous	0.531	Likely Pathogenic	-4.65	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.90	Pathogenic	0.02	Affected			0.2442	0.5327		0	-1	-0.9	-3.99
c.883A>G	T295A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T295A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into benign (REVEL, FoldX, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM). Four tools are uncertain (Rosetta, Foldetta, premPS, ESM1b). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the majority of conventional predictors lean toward a benign effect, whereas the SGM Consensus indicates a pathogenic signal. Thus, the variant is most likely benign based on the bulk of evidence, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.401658	Structured	0.295548	Uncertain	0.881	0.288	0.125											-7.276	In-Between	0.336	Likely Benign	Likely Benign	0.22	Likely Benign	0.1	1.17	Ambiguous	0.70	Ambiguous	0.56	Ambiguous	0.340	Likely Benign	-3.51	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.96	Pathogenic	0.11	Tolerated			0.4623	0.4190		1	0	2.5	-30.03
c.883A>T	T295S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; premPS is inconclusive. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority (3 benign vs. 1 pathogenic); and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.401658	Structured	0.295548	Uncertain	0.881	0.288	0.125											-4.904	Likely Benign	0.335	Likely Benign	Likely Benign	-0.16	Likely Benign	0.2	0.28	Likely Benign	0.06	Likely Benign	0.54	Ambiguous	0.218	Likely Benign	-2.16	Neutral	0.999	Probably Damaging	0.992	Probably Damaging	2.02	Pathogenic	0.14	Tolerated			0.3910	0.4473		1	1	-0.1	-14.03
c.884C>A	T295N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T295N missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, ESM1b, and Foldetta, while those that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, seven tools predict pathogenicity versus four predicting benign, with no ClinVar evidence to contradict this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.401658	Structured	0.295548	Uncertain	0.881	0.288	0.125											-6.588	Likely Benign	0.793	Likely Pathogenic	Ambiguous	0.24	Likely Benign	0.1	0.66	Ambiguous	0.45	Likely Benign	0.89	Ambiguous	0.438	Likely Benign	-3.51	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.93	Pathogenic	0.03	Affected			0.1522	0.4457		0	0	-2.8	13.00
c.884C>G	T295S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; premPS is inconclusive. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority (3 benign vs. 1 pathogenic); and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.401658	Structured	0.295548	Uncertain	0.881	0.288	0.125											-4.904	Likely Benign	0.335	Likely Benign	Likely Benign	-0.16	Likely Benign	0.2	0.28	Likely Benign	0.06	Likely Benign	0.54	Ambiguous	0.196	Likely Benign	-2.16	Neutral	0.999	Probably Damaging	0.992	Probably Damaging	2.02	Pathogenic	0.14	Tolerated			0.3910	0.4473		1	1	-0.1	-14.03
c.884C>T	T295I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T295I is reported in gnomAD (ID 6‑33437789‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two consensus groups: benign predictions come from FoldX and Foldetta, while pathogenic predictions are supported by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by AlphaMissense‑Optimized, Rosetta, and premPS and are treated as inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic effect, with only a minority of tools indicating benign or uncertain outcomes. This prediction does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.401658	Structured	0.295548	Uncertain	0.881	0.288	0.125								6-33437789-C-T	4	2.48e-6	-9.330	Likely Pathogenic	0.892	Likely Pathogenic	Ambiguous	0.21	Likely Benign	0.2	0.55	Ambiguous	0.38	Likely Benign	0.58	Ambiguous	0.607	Likely Pathogenic	-4.87	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.88	Pathogenic	0.04	Affected	3.38	23	0.1025	0.5599		-1	0	5.2	12.05
c.886T>A	S296T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S296T missense variant is not reported in ClinVar and is absent from gnomAD. Consensus from most in silico predictors shows a split: six tools (REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT) and AlphaMissense‑Optimized predict a benign effect, whereas four tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default) predict pathogenicity. ESM1b remains uncertain. High‑accuracy assessments give a more definitive picture: AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.444081	Structured	0.282669	Uncertain	0.887	0.284	0.250											-7.020	In-Between	0.645	Likely Pathogenic	Likely Benign	0.09	Likely Benign	0.4	0.38	Likely Benign	0.24	Likely Benign	0.19	Likely Benign	0.201	Likely Benign	-2.10	Neutral	0.992	Probably Damaging	0.987	Probably Damaging	2.13	Pathogenic	0.13	Tolerated			0.1437	0.6340		1	1	0.1	14.03
c.886T>C	S296P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, and SIFT, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. When predictions are grouped by agreement, four tools predict benign and seven predict pathogenic, with premPS remaining uncertain. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. Thus, the majority of evidence leans toward pathogenicity, and this conclusion is consistent with the lack of ClinVar annotation and gnomAD absence, which do not contradict the prediction. Overall, the variant is most likely pathogenic based on the current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.444081	Structured	0.282669	Uncertain	0.887	0.284	0.250											-8.302	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.04	Likely Benign	0.4	0.18	Likely Benign	0.11	Likely Benign	0.72	Ambiguous	0.439	Likely Benign	-3.74	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.92	Pathogenic	0.12	Tolerated			0.2273	0.6320		1	-1	-0.8	10.04
c.886T>G	S296A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296A (ClinVar ID 469166.0) is listed as ClinVar status Uncertain and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign or neutral. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict pathogenic. Grouping by consensus, the benign‑predicting tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a benign effect. No evidence from the available tools suggests a deleterious impact. Therefore, the variant is most likely benign, and this conclusion is consistent with its ClinVar status of Uncertain rather than pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.444081	Structured	0.282669	Uncertain	0.887	0.284	0.250					Uncertain		1				-6.847	Likely Benign	0.247	Likely Benign	Likely Benign	0.50	Ambiguous	0.3	-0.26	Likely Benign	0.12	Likely Benign	0.35	Likely Benign	0.209	Likely Benign	-1.79	Neutral	0.992	Probably Damaging	0.987	Probably Damaging	1.97	Pathogenic	0.65	Tolerated	3.40	16	0.4958	0.5522		1	1	2.6	-16.00	182.5	26.6	-0.2	0.1	-0.5	0.0		X						Potentially Pathogenic	The hydroxyl group of the Ser296 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), stably hydrogen bonds with the carboxylate group of Asp330 in a neighboring β strand (res. Ala322-Asp332). The backbone carbonyl group of Ser296 also hydrogen bonds with the guanidinium group of Arg279 in another nearby β strand (res. Arg279-Cys285). In the variant simulations, the methyl group of the Ala296 side chain cannot hydrogen bond with Asp330, causing the carboxylate group positioning to fluctuate more than in the WT simulations.Although the residue swap does not seem to affect the anti-parallel β sheet assembly during the simulations, it is possible that the Ser296-Asp330 hydrogen bond plays a crucial role in maintaining the C2 domain fold. Notably, because Ser296 is located near the membrane interface, the potential effect of the residue swap on the SynGAP-membrane association cannot be addressed by solvent-only simulations.
c.887C>A	S296Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and premPS, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. The variant is most likely pathogenic based on predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.444081	Structured	0.282669	Uncertain	0.887	0.284	0.250											-12.148	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	1.46	Ambiguous	0.2	0.48	Likely Benign	0.97	Ambiguous	0.15	Likely Benign	0.486	Likely Benign	-4.34	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.93	Pathogenic	0.05	Affected			0.0800	0.5610		-3	-2	-0.5	76.10
c.887C>G	S296C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as benign. No predictions or stability results are missing or inconclusive. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.444081	Structured	0.282669	Uncertain	0.887	0.284	0.250											-7.842	In-Between	0.286	Likely Benign	Likely Benign	0.46	Likely Benign	0.1	-0.11	Likely Benign	0.18	Likely Benign	0.09	Likely Benign	0.361	Likely Benign	-1.46	Neutral	1.000	Probably Damaging	0.998	Probably Damaging	1.91	Pathogenic	0.05	Affected			0.1052	0.6052		0	-1	3.3	16.06
c.887C>T	S296F 2D AIThe SynGAP1 missense variant S296F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, and premPS. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive and therefore unavailable as evidence. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.444081	Structured	0.282669	Uncertain	0.887	0.284	0.250											-11.721	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	1.29	Ambiguous	1.6	0.24	Likely Benign	0.77	Ambiguous	0.29	Likely Benign	0.494	Likely Benign	-4.34	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.94	Pathogenic	0.04	Affected			0.0720	0.5905		-3	-2	3.6	60.10
c.889A>C	K297Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K297Q missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, Rosetta, and Foldetta. In contrast, the majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX is uncertain and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as benign. Overall, the preponderance of evidence points to a pathogenic effect for K297Q. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.422041	Structured	0.272593	Uncertain	0.880	0.285	0.375											-8.393	Likely Pathogenic	0.970	Likely Pathogenic	Likely Pathogenic	0.66	Ambiguous	0.3	0.14	Likely Benign	0.40	Likely Benign	1.06	Destabilizing	0.450	Likely Benign	-3.48	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.65	Pathogenic	0.01	Affected			0.4768	0.1738		1	1	0.4	-0.04
c.889A>G	K297E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome; the only inconclusive result is FoldX, which is listed as “Uncertain” and is treated as unavailable. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective predictions, K297E is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.422041	Structured	0.272593	Uncertain	0.880	0.285	0.375											-10.143	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	1.99	Ambiguous	0.4	2.43	Destabilizing	2.21	Destabilizing	1.16	Destabilizing	0.507	Likely Pathogenic	-3.54	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.61	Pathogenic	0.02	Affected			0.4073	0.1547		0	1	0.4	0.94
c.88C>A	H30N 2D AIThe SynGAP1 missense variant H30N is not reported in ClinVar and is absent from gnomAD. Consensus among most in silico predictors is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect, while only SIFT predicts pathogenicity. Grouping the tools, the benign‑predicting set (nine tools) overwhelmingly outweighs the single pathogenic prediction. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250											-3.096	Likely Benign	0.108	Likely Benign	Likely Benign										0.052	Likely Benign	-1.91	Neutral	0.273	Benign	0.380	Benign	3.92	Benign	0.00	Affected			0.2699	0.3818		2	1	-0.3	-23.04
c.88C>G	H30D 2D AIThe SynGAP1 missense variant H30D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for H30D, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250											-2.838	Likely Benign	0.318	Likely Benign	Likely Benign										0.150	Likely Benign	-2.25	Neutral	0.462	Possibly Damaging	0.599	Possibly Damaging	3.93	Benign	0.00	Affected			0.3048	0.3296		1	-1	-0.3	-22.05
c.88C>T	H30Y 2D AIThe SynGAP1 H30Y missense variant (ClinVar ID 972248.0) is listed as “Uncertain” and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumVar and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250					Uncertain		1				-3.047	Likely Benign	0.115	Likely Benign	Likely Benign										0.082	Likely Benign	-1.84	Neutral	0.273	Benign	0.478	Possibly Damaging	3.99	Benign	0.00	Affected	4.32	1	0.1572	0.4856		0	2	1.9	26.03
c.890A>C	K297T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K297T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are none, whereas those that predict a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy methods specifically show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.422041	Structured	0.272593	Uncertain	0.880	0.285	0.375											-10.110	Likely Pathogenic	0.987	Likely Pathogenic	Likely Pathogenic	1.55	Ambiguous	0.1	1.19	Ambiguous	1.37	Ambiguous	0.59	Ambiguous	0.551	Likely Pathogenic	-5.28	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.62	Pathogenic	0.01	Affected			0.2294	0.4024		0	-1	3.2	-27.07
c.890A>G	K297R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and FATHMM. Predictions that are uncertain or inconclusive are FoldX, Rosetta, premPS, and ESM1b. High‑accuracy methods give a consistent benign signal: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign; and Foldetta, a protein‑folding stability approach combining FoldX‑MD and Rosetta, predicts benign. Based on the aggregate of these predictions, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.422041	Structured	0.272593	Uncertain	0.880	0.285	0.375											-7.877	In-Between	0.314	Likely Benign	Likely Benign	-0.86	Ambiguous	0.3	0.67	Ambiguous	-0.10	Likely Benign	0.66	Ambiguous	0.257	Likely Benign	-2.36	Neutral	0.999	Probably Damaging	0.995	Probably Damaging	1.66	Pathogenic	0.19	Tolerated			0.4828	0.1506		3	2	-0.6	28.01
c.890A>T	K297M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297M is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, and premPS. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized classifies the variant as Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports Likely Pathogenic; whereas Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, reports a Benign effect. Overall, the preponderance of evidence (10 pathogenic vs. 4 benign predictions) points to the variant being most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.422041	Structured	0.272593	Uncertain	0.880	0.285	0.375											-11.472	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	0.09	Likely Benign	0.1	0.32	Likely Benign	0.21	Likely Benign	0.49	Likely Benign	0.538	Likely Pathogenic	-5.20	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.61	Pathogenic	0.00	Affected			0.1438	0.4394		0	-1	5.8	3.02
c.891G>C	K297N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.422041	Structured	0.272593	Uncertain	0.880	0.285	0.375											-11.328	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	1.08	Ambiguous	0.1	1.60	Ambiguous	1.34	Ambiguous	1.15	Destabilizing	0.253	Likely Benign	-4.31	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.61	Pathogenic	0.01	Affected			0.3797	0.2265		1	0	0.4	-14.07
c.891G>T	K297N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, K297N is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.422041	Structured	0.272593	Uncertain	0.880	0.285	0.375											-11.328	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	1.08	Ambiguous	0.1	1.60	Ambiguous	1.34	Ambiguous	1.15	Destabilizing	0.253	Likely Benign	-4.31	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.61	Pathogenic	0.01	Affected			0.3797	0.2265		1	0	0.4	-14.07
c.892C>A	P298T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain results and are treated as unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta remains uncertain. Overall, the preponderance of evidence points to a benign effect for P298T, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.328603	Structured	0.268765	Uncertain	0.860	0.283	0.500											-7.366	In-Between	0.104	Likely Benign	Likely Benign	1.44	Ambiguous	0.2	1.03	Ambiguous	1.24	Ambiguous	0.04	Likely Benign	0.209	Likely Benign	-0.13	Neutral	0.939	Possibly Damaging	0.739	Possibly Damaging	1.96	Pathogenic	1.00	Tolerated			0.1595	0.6349		0	-1	0.9	3.99
c.892C>G	P298A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Based on the preponderance of benign predictions and the lack of pathogenic consensus, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.328603	Structured	0.268765	Uncertain	0.860	0.283	0.500											-6.082	Likely Benign	0.074	Likely Benign	Likely Benign	1.22	Ambiguous	0.1	1.17	Ambiguous	1.20	Ambiguous	0.50	Likely Benign	0.191	Likely Benign	-0.98	Neutral	0.885	Possibly Damaging	0.589	Possibly Damaging	1.94	Pathogenic	0.66	Tolerated			0.3761	0.5787		1	-1	3.4	-26.04
c.892C>T	P298S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298S is listed in ClinVar as Benign (ClinVar ID 2965590.0) and is present in gnomAD (ID 6‑33437797‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. No evidence from FoldX, Rosetta, or premPS is available to support either outcome. Overall, the majority of predictions support a benign impact, aligning with the ClinVar designation. Thus, the variant is most likely benign and does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.328603	Structured	0.268765	Uncertain	0.860	0.283	0.500					Benign		1	6-33437797-C-T	5	3.10e-6	-6.342	Likely Benign	0.144	Likely Benign	Likely Benign	1.38	Ambiguous	0.2	1.41	Ambiguous	1.40	Ambiguous	0.58	Ambiguous	0.189	Likely Benign	-1.20	Neutral	0.991	Probably Damaging	0.898	Possibly Damaging	2.03	Pathogenic	0.85	Tolerated	3.39	20	0.3678	0.5855		-1	1	0.8	-10.04
c.893C>A	P298H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P298H missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Remaining tools (AlphaMissense‑Default, FoldX, Rosetta, Foldetta, premPS) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is uncertain. Overall, the majority of predictions (five pathogenic vs. three benign) and the SGM Consensus support a pathogenic interpretation. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.328603	Structured	0.268765	Uncertain	0.860	0.283	0.500											-9.777	Likely Pathogenic	0.443	Ambiguous	Likely Benign	1.57	Ambiguous	0.2	1.49	Ambiguous	1.53	Ambiguous	0.83	Ambiguous	0.313	Likely Benign	-2.37	Neutral	0.999	Probably Damaging	0.964	Probably Damaging	1.92	Pathogenic	0.04	Affected			0.1769	0.4943		0	-2	-1.6	40.02
c.893C>G	P298R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298R has no ClinVar entry and is not reported in gnomAD. Computational predictors fall into two consensus groups: benign predictions come from REVEL, FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported only by Foldetta and premPS. High‑accuracy tools give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta reports an uncertain stability change. Overall, the majority of evidence points toward a pathogenic effect, and this assessment is not contradicted by ClinVar, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.268765	Uncertain	0.860	0.283	0.500											-11.427	Likely Pathogenic	0.733	Likely Pathogenic	Likely Benign	0.45	Likely Benign	0.0	2.08	Destabilizing	1.27	Ambiguous	0.61	Ambiguous	0.280	Likely Benign	-1.83	Neutral	0.997	Probably Damaging	0.952	Probably Damaging	2.03	Pathogenic	0.09	Tolerated			0.1299	0.3872		0	-2	-2.9	59.07
c.893C>T	P298L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P298L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome; and Foldetta’s stability prediction is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.328603	Structured	0.268765	Uncertain	0.860	0.283	0.500											-7.334	In-Between	0.107	Likely Benign	Likely Benign	0.60	Ambiguous	0.2	1.53	Ambiguous	1.07	Ambiguous	-0.16	Likely Benign	0.267	Likely Benign	-0.82	Neutral	0.885	Possibly Damaging	0.589	Possibly Damaging	1.91	Pathogenic	0.21	Tolerated			0.2137	0.6795		-3	-3	5.4	16.04
c.895C>A	R299S 2D 3DClick to see structure in 3D Viewer AISynGAP1 R299S is not reported in ClinVar and is absent from gnomAD. Among in‑silico predictors, benign calls come from REVEL and SIFT, while pathogenic calls are made by FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, ESM1b, and AlphaMissense‑Optimized. High‑accuracy methods give a pathogenic verdict: AlphaMissense‑Optimized is inconclusive, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) also predicts pathogenic. Overall, the evidence points to a pathogenic effect, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.321458	Structured	0.262979	Uncertain	0.819	0.295	0.500											-7.276	In-Between	0.882	Likely Pathogenic	Ambiguous	2.86	Destabilizing	0.3	1.46	Ambiguous	2.16	Destabilizing	1.07	Destabilizing	0.241	Likely Benign	-3.20	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.75	Pathogenic	0.07	Tolerated			0.2780	0.5057		0	-1	3.7	-69.11
c.895C>G	R299G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized indicates a benign change, but the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. With the majority of evidence pointing to a damaging effect, the variant is most likely pathogenic. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.321458	Structured	0.262979	Uncertain	0.819	0.295	0.500											-8.354	Likely Pathogenic	0.629	Likely Pathogenic	Likely Benign	3.58	Destabilizing	0.2	3.16	Destabilizing	3.37	Destabilizing	1.37	Destabilizing	0.248	Likely Benign	-3.84	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.79	Pathogenic	0.02	Affected			0.3361	0.4150		-3	-2	4.1	-99.14
c.895C>T	R299C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R299C is listed in ClinVar with an uncertain significance (ClinVar ID 1335623.0) and is present in gnomAD (ID 6‑33437800‑C‑T). Prediction tools that classify the variant as benign include REVEL, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Other stability predictors (FoldX, Rosetta, premPS) are also uncertain. Overall, the balance of evidence favors a pathogenic interpretation, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of disease relevance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.321458	Structured	0.262979	Uncertain	0.819	0.295	0.500					Conflicting		2	6-33437800-C-T	3	1.86e-6	-6.326	Likely Benign	0.572	Likely Pathogenic	Likely Benign	1.85	Ambiguous	0.4	0.61	Ambiguous	1.23	Ambiguous	0.76	Ambiguous	0.344	Likely Benign	-3.54	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.65	Pathogenic	0.06	Tolerated	3.39	19	0.3035	0.4564		-4	-3	7.0	-53.05	210.7	91.3	0.1	0.0	0.0	0.2	X	X						Potentially Pathogenic	The guanidinium group of Arg299, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), forms hydrogen bonds that stabilize the tight turn. In the WT simulations, the Arg299 side chain hydrogen bonds with the loop backbone carbonyl groups (e.g., Ser302, Thr305, Leu274, Gly303), the hydroxyl group of Ser300, and even forms a salt bridge with the carboxylate group of Asp304.In the variant simulations, the thiol group of the Cys299 side chain is unable to form any of these well-coordinated or strong interactions, which could affect the initial formation of the secondary hairpin loop during folding. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Moreover, the positively charged Arg299 side chain faces the polar head group region of the inner leaflet membrane and could directly anchor the C2 domain to the membrane. In short, the residue swap could negatively affect both protein folding and the stability of the SynGAP-membrane association.
c.896G>A	R299H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R299H is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437801‑G‑A). Functional prediction tools cluster into two groups: benign predictions from REVEL and AlphaMissense‑Optimized, and pathogenic predictions from FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; Rosetta, ESM1b, and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a tie between pathogenic and uncertain calls. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar uncertain designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.321458	Structured	0.262979	Uncertain	0.819	0.295	0.500					Conflicting		2	6-33437801-G-A	10	6.20e-6	-7.731	In-Between	0.388	Ambiguous	Likely Benign	3.97	Destabilizing	1.0	0.94	Ambiguous	2.46	Destabilizing	1.41	Destabilizing	0.238	Likely Benign	-3.35	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.69	Pathogenic	0.02	Affected	3.39	19	0.3293	0.2982		2	0	1.3	-19.05	211.2	72.5	-0.1	0.2	-0.2	0.3	X							Potentially Pathogenic	The guanidinium group of Arg299, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), forms hydrogen bonds that stabilize the tight turn. In the WT simulations, the Arg299 side chain hydrogen bonds with the loop backbone carbonyl groups (e.g., Ser302, Thr305, Leu274, Gly303), the hydroxyl group of Ser300, and even forms a salt bridge with the carboxylate group of Asp304.In the variant simulations, the imidazole ring of His299 (epsilon protonated state) hydrogen bonds with the carbonyl group of Asp304 and the hydroxyl group of Ser300. However, it does not form as many or as strong interactions as arginine, which could affect the initial formation of the secondary hairpin loop during folding. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant.Additionally, His299 prefers to hydrophobically interact with other hydrophobic residues inside the C2 domain core (e.g., Val306, Leu274), which destabilizes the C2 domain. Indeed, the β strand partially unfolds during the second simulation. Moreover, the positively charged Arg299 side chain faces the polar head group region of the inner leaflet membrane and could directly anchor the C2 domain to the membrane. In short, the residue swap could negatively affect both protein folding and the stability of the SynGAP-membrane association.
c.896G>C	R299P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299P is not reported in ClinVar or gnomAD, indicating no publicly available frequency data. Prediction tools cluster into benign and pathogenic groups: benign predictions include REVEL and AlphaMissense‑Optimized, while pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, SIFT, FATHMM, and AlphaMissense‑Default; ESM1b is uncertain. The SGM‑Consensus label is Likely Pathogenic. High‑accuracy tools give a clear signal: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta also predicts pathogenic. Overall, the predictions strongly favor a pathogenic interpretation, with no ClinVar status to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.321458	Structured	0.262979	Uncertain	0.819	0.295	0.500											-7.662	In-Between	0.722	Likely Pathogenic	Likely Benign	4.10	Destabilizing	0.2	3.01	Destabilizing	3.56	Destabilizing	1.19	Destabilizing	0.295	Likely Benign	-4.09	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.68	Pathogenic	0.02	Affected			0.2072	0.5379		0	-2	2.9	-59.07
c.896G>T	R299L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Stability‑based methods FoldX, Rosetta, Foldetta, and premPS returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of consensus predictions favor a pathogenic effect, and the high‑accuracy tools do not overturn this trend. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for R299L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.321458	Structured	0.262979	Uncertain	0.819	0.295	0.500											-5.171	Likely Benign	0.645	Likely Pathogenic	Likely Benign	1.37	Ambiguous	0.6	0.77	Ambiguous	1.07	Ambiguous	0.59	Ambiguous	0.356	Likely Benign	-4.03	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.65	Pathogenic	0.02	Affected			0.2027	0.5202		-3	-2	8.3	-43.03
c.898T>A	S300T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM‑Consensus (3 benign vs. 1 pathogenic) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or stability result is inconclusive. Overall, the evidence overwhelmingly supports a benign classification, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.356642	Structured	0.256848	Uncertain	0.742	0.280	0.375											-4.648	Likely Benign	0.069	Likely Benign	Likely Benign	0.85	Ambiguous	0.1	-0.30	Likely Benign	0.28	Likely Benign	-0.33	Likely Benign	0.056	Likely Benign	0.50	Neutral	0.003	Benign	0.002	Benign	1.94	Pathogenic	0.85	Tolerated			0.1409	0.6428		1	1	0.1	14.03
c.898T>C	S300P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The remaining tools—FoldX, Foldetta, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.356642	Structured	0.256848	Uncertain	0.742	0.280	0.375											-7.379	In-Between	0.110	Likely Benign	Likely Benign	1.24	Ambiguous	1.0	0.06	Likely Benign	0.65	Ambiguous	0.50	Likely Benign	0.086	Likely Benign	-2.46	Neutral	0.784	Possibly Damaging	0.390	Benign	1.54	Pathogenic	0.02	Affected			0.2192	0.5585		1	-1	-0.8	10.04
c.898T>G	S300A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. Rosetta and Foldetta give uncertain results and are therefore not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign (3 benign vs. 1 pathogenic). Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.356642	Structured	0.256848	Uncertain	0.742	0.280	0.375											-5.420	Likely Benign	0.060	Likely Benign	Likely Benign	0.08	Likely Benign	0.3	1.07	Ambiguous	0.58	Ambiguous	0.08	Likely Benign	0.031	Likely Benign	-1.18	Neutral	0.139	Benign	0.060	Benign	1.56	Pathogenic	0.20	Tolerated			0.5135	0.4949	Weaken	1	1	2.6	-16.00
c.899C>A	S300Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300Y has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Foldetta, premPS, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Two tools (AlphaMissense‑Default and Rosetta) are uncertain and do not influence the consensus. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not contradict any ClinVar status (none is available). Thus, based on current predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.356642	Structured	0.256848	Uncertain	0.742	0.280	0.375											-10.464	Likely Pathogenic	0.422	Ambiguous	Likely Benign	-0.08	Likely Benign	0.4	0.55	Ambiguous	0.24	Likely Benign	0.28	Likely Benign	0.116	Likely Benign	-2.52	Deleterious	0.975	Probably Damaging	0.686	Possibly Damaging	1.52	Pathogenic	0.01	Affected			0.0678	0.5395		-3	-2	-0.5	76.10
c.899C>G	S300C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300C is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437804‑C‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Rosetta and Foldetta give uncertain results and are therefore not considered evidence for either side. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of reliable predictions indicate a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.356642	Structured	0.256848	Uncertain	0.742	0.280	0.375								6-33437804-C-G			-6.749	Likely Benign	0.108	Likely Benign	Likely Benign	0.31	Likely Benign	0.2	1.45	Ambiguous	0.88	Ambiguous	0.34	Likely Benign	0.129	Likely Benign	-2.45	Neutral	0.975	Probably Damaging	0.815	Possibly Damaging	1.55	Pathogenic	0.01	Affected	3.47	19	0.1005	0.6493		-1	0	3.3	16.06
c.899C>T	S300F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S300F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The remaining tool, AlphaMissense‑Default, gives an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions lean toward pathogenicity, while two high‑accuracy methods support a benign effect. Thus, the variant is most likely pathogenic based on the current computational evidence, which does not contradict its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.356642	Structured	0.256848	Uncertain	0.742	0.280	0.375					Uncertain		1				-10.222	Likely Pathogenic	0.353	Ambiguous	Likely Benign	-0.29	Likely Benign	0.4	0.16	Likely Benign	-0.07	Likely Benign	0.04	Likely Benign	0.117	Likely Benign	-2.66	Deleterious	0.975	Probably Damaging	0.596	Possibly Damaging	1.52	Pathogenic	0.01	Affected	3.47	19	0.0579	0.5701		-3	-2	3.6	60.10	233.6	-67.6	-0.1	0.0	0.4	0.2	X	X						Potentially Pathogenic	The hydroxyl group of the Ser300 side chain, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), hydrogen bonds with the guanidinium group of Arg299 and the backbone amide group and side chain of Ser302. Thus, in the WT simulations, it contributes to the β hairpin stability. In the variant simulations, the phenol ring of Phe300 cannot form any side chain-related hydrogen bonds, and Arg299 is moved away from its central hairpin loop position.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel.
c.89A>C	H30P 2D AIThe SynGAP1 H30P missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250											-1.933	Likely Benign	0.077	Likely Benign	Likely Benign										0.202	Likely Benign	-2.77	Deleterious	0.676	Possibly Damaging	0.599	Possibly Damaging	3.89	Benign	0.00	Affected			0.2527	0.4723		0	-2	1.6	-40.02
c.89A>G	H30R 2D AIThe SynGAP1 missense variant H30R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250											-2.156	Likely Benign	0.186	Likely Benign	Likely Benign										0.138	Likely Benign	-2.17	Neutral	0.462	Possibly Damaging	0.599	Possibly Damaging	3.94	Benign	0.00	Affected			0.2762	0.3590		2	0	-1.3	19.05
c.89A>T	H30L 2D AIThe SynGAP1 H30L missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250											-2.073	Likely Benign	0.117	Likely Benign	Likely Benign										0.163	Likely Benign	-2.88	Deleterious	0.462	Possibly Damaging	0.599	Possibly Damaging	3.94	Benign	0.00	Affected			0.1523	0.5793		-2	-3	7.0	-23.98
c.8G>A	R3K 2D AIThe SynGAP1 missense variant R3K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect. The prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.550331	Binding	0.358	0.920	0.875											-4.378	Likely Benign	0.254	Likely Benign	Likely Benign										0.062	Likely Benign	-0.45	Neutral	0.001	Benign	0.000	Benign	4.09	Benign	0.00	Affected			0.5842	0.4564	Weaken	3	2	0.6	-28.01
c.8G>C	R3T 2D AIThe SynGAP1 missense variant R3T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.550331	Binding	0.358	0.920	0.875											-3.693	Likely Benign	0.285	Likely Benign	Likely Benign										0.053	Likely Benign	-0.55	Neutral	0.208	Benign	0.018	Benign	4.01	Benign	0.00	Affected			0.1809	0.5145		-1	-1	3.8	-55.08
c.8G>T	R3M 2D AIThe SynGAP1 missense variant R3M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus methods give a consistent benign signal: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and Foldetta data are unavailable. Overall, the majority of evidence supports a benign classification, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.550331	Binding	0.358	0.920	0.875											-4.655	Likely Benign	0.618	Likely Pathogenic	Likely Benign										0.097	Likely Benign	0.00	Neutral	0.872	Possibly Damaging	0.162	Benign	3.96	Benign	0.00	Affected			0.1906	0.4795		0	-1	6.4	-24.99
c.901G>A	A301T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33437806‑G‑A). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is benign. Overall, the majority of evidence points to a benign effect, and this is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.429200	Structured	0.258424	Uncertain	0.647	0.272	0.375					Uncertain		5	6-33437806-G-A	2	1.24e-6	-3.448	Likely Benign	0.070	Likely Benign	Likely Benign	0.36	Likely Benign	0.2	-0.33	Likely Benign	0.02	Likely Benign	0.03	Likely Benign	0.150	Likely Benign	-0.25	Neutral	0.997	Probably Damaging	0.989	Probably Damaging	4.15	Benign	0.22	Tolerated	4.32	14	0.1362	0.7201		1	0	-2.5	30.03	219.8	-42.8	-0.1	0.0	-0.5	0.2								Uncertain	The methyl group of Ala301, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), points outward from the β hairpin loop, and its backbone atoms do not participate in the loop formation in the WT simulations. In the variant simulations, the hydroxyl group of the Thr301 side chain also mostly points outward; however, the guanidinium group of Arg299 is moved away from its central hairpin loop position.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel.
c.901G>C	A301P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools—polyPhen‑2 HumDiv and polyPhen‑2 HumVar—predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.429200	Structured	0.258424	Uncertain	0.647	0.272	0.375											-3.808	Likely Benign	0.085	Likely Benign	Likely Benign	-0.47	Likely Benign	0.1	-0.41	Likely Benign	-0.44	Likely Benign	0.40	Likely Benign	0.225	Likely Benign	-0.83	Neutral	0.999	Probably Damaging	0.995	Probably Damaging	4.11	Benign	0.06	Tolerated			0.1907	0.5371		1	-1	-3.4	26.04
c.901G>T	A301S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301S is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess sequence conservation and functional impact uniformly indicate a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy methods corroborate the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. No evidence from these analyses suggests a deleterious effect. Therefore, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.429200	Structured	0.258424	Uncertain	0.647	0.272	0.375											-2.488	Likely Benign	0.066	Likely Benign	Likely Benign	0.20	Likely Benign	0.1	-0.32	Likely Benign	-0.06	Likely Benign	0.22	Likely Benign	0.151	Likely Benign	-0.28	Neutral	0.992	Probably Damaging	0.983	Probably Damaging	4.21	Benign	0.13	Tolerated			0.2706	0.6022		1	1	-2.6	16.00
c.902C>A	A301D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301D is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM all predict benign, whereas polyPhen‑2 (HumDiv and HumVar) and ESM1b predict pathogenic. Tools with uncertain outputs—Rosetta, Foldetta, and AlphaMissense‑Default—do not provide decisive evidence. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized classifies the variant as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign verdict; Foldetta remains inconclusive. Taken together, the preponderance of evidence indicates that A301D is most likely benign, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.429200	Structured	0.258424	Uncertain	0.647	0.272	0.375											-10.276	Likely Pathogenic	0.488	Ambiguous	Likely Benign	-0.37	Likely Benign	0.2	-1.15	Ambiguous	-0.76	Ambiguous	0.23	Likely Benign	0.224	Likely Benign	-0.35	Neutral	0.999	Probably Damaging	0.995	Probably Damaging	4.17	Benign	0.07	Tolerated			0.1599	0.1705		0	-2	-5.3	44.01
c.902C>G	A301G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as Benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, classifies the variant as Benign. Overall, the consensus of the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar claim. Therefore, the variant is most likely benign, and this is not contradictory to ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.429200	Structured	0.258424	Uncertain	0.647	0.272	0.375											-3.085	Likely Benign	0.072	Likely Benign	Likely Benign	0.27	Likely Benign	0.1	0.34	Likely Benign	0.31	Likely Benign	0.37	Likely Benign	0.128	Likely Benign	-0.37	Neutral	0.992	Probably Damaging	0.983	Probably Damaging	4.18	Benign	0.28	Tolerated			0.2425	0.5054		1	0	-2.2	-14.03
c.902C>T	A301V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Thus, the overall evidence supports a benign classification for A301V, and this conclusion is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.429200	Structured	0.258424	Uncertain	0.647	0.272	0.375											-2.476	Likely Benign	0.095	Likely Benign	Likely Benign	0.25	Likely Benign	0.1	0.48	Likely Benign	0.37	Likely Benign	0.06	Likely Benign	0.116	Likely Benign	-0.49	Neutral	0.997	Probably Damaging	0.983	Probably Damaging	4.14	Benign	0.26	Tolerated			0.1096	0.6264		0	0	2.4	28.05
c.904T>A	S302T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302T is not reported in ClinVar and is absent from gnomAD. All available in silico predictors classify the substitution as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.414856	Structured	0.263489	Uncertain	0.616	0.258	0.375											-4.742	Likely Benign	0.072	Likely Benign	Likely Benign	0.20	Likely Benign	0.1	0.10	Likely Benign	0.15	Likely Benign	-0.08	Likely Benign	0.043	Likely Benign	-0.55	Neutral	0.037	Benign	0.042	Benign	4.16	Benign	0.15	Tolerated			0.1715	0.6886		1	1	0.1	14.03
c.904T>C	S302P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302P is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only Rosetta predicts a pathogenic outcome, while FoldX and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also supports a benign classification. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains inconclusive. Overall, the preponderance of evidence points to a benign impact for S302P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.414856	Structured	0.263489	Uncertain	0.616	0.258	0.375											-2.485	Likely Benign	0.121	Likely Benign	Likely Benign	1.19	Ambiguous	0.4	2.74	Destabilizing	1.97	Ambiguous	0.14	Likely Benign	0.101	Likely Benign	-0.89	Neutral	0.157	Benign	0.153	Benign	4.11	Benign	0.20	Tolerated			0.2522	0.6243		1	-1	-0.8	10.04
c.904T>G	S302A 2D AIThe SynGAP1 missense variant S302A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta. No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not currently catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.414856	Structured	0.263489	Uncertain	0.616	0.258	0.375											-2.583	Likely Benign	0.058	Likely Benign	Likely Benign	0.21	Likely Benign	0.4	0.65	Ambiguous	0.43	Likely Benign	0.02	Likely Benign	0.044	Likely Benign	-0.41	Neutral	0.000	Benign	0.001	Benign	4.16	Benign	0.20	Tolerated			0.5358	0.5407	Strenghten	1	1	2.6	-16.00
c.905C>A	S302Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are SIFT, polyPhen‑2 HumDiv, and ESM1b. Two tools give uncertain results: AlphaMissense‑Default and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta also predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.414856	Structured	0.263489	Uncertain	0.616	0.258	0.375											-9.674	Likely Pathogenic	0.355	Ambiguous	Likely Benign	-0.02	Likely Benign	0.1	0.56	Ambiguous	0.27	Likely Benign	-0.17	Likely Benign	0.070	Likely Benign	-1.03	Neutral	0.801	Possibly Damaging	0.383	Benign	4.07	Benign	0.01	Affected			0.0882	0.5990		-3	-2	-0.5	76.10
c.905C>G	S302C 2D AIThe SynGAP1 missense variant S302C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, premPS, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain predictions come from Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for S302C, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.414856	Structured	0.263489	Uncertain	0.616	0.258	0.375											-7.290	In-Between	0.105	Likely Benign	Likely Benign	0.32	Likely Benign	0.5	1.24	Ambiguous	0.78	Ambiguous	-0.04	Likely Benign	0.070	Likely Benign	-0.83	Neutral	0.833	Possibly Damaging	0.455	Possibly Damaging	4.05	Benign	0.02	Affected			0.1221	0.6514		0	-1	3.3	16.06
c.905C>T	S302F 2D AIThe SynGAP1 missense variant S302F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and ESM1b; Rosetta’s output is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Taken together, the majority of evidence supports a benign impact for S302F, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.414856	Structured	0.263489	Uncertain	0.616	0.258	0.375											-9.483	Likely Pathogenic	0.321	Likely Benign	Likely Benign	-0.04	Likely Benign	0.5	0.71	Ambiguous	0.34	Likely Benign	-0.21	Likely Benign	0.073	Likely Benign	-0.92	Neutral	0.570	Possibly Damaging	0.383	Benign	4.06	Benign	0.01	Affected			0.0705	0.6092		-3	-2	3.6	60.10
c.907G>A	G303R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G303R is catalogued in gnomAD (6-33437812-G-A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome; the remaining tools (FoldX, Foldetta, premPS, ESM1b) are inconclusive. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, while Foldetta remains uncertain. Taken together, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.450668	Structured	0.271087	Uncertain	0.630	0.254	0.250								6-33437812-G-A	1	6.20e-7	-7.493	In-Between	0.724	Likely Pathogenic	Likely Benign	1.44	Ambiguous	0.4	0.23	Likely Benign	0.84	Ambiguous	0.73	Ambiguous	0.048	Likely Benign	-1.38	Neutral	0.001	Benign	0.003	Benign	3.99	Benign	0.06	Tolerated	3.55	18	0.0839	0.4490		-2	-3	-4.1	99.14
c.907G>C	G303R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. The remaining tools—FoldX, Foldetta, premPS, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, while Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.450668	Structured	0.271087	Uncertain	0.630	0.254	0.250											-7.493	In-Between	0.724	Likely Pathogenic	Likely Benign	1.44	Ambiguous	0.4	0.23	Likely Benign	0.84	Ambiguous	0.73	Ambiguous	0.048	Likely Benign	-1.38	Neutral	0.001	Benign	0.003	Benign	3.99	Benign	0.06	Tolerated	3.55	18	0.0839	0.4490		-2	-3	-4.1	99.14
c.907G>T	G303W 2D 3DClick to see structure in 3D Viewer AIClinVar reports no entry for this SynGAP1 G303W variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta’s stability prediction is also unavailable. Overall, the evidence is evenly split between benign and pathogenic predictions, providing no clear bias toward either outcome. This balanced prediction does not contradict ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.450668	Structured	0.271087	Uncertain	0.630	0.254	0.250											-9.041	Likely Pathogenic	0.579	Likely Pathogenic	Likely Benign	1.69	Ambiguous	0.3	1.11	Ambiguous	1.40	Ambiguous	0.28	Likely Benign	0.157	Likely Benign	-1.63	Neutral	0.983	Probably Damaging	0.813	Possibly Damaging	3.93	Benign	0.00	Affected			0.0663	0.4553		-7	-2	-0.5	129.16
c.908G>A	G303E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303E is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437813‑G‑A). Across the available in‑silico predictors, benign calls are made by REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by SIFT and ESM1b; the remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Default) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta remains uncertain. Taken together, the majority of evidence points to a benign effect; this conclusion is not contradicted by any ClinVar annotation, as no pathogenic classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.450668	Structured	0.271087	Uncertain	0.630	0.254	0.250								6-33437813-G-A	3	1.86e-6	-9.339	Likely Pathogenic	0.549	Ambiguous	Likely Benign	1.87	Ambiguous	0.5	0.37	Likely Benign	1.12	Ambiguous	0.89	Ambiguous	0.063	Likely Benign	-1.56	Neutral	0.001	Benign	0.005	Benign	4.04	Benign	0.05	Affected	3.55	18	0.1155	0.4172		-2	0	-3.1	72.06
c.908G>C	G303A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta’s stability analysis is uncertain. Overall, the variant is most likely benign based on the consensus of predictive tools, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.450668	Structured	0.271087	Uncertain	0.630	0.254	0.250											-1.965	Likely Benign	0.105	Likely Benign	Likely Benign	1.66	Ambiguous	0.2	-0.51	Ambiguous	0.58	Ambiguous	0.10	Likely Benign	0.034	Likely Benign	-0.90	Neutral	0.112	Benign	0.058	Benign	4.07	Benign	0.35	Tolerated			0.3724	0.5325		1	0	2.2	14.03
c.908G>T	G303V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign) all indicate a tolerated change. Pathogenic signals arise only from SIFT and FoldX, while Rosetta and Foldetta are inconclusive. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields Likely Benign, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.450668	Structured	0.271087	Uncertain	0.630	0.254	0.250											-3.046	Likely Benign	0.198	Likely Benign	Likely Benign	3.06	Destabilizing	0.6	-0.72	Ambiguous	1.17	Ambiguous	0.14	Likely Benign	0.071	Likely Benign	-1.57	Neutral	0.011	Benign	0.017	Benign	3.96	Benign	0.01	Affected			0.1002	0.4577		-1	-3	4.6	42.08
c.90C>A	H30Q 2D AIThe SynGAP1 H30Q missense change is catalogued in gnomAD (ID 6‑33423499‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: six methods (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score all indicate a benign effect, while three tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT) predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus (derived from the four benign‑predicting tools) also yields a benign verdict. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with ClinVar, which currently contains no classification for H30Q. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250								6-33423499-C-A	1	6.20e-7	-3.016	Likely Benign	0.142	Likely Benign	Likely Benign										0.068	Likely Benign	-2.21	Neutral	0.462	Possibly Damaging	0.599	Possibly Damaging	3.93	Benign	0.00	Affected	4.32	1	0.2409	0.4422		0	3	-0.3	-9.01
c.90C>G	H30Q 2D AIThe SynGAP1 missense variant H30Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250											-3.016	Likely Benign	0.142	Likely Benign	Likely Benign										0.068	Likely Benign	-2.21	Neutral	0.462	Possibly Damaging	0.599	Possibly Damaging	3.93	Benign	0.00	Affected	4.32	1	0.2409	0.4422		0	3	-0.3	-9.01
c.910G>A	D304N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D304N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250					Uncertain		1				-6.194	Likely Benign	0.391	Ambiguous	Likely Benign	0.30	Likely Benign	0.1	-0.08	Likely Benign	0.11	Likely Benign	0.21	Likely Benign	0.345	Likely Benign	-4.18	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.81	Pathogenic	0.03	Affected	3.38	23	0.1353	0.7205		1	2	0.0	-0.98
c.910G>C	D304H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304H missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into three groups: benign predictions come from REVEL, Rosetta, and premPS; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; the remaining tools (FoldX, Foldetta, AlphaMissense‑Optimized) give uncertain results. High‑accuracy assessments reinforce this pattern: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which is currently absent. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250											-8.160	Likely Pathogenic	0.822	Likely Pathogenic	Ambiguous	0.89	Ambiguous	0.1	0.16	Likely Benign	0.53	Ambiguous	0.45	Likely Benign	0.417	Likely Benign	-5.67	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.75	Pathogenic	0.01	Affected			0.1660	0.7498		1	-1	0.3	22.05
c.910G>T	D304Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304Y missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, Foldetta, and premPS, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. With the majority of evidence pointing toward pathogenicity, the variant is most likely pathogenic; this assessment does not conflict with ClinVar, which contains no entry for D304Y. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250											-10.495	Likely Pathogenic	0.845	Likely Pathogenic	Ambiguous	0.60	Ambiguous	0.2	0.14	Likely Benign	0.37	Likely Benign	0.37	Likely Benign	0.468	Likely Benign	-6.29	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.76	Pathogenic	0.00	Affected			0.0623	0.6566		-4	-3	2.2	48.09
c.911A>C	D304A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304A variant has no ClinVar entry and is not listed in gnomAD. Prediction tools that classify it as benign include premPS, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact. This prediction does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250											-6.258	Likely Benign	0.604	Likely Pathogenic	Likely Benign	1.00	Ambiguous	0.1	0.54	Ambiguous	0.77	Ambiguous	0.39	Likely Benign	0.523	Likely Pathogenic	-5.97	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.80	Pathogenic	0.02	Affected			0.4457	0.6642		0	-2	5.3	-44.01
c.911A>G	D304G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default, FoldX, Rosetta, and Foldetta are uncertain and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta remaining uncertain. Overall, the majority of tools (five pathogenic vs. four benign) and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250											-2.713	Likely Benign	0.546	Ambiguous	Likely Benign	1.02	Ambiguous	0.2	0.95	Ambiguous	0.99	Ambiguous	0.47	Likely Benign	0.380	Likely Benign	-5.32	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.75	Pathogenic	0.02	Affected			0.4590	0.6451		1	-1	3.1	-58.04
c.911A>T	D304V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304V missense variant is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include Rosetta and premPS, while the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for D304V. This conclusion is not contradicted by ClinVar, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250											-8.280	Likely Pathogenic	0.803	Likely Pathogenic	Ambiguous	1.35	Ambiguous	0.3	0.14	Likely Benign	0.75	Ambiguous	0.35	Likely Benign	0.541	Likely Pathogenic	-6.22	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.81	Pathogenic	0.00	Affected			0.0971	0.6999		-2	-3	7.7	-15.96
c.912C>A	D304E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304E missense variant has no ClinVar entry and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence supports a benign effect, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250											-2.715	Likely Benign	0.233	Likely Benign	Likely Benign	0.34	Likely Benign	0.1	0.21	Likely Benign	0.28	Likely Benign	0.48	Likely Benign	0.186	Likely Benign	-3.29	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.77	Pathogenic	0.04	Affected			0.1504	0.6998		3	2	0.0	14.03
c.912C>G	D304E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304E missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Overall, the balance of evidence favors a benign classification, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250											-2.715	Likely Benign	0.233	Likely Benign	Likely Benign	0.34	Likely Benign	0.1	0.21	Likely Benign	0.28	Likely Benign	0.48	Likely Benign	0.186	Likely Benign	-3.29	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.77	Pathogenic	0.04	Affected			0.1504	0.6998		3	2	0.0	14.03
c.913A>C	T305P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T305P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of tools (7 pathogenic vs. 5 benign) lean toward a pathogenic impact, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.359901	Structured	0.299706	Uncertain	0.872	0.274	0.125											-5.203	Likely Benign	0.177	Likely Benign	Likely Benign	3.64	Destabilizing	1.1	6.02	Destabilizing	4.83	Destabilizing	0.71	Ambiguous	0.293	Likely Benign	-2.83	Deleterious	0.997	Probably Damaging	0.929	Probably Damaging	1.72	Pathogenic	0.06	Tolerated			0.2206	0.5333		0	-1	-0.9	-3.99
c.913A>G	T305A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T305A variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33437818‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.359901	Structured	0.299706	Uncertain	0.872	0.274	0.125					Conflicting		2	6-33437818-A-G	13	8.05e-6	-4.307	Likely Benign	0.078	Likely Benign	Likely Benign	1.30	Ambiguous	0.6	1.55	Ambiguous	1.43	Ambiguous	0.77	Ambiguous	0.144	Likely Benign	-2.10	Neutral	0.939	Possibly Damaging	0.645	Possibly Damaging	1.76	Pathogenic	0.12	Tolerated	3.40	20	0.4277	0.4403		1	0	2.5	-30.03	177.9	43.5	-0.2	0.1	0.4	0.0								Uncertain	The hydroxyl group of Thr305, located at the beginning of an anti-parallel β strand (res. Thr305-Asn315), hydrogen bonds with the carboxylate groups of Glu270 and Asp304 in the anti-parallel β strand and the adjacent β hairpin loop, respectively. In the variant simulations, the methyl group of the Ala305 side chain cannot hydrogen bond with either of the acidic residues, which could weaken the integrity of the tertiary structure and the β hairpin loop. Indeed, the guanidinium group of Arg299 does not acquire its central hairpin loop position due to the residue swap.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel.
c.913A>T	T305S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are provided by Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.359901	Structured	0.299706	Uncertain	0.872	0.274	0.125											-2.899	Likely Benign	0.107	Likely Benign	Likely Benign	0.45	Likely Benign	0.4	1.21	Ambiguous	0.83	Ambiguous	0.55	Ambiguous	0.135	Likely Benign	-0.60	Neutral	0.760	Possibly Damaging	0.484	Possibly Damaging	1.86	Pathogenic	0.54	Tolerated			0.3579	0.4496		1	1	-0.1	-14.03
c.914C>A	T305N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T305N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign, and the SGM‑Consensus score is “Likely Benign.” Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, and the combined Foldetta) return uncertain or inconclusive results. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign, and Foldetta remains uncertain. Overall, the majority of evidence supports a benign impact for T305N, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.359901	Structured	0.299706	Uncertain	0.872	0.274	0.125											-3.261	Likely Benign	0.158	Likely Benign	Likely Benign	1.18	Ambiguous	0.2	1.65	Ambiguous	1.42	Ambiguous	0.09	Likely Benign	0.098	Likely Benign	0.71	Neutral	0.046	Benign	0.040	Benign	2.34	Pathogenic	0.67	Tolerated			0.1327	0.4352		0	0	-2.8	13.00
c.914C>G	T305S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are provided by Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.359901	Structured	0.299706	Uncertain	0.872	0.274	0.125											-2.899	Likely Benign	0.107	Likely Benign	Likely Benign	0.45	Likely Benign	0.4	1.21	Ambiguous	0.83	Ambiguous	0.55	Ambiguous	0.104	Likely Benign	-0.60	Neutral	0.760	Possibly Damaging	0.484	Possibly Damaging	1.86	Pathogenic	0.54	Tolerated			0.3579	0.4496		1	1	-0.1	-14.03
c.914C>T	T305I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437819‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Overall, the balance of evidence from high‑confidence predictors leans toward a benign impact, and this assessment does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.359901	Structured	0.299706	Uncertain	0.872	0.274	0.125					Uncertain		1	6-33437819-C-T	1	6.20e-7	-5.222	Likely Benign	0.305	Likely Benign	Likely Benign	0.37	Likely Benign	0.2	0.58	Ambiguous	0.48	Likely Benign	0.25	Likely Benign	0.224	Likely Benign	-2.90	Deleterious	0.997	Probably Damaging	0.929	Probably Damaging	1.70	Pathogenic	0.04	Affected	3.40	20	0.0939	0.5693		-1	0	5.2	12.05
c.916G>A	V306I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306I is not reported in ClinVar (no ClinVar ID) but is present in gnomAD (variant ID 6-33437821‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No prediction or stability assessment is missing; all available data are considered. Based on the preponderance of benign predictions and the lack of ClinVar evidence to the contrary, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.363090	Structured	0.315026	Uncertain	0.896	0.287	0.125								6-33437821-G-A	11	6.82e-6	-5.989	Likely Benign	0.121	Likely Benign	Likely Benign	1.13	Ambiguous	0.2	0.38	Likely Benign	0.76	Ambiguous	0.19	Likely Benign	0.154	Likely Benign	-0.17	Neutral	0.999	Probably Damaging	0.993	Probably Damaging	1.75	Pathogenic	0.36	Tolerated	3.38	19	0.0603	0.3461		3	4	0.3	14.03
c.916G>C	V306L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V306L missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta is inconclusive. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.363090	Structured	0.315026	Uncertain	0.896	0.287	0.125											-3.633	Likely Benign	0.267	Likely Benign	Likely Benign	2.14	Destabilizing	0.2	1.47	Ambiguous	1.81	Ambiguous	0.75	Ambiguous	0.161	Likely Benign	-1.01	Neutral	0.999	Probably Damaging	0.996	Probably Damaging	1.76	Pathogenic	0.21	Tolerated			0.0823	0.4117		2	1	-0.4	14.03
c.916G>T	V306F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306F is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, and AlphaMissense‑Optimized, whereas the remaining tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a pathogenic effect. Overall, the majority of evidence supports a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.363090	Structured	0.315026	Uncertain	0.896	0.287	0.125											-9.311	Likely Pathogenic	0.700	Likely Pathogenic	Likely Benign	13.59	Destabilizing	1.4	6.99	Destabilizing	10.29	Destabilizing	0.23	Likely Benign	0.336	Likely Benign	-3.28	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.74	Pathogenic	0.01	Affected			0.0535	0.3318		-1	-1	-1.4	48.04
c.917T>A	V306D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306D is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All available in‑silico predictors that were evaluated return a pathogenic or likely‑pathogenic assessment: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.363090	Structured	0.315026	Uncertain	0.896	0.287	0.125					Uncertain		1				-18.289	Likely Pathogenic	0.986	Likely Pathogenic	Likely Pathogenic	4.40	Destabilizing	0.3	4.29	Destabilizing	4.35	Destabilizing	2.44	Destabilizing	0.530	Likely Pathogenic	-5.44	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.74	Pathogenic	0.00	Affected	3.38	19	0.1317	0.0768		-2	-3	-7.7	15.96	212.3	-18.3	-0.2	0.4	0.0	0.2	X		X				X	Potentially Pathogenic	The isopropyl group of Val396, located at the beginning of an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Leu274, Trp308, Ala271) in the WT simulations. However, in the variant simulations, the negatively charged carboxylate group of the Asp306 side chain is not suitable for this hydrophobic niche. Consequently, the side chain moves out to interact with Ser300 in the β strand (res. Met289-Arg299) and the guanidinium group of Arg299 in the β hairpin loop.In the third simulation, the residue swap disrupts the C2 domain secondary structure and tertiary assembly to a large degree when the amino group of the Lys297 side chain rotates to form a salt bridge with Asp306. This drastic effect could potentially reflect the challenge presented by the residue swap during the C2 domain folding. Because the residue swap affects the C2 domain structure, the SynGAP-membrane association could also be impacted. However, this is beyond the scope of the solvent-only simulations to unravel.
c.917T>C	V306A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas the remaining tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome; ESM1b is uncertain and therefore not counted. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and a pathogenic prediction from Foldetta. Taken together, the preponderance of evidence indicates that V306A is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.363090	Structured	0.315026	Uncertain	0.896	0.287	0.125											-7.924	In-Between	0.599	Likely Pathogenic	Likely Benign	2.76	Destabilizing	0.1	3.00	Destabilizing	2.88	Destabilizing	2.25	Destabilizing	0.300	Likely Benign	-2.94	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.77	Pathogenic	0.05	Affected			0.2687	0.1989		0	0	-2.4	-28.05
c.917T>G	V306G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign effect. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. All available evidence points to a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.363090	Structured	0.315026	Uncertain	0.896	0.287	0.125											-12.313	Likely Pathogenic	0.795	Likely Pathogenic	Ambiguous	4.39	Destabilizing	0.2	5.89	Destabilizing	5.14	Destabilizing	2.46	Destabilizing	0.529	Likely Pathogenic	-5.48	Deleterious	0.998	Probably Damaging	1.000	Probably Damaging	1.78	Pathogenic	0.00	Affected			0.1874	0.2035		-1	-3	-4.6	-42.08
c.919T>A	F307I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307I is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign are FoldX, Rosetta, and Foldetta. Tools that predict it as pathogenic include SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments give AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Benign. Overall, the majority of predictions (10/13) indicate pathogenicity, while only three tools suggest benign. Therefore, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-13.114	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	0.49	Likely Benign	0.2	0.19	Likely Benign	0.34	Likely Benign	0.61	Ambiguous	0.632	Likely Pathogenic	-5.52	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	2.06	Pathogenic	0.01	Affected			0.2531	0.3036		1	0	1.7	-34.02
c.919T>C	F307L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta and Foldetta, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (FoldX and premPS) give uncertain results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized and the SGM Consensus both indicate a likely pathogenic effect, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the bulk of evidence points to a pathogenic impact, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-10.173	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.54	Ambiguous	0.1	0.14	Likely Benign	0.34	Likely Benign	0.57	Ambiguous	0.597	Likely Pathogenic	-5.52	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	2.04	Pathogenic	0.01	Affected			0.2800	0.4207		2	0	1.0	-34.02
c.919T>G	F307V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307V is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include Rosetta and premPS, whereas the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the consensus score SGM‑Consensus all classify the change as pathogenic or likely pathogenic. High‑accuracy methods give a pathogenic call from AlphaMissense‑Optimized, a likely pathogenic result from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an inconclusive result from Foldetta (combining FoldX‑MD and Rosetta). No prediction is missing or inconclusive enough to alter the overall assessment. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-12.262	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.91	Ambiguous	0.1	0.10	Likely Benign	0.51	Ambiguous	0.36	Likely Benign	0.605	Likely Pathogenic	-6.43	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	2.29	Pathogenic	0.05	Affected			0.2523	0.3393		-1	-1	1.4	-48.04
c.91C>G	R31G 2D AIThe SynGAP1 missense variant R31G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for R31G, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.549308	Disordered	0.437905	Uncertain	0.324	0.878	0.250											-3.259	Likely Benign	0.269	Likely Benign	Likely Benign										0.141	Likely Benign	-1.77	Neutral	0.686	Possibly Damaging	0.630	Possibly Damaging	3.97	Benign	0.00	Affected			0.3389	0.3942		-3	-2	4.1	-99.14
c.920T>A	F307Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307Y is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict the ClinVar status, which currently contains no assertion for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-9.870	Likely Pathogenic	0.889	Likely Pathogenic	Ambiguous	0.36	Likely Benign	0.1	-0.21	Likely Benign	0.08	Likely Benign	0.11	Likely Benign	0.596	Likely Pathogenic	-2.76	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	1.96	Pathogenic	0.05	Affected			0.1570	0.2325		7	3	-4.1	16.00
c.920T>C	F307S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. In silico predictors that provide a definitive call all classify the variant as pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely pathogenic verdict. Predictions that are inconclusive or uncertain include FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-12.282	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	1.58	Ambiguous	0.2	1.22	Ambiguous	1.40	Ambiguous	0.99	Ambiguous	0.766	Likely Pathogenic	-7.32	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.97	Pathogenic	0.01	Affected			0.4576	0.0758		-3	-2	-3.6	-60.10
c.920T>G	F307C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F307C missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). In silico predictors overwhelmingly indicate a deleterious effect: all tools that provide a definitive call—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The only predictions that are inconclusive are FoldX, Rosetta, and Foldetta, which are treated as unavailable. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. **Based on the consensus of the available predictions, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-11.484	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	1.36	Ambiguous	0.1	1.44	Ambiguous	1.40	Ambiguous	1.05	Destabilizing	0.754	Likely Pathogenic	-7.35	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.92	Pathogenic	0.00	Affected			0.2729	0.1628		-4	-2	-0.3	-44.04
c.921C>A	F307L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta and Foldetta, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (FoldX and premPS) give uncertain results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized and the SGM Consensus both indicate a likely pathogenic effect, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the bulk of evidence points to a pathogenic impact, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-10.173	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.54	Ambiguous	0.1	0.14	Likely Benign	0.34	Likely Benign	0.57	Ambiguous	0.529	Likely Pathogenic	-5.52	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	2.04	Pathogenic	0.01	Affected			0.2800	0.4207		2	0	1.0	-34.02
c.921C>G	F307L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta and Foldetta, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic. Uncertain results are reported by FoldX and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the consensus of the majority of tools points to a pathogenic effect, and this is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-10.173	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.54	Ambiguous	0.1	0.14	Likely Benign	0.34	Likely Benign	0.57	Ambiguous	0.529	Likely Pathogenic	-5.52	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	2.04	Pathogenic	0.01	Affected			0.2800	0.4207		2	0	1.0	-34.02
c.922T>A	W308R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.333942	Uncertain	0.907	0.314	0.125											-12.264	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	5.40	Destabilizing	0.5	4.27	Destabilizing	4.84	Destabilizing	1.88	Destabilizing	0.868	Likely Pathogenic	-12.87	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.48	Pathogenic	0.00	Affected	3.38	19	0.4751	0.0361		2	-3	-3.6	-30.03	290.4	-26.7	-0.1	0.1	0.0	0.2	X		X				X	Potentially Pathogenic	The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The guanidinium group of Arg308 is comparably sized to the tryptophan it replaced; however, it is also positively charged.In the variant simulations, the charged side chain remains buried deep in the hydrophobic part of the C2 domain, where it forms new hydrogen bonds with the backbone carbonyl atoms of surrounding residues (e.g., Val306, Ile268). However, the residue swap is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association.
c.922T>C	W308R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308R is listed in ClinVar (ID 391294.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.333942	Uncertain	0.907	0.314	0.125					Pathogenic		1				-12.264	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	5.40	Destabilizing	0.5	4.27	Destabilizing	4.84	Destabilizing	1.88	Destabilizing	0.868	Likely Pathogenic	-12.87	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.48	Pathogenic	0.00	Affected	3.38	19	0.4751	0.0361		2	-3	-3.6	-30.03	290.4	-26.7	-0.1	0.1	0.0	0.2	X		X				X	Potentially Pathogenic	The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The guanidinium group of Arg308 is comparably sized to the tryptophan it replaced; however, it is also positively charged.In the variant simulations, the charged side chain remains buried deep in the hydrophobic part of the C2 domain, where it forms new hydrogen bonds with the backbone carbonyl atoms of surrounding residues (e.g., Val306, Ile268). However, the residue swap is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association.
c.922T>G	W308G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308G is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. No tool predicts a benign effect, so the benign group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.333942	Uncertain	0.907	0.314	0.125											-16.271	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	6.88	Destabilizing	0.2	5.07	Destabilizing	5.98	Destabilizing	1.97	Destabilizing	0.860	Likely Pathogenic	-11.95	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	0.48	Pathogenic	0.00	Affected			0.4884	0.1644		-7	-2	0.5	-129.16
c.923G>C	W308S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308S is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.333942	Uncertain	0.907	0.314	0.125											-15.425	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	6.42	Destabilizing	0.2	5.31	Destabilizing	5.87	Destabilizing	1.93	Destabilizing	0.861	Likely Pathogenic	-12.87	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.48	Pathogenic	0.00	Affected			0.5089	0.1406	Weaken	-2	-3	0.1	-99.14
c.923G>T	W308L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates “Likely Pathogenic.” Only Rosetta and premPS yield uncertain results, which are treated as unavailable evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No tools predict benign effects. **Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.333942	Uncertain	0.907	0.314	0.125											-13.349	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	3.53	Destabilizing	0.5	1.52	Ambiguous	2.53	Destabilizing	0.53	Ambiguous	0.811	Likely Pathogenic	-11.95	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	0.49	Pathogenic	0.00	Affected			0.2731	0.2754		-2	-2	4.7	-73.05
c.924G>C	W308C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308C is listed in ClinVar as Pathogenic (ClinVar ID 981381.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Pathogenic”; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.333942	Uncertain	0.907	0.314	0.125					Pathogenic/Likely path.		2				-12.791	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	5.56	Destabilizing	0.3	4.38	Destabilizing	4.97	Destabilizing	1.26	Destabilizing	0.738	Likely Pathogenic	-11.95	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.48	Pathogenic	0.00	Affected	3.38	19	0.4390	0.1621		-8	-2	3.4	-83.07	230.8	60.5	-0.3	0.1	-0.4	0.4							X	Potentially Pathogenic	The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The introduced Cys308 is smaller than the tryptophan it replaced. The thiol group of the Cys308 side chain is well-suited for the inner hydrophobic part of the C2 domain. Although the negative effects are essentially missing from the simulations, the side chain size difference between the residues is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association.
c.924G>T	W308C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308C is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a deleterious effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.333942	Uncertain	0.907	0.314	0.125											-12.791	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	5.56	Destabilizing	0.3	4.38	Destabilizing	4.97	Destabilizing	1.26	Destabilizing	0.738	Likely Pathogenic	-11.95	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.48	Pathogenic	0.00	Affected	3.38	19	0.4390	0.1621		-8	-2	3.4	-83.07	230.8	60.5	-0.3	0.1	-0.4	0.4							X	Potentially Pathogenic	The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The introduced Cys308 is smaller than the tryptophan it replaced. The thiol group of the Cys308 side chain is well-suited for the inner hydrophobic part of the C2 domain. Although the negative effects are essentially missing from the simulations, the side chain size difference between the residues is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association.
c.925G>A	G309S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include REVEL and SIFT, whereas a majority of other in silico predictors (AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SGM‑Consensus, and FoldX) predict it to be pathogenic. Tools with uncertain outcomes (Foldetta, Rosetta, premPS) provide no definitive evidence. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that G309S is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.275179	Structured	0.338439	Uncertain	0.882	0.342	0.125											-11.335	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	2.82	Destabilizing	0.5	0.73	Ambiguous	1.78	Ambiguous	0.72	Ambiguous	0.487	Likely Benign	-5.52	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.73	Pathogenic	0.07	Tolerated			0.2828	0.5591		1	0	-0.4	30.03
c.925G>C	G309R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely pathogenic outcome. No tool in the dataset predicts a benign effect. Uncertainty remains for FoldX, Rosetta, Foldetta, and premPS, which are listed as uncertain and do not influence the overall assessment. High‑accuracy evaluations show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.275179	Structured	0.338439	Uncertain	0.882	0.342	0.125											-14.375	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.99	Ambiguous	0.5	0.52	Ambiguous	1.26	Ambiguous	0.55	Ambiguous	0.572	Likely Pathogenic	-7.35	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.70	Pathogenic	0.04	Affected			0.0964	0.5097		-3	-2	-4.1	99.14
c.925G>T	G309C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a deleterious effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score, all of which classify the change as pathogenic or likely pathogenic. Tools with inconclusive results—Rosetta, Foldetta, and premPS—return uncertain outcomes and do not alter the overall assessment. High‑accuracy methods further support a damaging effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta’s stability analysis is inconclusive. Taken together, the evidence strongly favors a pathogenic interpretation, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.275179	Structured	0.338439	Uncertain	0.882	0.342	0.125											-14.331	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	2.60	Destabilizing	0.4	1.09	Ambiguous	1.85	Ambiguous	0.67	Ambiguous	0.656	Likely Pathogenic	-8.27	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.66	Pathogenic	0.00	Affected			0.1378	0.4574		-3	-3	2.9	46.09
c.926G>A	G309D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are provided by SIFT and Rosetta, whereas the remaining 12 tools (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus) are pathogenic. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta is inconclusive. Taken together, the majority of evidence supports a pathogenic effect. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.275179	Structured	0.338439	Uncertain	0.882	0.342	0.125											-15.264	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	2.89	Destabilizing	0.5	-0.03	Likely Benign	1.43	Ambiguous	0.75	Ambiguous	0.523	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.88	Pathogenic	0.06	Tolerated			0.1889	0.2678		1	-1	-3.1	58.04
c.926G>C	G309A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G309A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, SIFT, and Rosetta, whereas pathogenic calls are made by FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Foldetta, premPS, and ESM1b. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenic, while Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for G309A. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.275179	Structured	0.338439	Uncertain	0.882	0.342	0.125											-7.980	In-Between	0.986	Likely Pathogenic	Likely Pathogenic	2.44	Destabilizing	0.4	0.30	Likely Benign	1.37	Ambiguous	0.71	Ambiguous	0.373	Likely Benign	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.69	Pathogenic	0.09	Tolerated			0.3949	0.4974		1	0	2.2	14.03
c.926G>T	G309V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309V is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.275179	Structured	0.338439	Uncertain	0.882	0.342	0.125											-13.595	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.55	Destabilizing	0.5	3.61	Destabilizing	4.08	Destabilizing	0.76	Ambiguous	0.531	Likely Pathogenic	-8.27	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.67	Pathogenic	0.00	Affected			0.1256	0.3910		-1	-3	4.6	42.08
c.928G>A	E310K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310K is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all return a deleterious signal: REVEL, FoldX (uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenic or likely pathogenic. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, the variant is most likely pathogenic based on the available predictions, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.346136	Uncertain	0.914	0.337	0.125					Conflicting		4				-14.601	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	1.97	Ambiguous	1.2	3.66	Destabilizing	2.82	Destabilizing	1.02	Destabilizing	0.764	Likely Pathogenic	-3.68	Deleterious	1.000	Probably Damaging	0.995	Probably Damaging	1.19	Pathogenic	0.01	Affected	3.38	19	0.2496	0.8453		0	1	-0.4	-0.94	213.4	58.0	0.1	0.0	0.2	0.1		X						Potentially Pathogenic	The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the side chain hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand (res. Met289-Arg299). Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the amino group of the Lys310 side chain hydrogen bonds with the GAP domain residues and forms a salt bridge with Glu613. Although no apparent negative effects are seen due to the residue swap, it is possible that the loss of hydrogen bonding with the hydroxyl group of the Thr295 side chain causes problems during folding, potentially compromising the twisting of the β sheet.
c.928G>C	E310Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign are Rosetta and Foldetta, whereas the remaining tools—REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict pathogenicity. FoldX and premPS give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized reports a pathogenic effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Likely Pathogenic; Foldetta, a protein‑folding stability approach combining FoldX‑MD and Rosetta, predicts a benign outcome. Overall, the majority of evidence points to a pathogenic impact, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.346136	Uncertain	0.914	0.337	0.125											-11.093	Likely Pathogenic	0.981	Likely Pathogenic	Likely Pathogenic	1.16	Ambiguous	0.5	-0.38	Likely Benign	0.39	Likely Benign	0.85	Ambiguous	0.688	Likely Pathogenic	-2.76	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.24	Pathogenic	0.01	Affected			0.1334	0.8341		2	2	0.0	-0.98
c.929A>C	E310A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E310A missense variant is not reported in ClinVar or gnomAD. Prediction tools largely converge on a pathogenic effect: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, while premPS is the sole benign predictor. Uncertain calls come from FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus labels it likely pathogenic, and Foldetta remains inconclusive. With the overwhelming majority of evidence pointing to deleterious impact and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.346136	Uncertain	0.914	0.337	0.125											-13.878	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	1.65	Ambiguous	0.6	1.65	Ambiguous	1.65	Ambiguous	0.50	Likely Benign	0.850	Likely Pathogenic	-5.52	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.16	Pathogenic	0.01	Affected			0.3980	0.8097		0	-1	5.3	-58.04
c.929A>G	E310G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310G is listed in ClinVar as Pathogenic (ClinVar ID 2732842.0) and is not reported in gnomAD. Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only premPS predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Consequently, the variant is most likely pathogenic, and this prediction is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.346136	Uncertain	0.914	0.337	0.125					Pathogenic		1				-14.132	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	2.38	Destabilizing	0.7	3.56	Destabilizing	2.97	Destabilizing	0.36	Likely Benign	0.848	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	1.12	Pathogenic	0.00	Affected	3.38	19	0.2736	0.6932		-2	0	3.1	-72.06
c.929A>T	E310V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E310V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are Rosetta and premPS, while the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. FoldX and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that E310V is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.346136	Uncertain	0.914	0.337	0.125											-15.494	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	1.08	Ambiguous	0.9	0.06	Likely Benign	0.57	Ambiguous	0.14	Likely Benign	0.871	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.12	Pathogenic	0.00	Affected			0.0849	0.8729		-2	-2	7.7	-29.98
c.92G>A	R31Q 2D AIThe SynGAP1 missense variant R31Q is listed in ClinVar (ID 1977609.0) with an “Uncertain” status and is present in gnomAD (6‑33423501‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification and suggests the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.549308	Disordered	0.437905	Uncertain	0.324	0.878	0.250					Uncertain		1	6-33423501-G-A	7	4.34e-6	-4.434	Likely Benign	0.136	Likely Benign	Likely Benign										0.051	Likely Benign	-0.92	Neutral	0.829	Possibly Damaging	0.614	Possibly Damaging	4.01	Benign	0.00	Affected	4.32	1	0.3605	0.3355		1	1	1.0	-28.06
c.92G>C	R31P 2D AIThe SynGAP1 missense variant R31P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of computational evidence points to a benign impact for R31P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.549308	Disordered	0.437905	Uncertain	0.324	0.878	0.250											-3.185	Likely Benign	0.300	Likely Benign	Likely Benign										0.209	Likely Benign	-1.64	Neutral	0.841	Possibly Damaging	0.809	Possibly Damaging	3.96	Benign	0.00	Affected			0.2220	0.5005		0	-2	2.9	-59.07
c.92G>T	R31L 2D AIThe SynGAP1 missense variant R31L is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict pathogenic. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools specifically indicate benign: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta data are missing. Overall, the majority of reliable predictions lean toward a benign effect, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.549308	Disordered	0.437905	Uncertain	0.324	0.878	0.250											-3.147	Likely Benign	0.360	Ambiguous	Likely Benign										0.149	Likely Benign	-1.79	Neutral	0.686	Possibly Damaging	0.630	Possibly Damaging	4.01	Benign	0.00	Affected			0.2264	0.5148		-3	-2	8.3	-43.03
c.930G>C	E310D 2D 3DClick to see structure in 3D Viewer AISynGAP1 E310D is reported in ClinVar (ID 975473.0) as Pathogenic and is not found in gnomAD. Prediction tools that assess the variant’s effect all converge on a deleterious outcome: REVEL, FoldX (uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, leaving no tool in the benign category. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also reports Pathogenic. The single uncertain result from FoldX is treated as unavailable. Overall, the variant is most likely pathogenic, and this assessment is consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.346136	Uncertain	0.914	0.337	0.125					Likely Pathogenic		1				-11.218	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	1.87	Ambiguous	0.5	2.39	Destabilizing	2.13	Destabilizing	1.04	Destabilizing	0.666	Likely Pathogenic	-2.76	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.19	Pathogenic	0.02	Affected	3.38	19	0.1981	0.5222		3	2	0.0	-14.03	232.6	27.2	0.1	0.0	0.1	0.1						X		Potentially Benign	The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand. Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 potentially plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the carboxylate group of Asp310 can form the same interactions as glutamate; however, due to its one hydrocarbon shorter length, the connections are less stable or less optimal.
c.930G>T	E310D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity uniformly favor a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL (Pathogenic), Rosetta (Pathogenic), Foldetta (Pathogenic), premPS (Pathogenic), PROVEAN (Pathogenic), polyPhen‑2 HumDiv (Pathogenic), polyPhen‑2 HumVar (Pathogenic), SIFT (Pathogenic), ESM1b (Pathogenic), FATHMM (Pathogenic), AlphaMissense‑Default (Pathogenic), and AlphaMissense‑Optimized (Pathogenic). No tool predicts a benign outcome; the only inconclusive result is FoldX (Uncertain). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for E310D. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.346136	Uncertain	0.914	0.337	0.125											-11.218	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	1.87	Ambiguous	0.5	2.39	Destabilizing	2.13	Destabilizing	1.04	Destabilizing	0.666	Likely Pathogenic	-2.76	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.19	Pathogenic	0.02	Affected	3.38	19	0.1981	0.5222		3	2	0.0	-14.03	232.6	27.2	0.1	0.0	0.1	0.1						X		Potentially Benign	The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand. Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 potentially plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the carboxylate group of Asp310 can form the same interactions as glutamate; however, due to its one hydrocarbon shorter length, the connections are less stable or less optimal.
c.931C>A	H311N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311N missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of evaluated tools predict pathogenicity, suggesting that H311N is most likely pathogenic. This prediction does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.229226	Structured	0.354792	Uncertain	0.902	0.314	0.125											-9.545	Likely Pathogenic	0.661	Likely Pathogenic	Likely Benign	0.82	Ambiguous	0.1	1.12	Ambiguous	0.97	Ambiguous	0.72	Ambiguous	0.475	Likely Benign	-5.35	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.89	Pathogenic	0.06	Tolerated			0.1566	0.2380		2	1	-0.3	-23.04
c.931C>G	H311D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess evolutionary conservation and protein function uniformly indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. The majority‑vote consensus (SGM‑Consensus) also reports it as likely pathogenic. Tools that evaluate structural stability give inconclusive results: FoldX, Rosetta, Foldetta, and premPS are listed as uncertain. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (derived from the same set of predictors) reports likely pathogenic, while Foldetta’s combined FoldX‑MD/Rosetta stability analysis remains uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect, which is consistent with the absence of a benign ClinVar annotation and the lack of population frequency data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.229226	Structured	0.354792	Uncertain	0.902	0.314	0.125											-13.513	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	1.27	Ambiguous	0.0	1.83	Ambiguous	1.55	Ambiguous	0.89	Ambiguous	0.633	Likely Pathogenic	-6.94	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.94	Pathogenic	0.02	Affected			0.2301	0.2008		1	-1	-0.3	-22.05
c.931C>T	H311Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools with uncertain or inconclusive results—Rosetta, Foldetta, and AlphaMissense‑Default—are treated as unavailable for pathogenicity assessment. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the predictions are split, with five tools favoring benign, five favoring pathogenic, and three inconclusive. Based on the available evidence, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.229226	Structured	0.354792	Uncertain	0.902	0.314	0.125											-4.513	Likely Benign	0.342	Ambiguous	Likely Benign	-0.06	Likely Benign	0.2	-1.58	Ambiguous	-0.82	Ambiguous	0.18	Likely Benign	0.456	Likely Benign	-3.80	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.86	Pathogenic	0.02	Affected			0.0965	0.4180		0	2	1.9	26.03
c.932A>C	H311P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign outcome; the remaining predictions are uncertain (FoldX, Foldetta, premPS, AlphaMissense‑Optimized). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the majority of evidence points to a deleterious impact on protein function. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for H311P. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.229226	Structured	0.354792	Uncertain	0.902	0.314	0.125											-10.454	Likely Pathogenic	0.869	Likely Pathogenic	Ambiguous	1.57	Ambiguous	0.6	2.39	Destabilizing	1.98	Ambiguous	0.74	Ambiguous	0.724	Likely Pathogenic	-7.76	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.87	Pathogenic	0.01	Affected			0.2173	0.4172		0	-2	1.6	-40.02
c.932A>G	H311R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, SIFT, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and premPS. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized indicates benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.229226	Structured	0.354792	Uncertain	0.902	0.314	0.125											-9.825	Likely Pathogenic	0.719	Likely Pathogenic	Likely Benign	0.43	Likely Benign	0.1	0.85	Ambiguous	0.64	Ambiguous	0.70	Ambiguous	0.532	Likely Pathogenic	-5.72	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.94	Pathogenic	0.14	Tolerated			0.1931	0.2490		2	0	-1.3	19.05
c.932A>T	H311L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311L missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include AlphaMissense‑Optimized, Foldetta, premPS, and Rosetta. Tools that predict a pathogenic outcome are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta predicting a benign effect. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.229226	Structured	0.354792	Uncertain	0.902	0.314	0.125											-10.119	Likely Pathogenic	0.575	Likely Pathogenic	Likely Benign	-0.53	Ambiguous	0.0	-0.04	Likely Benign	-0.29	Likely Benign	0.43	Likely Benign	0.663	Likely Pathogenic	-7.99	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.87	Pathogenic	0.02	Affected			0.0961	0.5292		-2	-3	7.0	-23.98
c.933C>A	H311Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and premPS. The high‑accuracy consensus methods give mixed signals: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, more tools (seven) predict pathogenicity than benign (four), and the SGM Consensus supports a pathogenic classification, while Foldetta offers a contrary benign prediction. The variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict the absence of a ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.229226	Structured	0.354792	Uncertain	0.902	0.314	0.125											-8.656	Likely Pathogenic	0.792	Likely Pathogenic	Ambiguous	0.15	Likely Benign	0.1	0.39	Likely Benign	0.27	Likely Benign	0.92	Ambiguous	0.414	Likely Benign	-5.95	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.94	Pathogenic	0.03	Affected			0.1490	0.3775		3	0	-0.3	-9.01
c.933C>G	H311Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311Q missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. With seven pathogenic versus four benign predictions, the overall consensus leans toward pathogenicity. This conclusion does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.229226	Structured	0.354792	Uncertain	0.902	0.314	0.125											-8.656	Likely Pathogenic	0.792	Likely Pathogenic	Ambiguous	0.15	Likely Benign	0.1	0.39	Likely Benign	0.27	Likely Benign	0.92	Ambiguous	0.414	Likely Benign	-5.95	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.94	Pathogenic	0.03	Affected			0.1490	0.3775		3	0	-0.3	-9.01
c.934T>A	F312I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312I is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect, so the benign group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-12.000	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	2.09	Destabilizing	0.3	3.10	Destabilizing	2.60	Destabilizing	1.72	Destabilizing	0.872	Likely Pathogenic	-5.52	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.23	Pathogenic	0.01	Affected			0.1997	0.2842		1	0	1.7	-34.02
c.934T>C	F312L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” The only tool with an inconclusive result is FoldX, which is listed as “Uncertain.” No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-9.891	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.16	Ambiguous	0.3	2.91	Destabilizing	2.04	Destabilizing	1.27	Destabilizing	0.852	Likely Pathogenic	-5.52	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	1.32	Pathogenic	0.05	Affected			0.2149	0.3813		2	0	1.0	-34.02
c.934T>G	F312V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312V is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the change as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-12.206	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	2.13	Destabilizing	0.1	3.46	Destabilizing	2.80	Destabilizing	1.80	Destabilizing	0.877	Likely Pathogenic	-6.43	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.25	Pathogenic	0.00	Affected			0.1998	0.2810		-1	-1	1.4	-48.04
c.935T>A	F312Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a deleterious effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default, all of which classify the change as pathogenic. No tool in the dataset predicts a benign outcome. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta provide uncertain results. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-7.571	In-Between	0.949	Likely Pathogenic	Ambiguous	1.04	Ambiguous	0.1	0.89	Ambiguous	0.97	Ambiguous	0.99	Ambiguous	0.744	Likely Pathogenic	-2.76	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	1.21	Pathogenic	0.02	Affected			0.1443	0.2728		7	3	-4.1	16.00
c.935T>C	F312S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All available in‑silico predictors classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, with no contradiction to ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-14.075	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.74	Destabilizing	0.3	5.64	Destabilizing	4.69	Destabilizing	2.70	Destabilizing	0.880	Likely Pathogenic	-7.35	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.17	Pathogenic	0.00	Affected			0.3563	0.1578		-3	-2	-3.6	-60.10
c.935T>G	F312C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312C is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Based on the unanimous pathogenic predictions and the absence of benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-11.991	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	2.98	Destabilizing	0.3	4.97	Destabilizing	3.98	Destabilizing	1.46	Destabilizing	0.870	Likely Pathogenic	-7.35	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.16	Pathogenic	0.00	Affected			0.2293	0.2010		-4	-2	-0.3	-44.04
c.936C>A	F312L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” The only tool with an inconclusive result is FoldX, which is listed as “Uncertain.” No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-9.891	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.16	Ambiguous	0.3	2.91	Destabilizing	2.04	Destabilizing	1.27	Destabilizing	0.615	Likely Pathogenic	-5.52	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	1.32	Pathogenic	0.05	Affected			0.2149	0.3813		2	0	1.0	-34.02
c.936C>G	F312L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” The only tool with an inconclusive result is FoldX, which is listed as “Uncertain.” No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-9.891	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.16	Ambiguous	0.3	2.91	Destabilizing	2.04	Destabilizing	1.27	Destabilizing	0.615	Likely Pathogenic	-5.52	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	1.32	Pathogenic	0.05	Affected			0.2149	0.3813		2	0	1.0	-34.02
c.937G>A	E313K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313K is listed in ClinVar as Benign (ClinVar ID 3695040.0) and is not reported in gnomAD. Prediction tools that report a benign effect are absent; all available predictors that provide a definitive call classify the variant as pathogenic. These include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus indicates Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is Uncertain. Based on the overwhelming pathogenic predictions, the variant is most likely pathogenic, which contradicts its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.170161	Structured	0.366526	Uncertain	0.898	0.304	0.125					Likely Benign		1				-12.902	Likely Pathogenic	0.959	Likely Pathogenic	Likely Pathogenic	0.64	Ambiguous	0.6	1.40	Ambiguous	1.02	Ambiguous	0.75	Ambiguous	0.575	Likely Pathogenic	-3.31	Deleterious	1.000	Probably Damaging	0.995	Probably Damaging	1.90	Pathogenic	0.02	Affected			0.2540	0.7708		0	1	-0.4	-0.94
c.937G>C	E313Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 E313Q is listed in ClinVar with an Uncertain significance status and is not reported in gnomAD. Prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, PROVEAN, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized indicates a benign effect, Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign stability, whereas the SGM‑Consensus remains pathogenic. Overall, the balance of evidence leans toward pathogenicity, and this assessment does not contradict the ClinVar designation of Uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.170161	Structured	0.366526	Uncertain	0.898	0.304	0.125					Uncertain		1				-11.420	Likely Pathogenic	0.629	Likely Pathogenic	Likely Benign	0.19	Likely Benign	0.1	0.55	Ambiguous	0.37	Likely Benign	0.50	Likely Benign	0.505	Likely Pathogenic	-2.42	Neutral	1.000	Probably Damaging	0.998	Probably Damaging	1.88	Pathogenic	0.05	Affected			0.1523	0.7396		2	2	0.0	-0.98
c.938A>C	E313A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313A is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized, whereas the remaining pathogenic‑or‑likely‑pathogenic predictors are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.170161	Structured	0.366526	Uncertain	0.898	0.304	0.125											-14.591	Likely Pathogenic	0.747	Likely Pathogenic	Likely Benign	1.07	Ambiguous	0.3	0.97	Ambiguous	1.02	Ambiguous	0.62	Ambiguous	0.680	Likely Pathogenic	-4.88	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.88	Pathogenic	0.02	Affected			0.3416	0.6743		0	-1	5.3	-58.04
c.938A>G	E313G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313G is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—all of which classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. Taken together, the overwhelming consensus from both general and high‑accuracy predictors indicates that E313G is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.170161	Structured	0.366526	Uncertain	0.898	0.304	0.125											-14.615	Likely Pathogenic	0.912	Likely Pathogenic	Ambiguous	2.00	Destabilizing	0.5	2.42	Destabilizing	2.21	Destabilizing	0.79	Ambiguous	0.750	Likely Pathogenic	-5.50	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	1.83	Pathogenic	0.01	Affected			0.2638	0.6680		0	-2	3.1	-72.06
c.938A>T	E313V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E313V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas a majority of tools (REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the preponderance of evidence points to a pathogenic effect for E313V. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.170161	Structured	0.366526	Uncertain	0.898	0.304	0.125											-13.169	Likely Pathogenic	0.821	Likely Pathogenic	Ambiguous	0.34	Likely Benign	0.1	-0.02	Likely Benign	0.16	Likely Benign	0.21	Likely Benign	0.655	Likely Pathogenic	-5.73	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.93	Pathogenic	0.05	Affected			0.1132	0.7900		-2	-2	7.7	-29.98
c.939G>C	E313D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and SIFT, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating a likely pathogenic effect, and Foldetta yielding an uncertain stability change. Overall, the balance of evidence points to a pathogenic interpretation; this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.170161	Structured	0.366526	Uncertain	0.898	0.304	0.125											-8.309	Likely Pathogenic	0.636	Likely Pathogenic	Likely Benign	0.87	Ambiguous	0.0	0.96	Ambiguous	0.92	Ambiguous	0.60	Ambiguous	0.346	Likely Benign	-1.66	Neutral	0.997	Probably Damaging	0.992	Probably Damaging	1.88	Pathogenic	0.14	Tolerated			0.1970	0.4640		3	2	0.0	-14.03
c.939G>T	E313D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and SIFT, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating a likely pathogenic outcome, and Foldetta yielding an uncertain stability change. Overall, the balance of evidence points to a pathogenic effect for E313D, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.170161	Structured	0.366526	Uncertain	0.898	0.304	0.125											-8.309	Likely Pathogenic	0.636	Likely Pathogenic	Likely Benign	0.87	Ambiguous	0.0	0.96	Ambiguous	0.92	Ambiguous	0.60	Ambiguous	0.346	Likely Benign	-1.66	Neutral	0.997	Probably Damaging	0.992	Probably Damaging	1.88	Pathogenic	0.14	Tolerated			0.1970	0.4640		3	2	0.0	-14.03
c.940T>A	F314I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a pathogenic effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict deleterious or pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. Tools with uncertain or inconclusive results include Rosetta, Foldetta, and ESM1b. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, while Foldetta’s stability prediction is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this is consistent with the lack of ClinVar annotation (i.e., no benign classification). Therefore, the variant is most likely pathogenic, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-7.059	In-Between	0.992	Likely Pathogenic	Likely Pathogenic	2.23	Destabilizing	0.4	1.08	Ambiguous	1.66	Ambiguous	1.31	Destabilizing	0.534	Likely Pathogenic	-4.98	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.26	Pathogenic	0.01	Affected			0.2052	0.2308		1	0	1.7	-34.02
c.940T>C	F314L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that F314L is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-6.004	Likely Benign	0.998	Likely Pathogenic	Likely Pathogenic	0.87	Ambiguous	0.1	0.82	Ambiguous	0.85	Ambiguous	1.21	Destabilizing	0.476	Likely Benign	-4.85	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	1.30	Pathogenic	0.05	Affected			0.2204	0.3089		2	0	1.0	-34.02
c.940T>G	F314V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). All available in silico predictors classify the variant as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect, so the benign group is empty. High‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta—each return a pathogenic prediction. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-8.907	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	3.31	Destabilizing	0.4	2.54	Destabilizing	2.93	Destabilizing	1.44	Destabilizing	0.594	Likely Pathogenic	-5.90	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.26	Pathogenic	0.00	Affected			0.2054	0.2075		-1	-1	1.4	-48.04
c.941T>A	F314Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and Rosetta, whereas a majority of tools (SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive—AlphaMissense‑Optimized, FoldX, and Foldetta—are treated as unavailable. High‑accuracy assessments further support pathogenicity: the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, while Foldetta’s combined stability analysis is uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-13.297	Likely Pathogenic	0.918	Likely Pathogenic	Ambiguous	1.33	Ambiguous	0.1	0.29	Likely Benign	0.81	Ambiguous	1.28	Destabilizing	0.374	Likely Benign	-2.62	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	1.20	Pathogenic	0.02	Affected			0.1427	0.2173		7	3	-4.1	16.00
c.941T>C	F314S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314S (located in the C2 domain) is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Thus, the variant is most likely pathogenic based on predictions, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-14.371	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	4.51	Destabilizing	0.4	3.36	Destabilizing	3.94	Destabilizing	2.59	Destabilizing	0.735	Likely Pathogenic	-6.95	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.15	Pathogenic	0.00	Affected			0.4113	0.0600		-3	-2	-3.6	-60.10
c.941T>G	F314C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. All available evidence points to a damaging effect. Consequently, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-12.458	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	3.37	Destabilizing	0.3	2.64	Destabilizing	3.01	Destabilizing	2.49	Destabilizing	0.674	Likely Pathogenic	-6.89	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.13	Pathogenic	0.00	Affected			0.2401	0.1075		-4	-2	-0.3	-44.04
c.942T>A	F314L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that F314L is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-6.004	Likely Benign	0.998	Likely Pathogenic	Likely Pathogenic	0.87	Ambiguous	0.1	0.82	Ambiguous	0.85	Ambiguous	1.21	Destabilizing	0.336	Likely Benign	-4.85	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	1.30	Pathogenic	0.05	Affected			0.2204	0.3089		2	0	1.0	-34.02
c.942T>G	F314L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that F314L is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-6.004	Likely Benign	0.998	Likely Pathogenic	Likely Pathogenic	0.87	Ambiguous	0.1	0.82	Ambiguous	0.85	Ambiguous	1.21	Destabilizing	0.336	Likely Benign	-4.85	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	1.30	Pathogenic	0.05	Affected			0.2204	0.3089		2	0	1.0	-34.02
c.943A>C	N315H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N315H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign stability. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.118441	Structured	0.379740	Uncertain	0.862	0.253	0.125											-6.374	Likely Benign	0.156	Likely Benign	Likely Benign	0.29	Likely Benign	0.2	0.22	Likely Benign	0.26	Likely Benign	0.28	Likely Benign	0.258	Likely Benign	-2.15	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.91	Pathogenic	0.76	Tolerated			0.1608	0.7296		2	1	0.3	23.04
c.943A>G	N315D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and FATHMM. The remaining tools (FoldX, premPS, AlphaMissense‑Default) are inconclusive. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority; and Foldetta predicts a benign stability change. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.118441	Structured	0.379740	Uncertain	0.862	0.253	0.125											-5.667	Likely Benign	0.536	Ambiguous	Likely Benign	1.27	Ambiguous	0.6	-0.30	Likely Benign	0.49	Likely Benign	0.88	Ambiguous	0.229	Likely Benign	-2.41	Neutral	0.999	Probably Damaging	0.995	Probably Damaging	2.02	Pathogenic	0.45	Tolerated			0.1972	0.4488		2	1	0.0	0.98
c.943A>T	N315Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. The high‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence slightly favors a pathogenic interpretation, with six pathogenic‑predicted tools versus five benign‑predicted tools, and the high‑accuracy consensus leaning pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.118441	Structured	0.379740	Uncertain	0.862	0.253	0.125											-8.303	Likely Pathogenic	0.339	Likely Benign	Likely Benign	-1.03	Ambiguous	0.5	-0.85	Ambiguous	-0.94	Ambiguous	-0.10	Likely Benign	0.420	Likely Benign	-3.81	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.93	Pathogenic	1.00	Tolerated			0.0613	0.6732		-2	-2	2.2	49.07
c.944A>C	N315T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Two tools, premPS and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of individual predictors (six benign vs. four pathogenic) and the Foldetta result support a benign classification, while the SGM Consensus suggests pathogenicity. Thus, the variant is most likely benign based on the preponderance of evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.118441	Structured	0.379740	Uncertain	0.862	0.253	0.125											-7.071	In-Between	0.211	Likely Benign	Likely Benign	0.31	Likely Benign	0.1	-0.36	Likely Benign	-0.03	Likely Benign	0.62	Ambiguous	0.333	Likely Benign	-2.91	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.95	Pathogenic	0.53	Tolerated			0.1471	0.8068		0	0	2.8	-13.00
c.944A>G	N315S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.118441	Structured	0.379740	Uncertain	0.862	0.253	0.125											-4.847	Likely Benign	0.068	Likely Benign	Likely Benign	0.85	Ambiguous	0.2	0.78	Ambiguous	0.82	Ambiguous	0.68	Ambiguous	0.250	Likely Benign	-1.84	Neutral	0.999	Probably Damaging	0.992	Probably Damaging	2.03	Pathogenic	0.60	Tolerated			0.4022	0.7395		1	1	2.7	-27.03
c.944A>T	N315I 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant N315I is not reported in ClinVar and is absent from gnomAD. In silico predictors that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, and AlphaMissense‑Optimized. Predictors that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta, which integrates FoldX‑MD (uncertain) and Rosetta (benign), is considered unavailable. Overall, the balance of evidence leans toward pathogenicity, and this assessment does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.118441	Structured	0.379740	Uncertain	0.862	0.253	0.125											-9.666	Likely Pathogenic	0.500	Ambiguous	Likely Benign	-0.72	Ambiguous	0.4	-0.17	Likely Benign	-0.45	Likely Benign	0.36	Likely Benign	0.496	Likely Benign	-5.19	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.90	Pathogenic	0.43	Tolerated			0.0763	0.7235		-2	-3	8.0	-0.94
c.945C>A	N315K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315K is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and Foldetta. Tools that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and premPS. High‑accuracy assessments show that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No other high‑accuracy tool provides a conclusive result. Overall, the majority of predictions (seven pathogenic vs. five benign, with two uncertain) indicate that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.118441	Structured	0.379740	Uncertain	0.862	0.253	0.125											-10.380	Likely Pathogenic	0.872	Likely Pathogenic	Ambiguous	-0.03	Likely Benign	0.1	0.08	Likely Benign	0.03	Likely Benign	0.87	Ambiguous	0.340	Likely Benign	-3.27	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.98	Pathogenic	0.54	Tolerated			0.2268	0.6436		1	0	-0.4	14.07
c.945C>G	N315K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315K is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and Foldetta. Tools that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and premPS. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence (seven pathogenic vs. five benign, with two uncertain) points to a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.118441	Structured	0.379740	Uncertain	0.862	0.253	0.125											-10.380	Likely Pathogenic	0.872	Likely Pathogenic	Ambiguous	-0.03	Likely Benign	0.1	0.08	Likely Benign	0.03	Likely Benign	0.87	Ambiguous	0.340	Likely Benign	-3.27	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.98	Pathogenic	0.54	Tolerated			0.2268	0.6436		1	0	-0.4	14.07
c.946A>C	N316H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N316H is not reported in ClinVar (status: None) and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, and AlphaMissense‑Optimized. Tools that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts a benign effect; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (pathogenic), FATHMM (pathogenic), and PROVEAN (pathogenic), indicates a likely pathogenic outcome; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign impact. FoldX and premPS are inconclusive. Overall, the balance of evidence from the majority of prediction tools points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.118441	Structured	0.385187	Uncertain	0.817	0.246	0.125											-8.141	Likely Pathogenic	0.440	Ambiguous	Likely Benign	0.72	Ambiguous	0.4	0.07	Likely Benign	0.40	Likely Benign	0.62	Ambiguous	0.306	Likely Benign	-3.56	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.76	Pathogenic	0.02	Affected			0.1555	0.7702		2	1	0.3	23.04
c.946A>G	N316D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316D is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, Rosetta, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain and therefore not considered evidence. Overall, seven of the evaluated tools predict pathogenicity versus four predicting benignity, indicating that the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.118441	Structured	0.385187	Uncertain	0.817	0.246	0.125											-11.672	Likely Pathogenic	0.777	Likely Pathogenic	Likely Benign	1.18	Ambiguous	0.1	0.46	Likely Benign	0.82	Ambiguous	0.69	Ambiguous	0.293	Likely Benign	-3.20	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.76	Pathogenic	0.25	Tolerated			0.1978	0.4596		2	1	0.0	0.98
c.946A>T	N316Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316Y is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign impact. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.118441	Structured	0.385187	Uncertain	0.817	0.246	0.125											-11.226	Likely Pathogenic	0.767	Likely Pathogenic	Likely Benign	0.53	Ambiguous	0.5	-0.09	Likely Benign	0.22	Likely Benign	0.50	Likely Benign	0.454	Likely Benign	-5.70	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.81	Pathogenic	0.01	Affected			0.0574	0.6971		-2	-2	2.2	49.07
c.947A>C	N316T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. The remaining tools (AlphaMissense‑Default, ESM1b, Foldetta, premPS, Rosetta) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta also yields an uncertain stability change. Overall, the majority of available predictions lean toward pathogenicity, and this assessment does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely pathogenic based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.118441	Structured	0.385187	Uncertain	0.817	0.246	0.125											-7.538	In-Between	0.550	Ambiguous	Likely Benign	2.71	Destabilizing	0.2	1.27	Ambiguous	1.99	Ambiguous	0.57	Ambiguous	0.214	Likely Benign	-3.68	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.79	Pathogenic	0.08	Tolerated			0.1482	0.8474		0	0	2.8	-13.00
c.947A>G	N316S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316S is catalogued in gnomAD (ID 6‑33437852‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Stability‑related methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates Likely Benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.118441	Structured	0.385187	Uncertain	0.817	0.246	0.125								6-33437852-A-G	1	6.20e-7	-4.512	Likely Benign	0.149	Likely Benign	Likely Benign	1.19	Ambiguous	0.1	0.59	Ambiguous	0.89	Ambiguous	0.68	Ambiguous	0.151	Likely Benign	-2.22	Neutral	0.999	Probably Damaging	0.992	Probably Damaging	1.77	Pathogenic	0.38	Tolerated	3.38	23	0.4333	0.7751		1	1	2.7	-27.03
c.947A>T	N316I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and premPS, whereas the majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. No prediction is missing or inconclusive beyond the uncertain AlphaMissense‑Optimized result. Based on the preponderance of pathogenic predictions and the high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.118441	Structured	0.385187	Uncertain	0.817	0.246	0.125											-11.164	Likely Pathogenic	0.899	Likely Pathogenic	Ambiguous	2.74	Destabilizing	0.2	4.10	Destabilizing	3.42	Destabilizing	0.18	Likely Benign	0.318	Likely Benign	-6.37	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.00	Pathogenic	0.03	Affected			0.0734	0.7422		-2	-3	8.0	-0.94
c.948C>A	N316K 2D AIThe SynGAP1 missense variant N316K is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL and SIFT, whereas the majority of tools predict a pathogenic outcome: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. No other high‑confidence predictions are available. Overall, the preponderance of evidence points to a pathogenic effect for N316K, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.118441	Structured	0.385187	Uncertain	0.817	0.246	0.125											-10.711	Likely Pathogenic	0.972	Likely Pathogenic	Likely Pathogenic	0.52	Ambiguous	0.7	0.86	Ambiguous	0.69	Ambiguous	0.67	Ambiguous	0.254	Likely Benign	-3.87	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.77	Pathogenic	0.13	Tolerated			0.2220	0.6593		1	0	-0.4	14.07
c.948C>G	N316K 2D AISynGAP1 missense variant N316K is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and SIFT, whereas a majority of tools predict pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of computational predictions indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.118441	Structured	0.385187	Uncertain	0.817	0.246	0.125											-10.711	Likely Pathogenic	0.972	Likely Pathogenic	Likely Pathogenic	0.52	Ambiguous	0.7	0.86	Ambiguous	0.69	Ambiguous	0.67	Ambiguous	0.254	Likely Benign	-3.87	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.77	Pathogenic	0.13	Tolerated			0.2220	0.6593		1	0	-0.4	14.07
c.949C>A	L317M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L317M missense variant is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools show a split: benign calls come from REVEL, FoldX, Foldetta, and PROVEAN, whereas pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta predicts a benign effect on protein stability. No evidence from ClinVar contradicts these findings. Overall, the preponderance of pathogenic predictions and the SGM‑Consensus result suggest that the variant is most likely pathogenic, though the benign signal from Foldetta and other tools indicates uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.106997	Structured	0.394031	Uncertain	0.874	0.240	0.125											-9.558	Likely Pathogenic	0.788	Likely Pathogenic	Ambiguous	0.14	Likely Benign	0.1	0.84	Ambiguous	0.49	Likely Benign	0.94	Ambiguous	0.250	Likely Benign	-1.84	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.71	Pathogenic	0.04	Affected			0.0937	0.3122		4	2	-1.9	18.03
c.949C>G	L317V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L317V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely disagree: benign calls come from REVEL and AlphaMissense‑Optimized, while pathogenic calls are made by FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized predicting Benign, SGM‑Consensus predicting Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an Uncertain result. Overall, the majority of evidence points toward pathogenicity, with only two tools indicating benign. Because ClinVar contains no entry, there is no conflict with existing clinical interpretation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.106997	Structured	0.394031	Uncertain	0.874	0.240	0.125											-8.406	Likely Pathogenic	0.403	Ambiguous	Likely Benign	2.51	Destabilizing	0.1	0.97	Ambiguous	1.74	Ambiguous	1.12	Destabilizing	0.298	Likely Benign	-2.76	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	1.74	Pathogenic	0.03	Affected			0.1518	0.2950		2	1	0.4	-14.03
c.94A>C	T32P 2D AIThe SynGAP1 missense variant T32P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, two tools—polyPhen‑2 HumDiv and SIFT—classify the change as pathogenic. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; no Foldetta stability data are available. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.437154	Uncertain	0.349	0.879	0.375											-2.958	Likely Benign	0.055	Likely Benign	Likely Benign										0.102	Likely Benign	-0.94	Neutral	0.604	Possibly Damaging	0.185	Benign	4.14	Benign	0.00	Affected			0.2327	0.5818		0	-1	-0.9	-3.99
c.94A>G	T32A 2D AIThe SynGAP1 missense variant T32A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.437154	Uncertain	0.349	0.879	0.375											-3.330	Likely Benign	0.072	Likely Benign	Likely Benign										0.047	Likely Benign	-0.63	Neutral	0.043	Benign	0.016	Benign	4.21	Benign	0.00	Affected			0.4174	0.4742		1	0	2.5	-30.03
c.94A>T	T32S 2D AIThe SynGAP1 missense variant T32S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.437154	Uncertain	0.349	0.879	0.375											-2.618	Likely Benign	0.072	Likely Benign	Likely Benign										0.062	Likely Benign	-0.39	Neutral	0.171	Benign	0.050	Benign	4.18	Benign	0.00	Affected			0.3603	0.5174		1	1	-0.1	-14.03
c.950T>A	L317Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L317Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on these predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.106997	Structured	0.394031	Uncertain	0.874	0.240	0.125											-13.424	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	2.87	Destabilizing	0.2	2.47	Destabilizing	2.67	Destabilizing	1.61	Destabilizing	0.607	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.75	Pathogenic	0.00	Affected			0.1252	0.1251		-2	-2	-7.3	14.97
c.950T>C	L317P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L317P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tools predict a benign effect, so the benign group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.106997	Structured	0.394031	Uncertain	0.874	0.240	0.125											-14.778	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	3.61	Destabilizing	1.4	4.29	Destabilizing	3.95	Destabilizing	1.26	Destabilizing	0.654	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.82	Pathogenic	0.00	Affected			0.3405	0.1153		-3	-3	-5.4	-16.04
c.950T>G	L317R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L317R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.106997	Structured	0.394031	Uncertain	0.874	0.240	0.125											-14.185	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	3.33	Destabilizing	0.2	2.01	Destabilizing	2.67	Destabilizing	1.63	Destabilizing	0.569	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.75	Pathogenic	0.00	Affected			0.1501	0.0893		-3	-2	-8.3	43.03
c.952C>A	P318T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P318T is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly favor a deleterious effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenic or likely pathogenic. No tool in the dataset predicts a benign outcome; the only inconclusive results come from Rosetta, Foldetta, and premPS, which are treated as unavailable evidence. High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is uncertain. Consequently, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.111485	Structured	0.400936	Uncertain	0.858	0.234	0.000											-10.759	Likely Pathogenic	0.962	Likely Pathogenic	Likely Pathogenic	2.03	Destabilizing	0.2	1.54	Ambiguous	1.79	Ambiguous	0.84	Ambiguous	0.680	Likely Pathogenic	-7.09	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.84	Pathogenic	0.01	Affected			0.1583	0.6044		0	-1	0.9	3.99
c.952C>G	P318A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P318A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign outcome. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while AlphaMissense‑Optimized remains uncertain and Foldetta is also uncertain. Taken together, the overwhelming majority of evidence points to a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.111485	Structured	0.400936	Uncertain	0.858	0.234	0.000											-9.642	Likely Pathogenic	0.872	Likely Pathogenic	Ambiguous	1.90	Ambiguous	0.2	1.69	Ambiguous	1.80	Ambiguous	0.94	Ambiguous	0.546	Likely Pathogenic	-7.12	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.91	Pathogenic	0.04	Affected			0.3760	0.5585		1	-1	3.4	-26.04
c.952C>T	P318S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P318S is present in gnomAD (variant ID 6‑33437857‑C‑T) but has no ClinVar entry. Functional prediction tools uniformly indicate a deleterious effect. Pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta and Foldetta. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta remains uncertain. Taken together, the overwhelming majority of evidence supports a pathogenic classification, and this conclusion is consistent with the absence of a ClinVar record rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.111485	Structured	0.400936	Uncertain	0.858	0.234	0.000								6-33437857-C-T	1	6.19e-7	-9.954	Likely Pathogenic	0.956	Likely Pathogenic	Likely Pathogenic	2.22	Destabilizing	0.1	1.71	Ambiguous	1.97	Ambiguous	1.00	Destabilizing	0.626	Likely Pathogenic	-7.05	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.87	Pathogenic	0.03	Affected	3.38	23	0.3692	0.5653		-1	1	0.8	-10.04
c.953C>A	P318Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P318Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity. Only FoldX, Rosetta, and Foldetta provide uncertain results and are therefore not considered evidence for benign impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Consequently, the variant is most likely pathogenic based on the consensus of predictive algorithms, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.111485	Structured	0.400936	Uncertain	0.858	0.234	0.000											-11.403	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	1.64	Ambiguous	0.2	1.29	Ambiguous	1.47	Ambiguous	1.18	Destabilizing	0.638	Likely Pathogenic	-7.05	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.83	Pathogenic	0.01	Affected			0.1467	0.4731		0	-1	-1.9	31.01
c.953C>G	P318R 2D 3DClick to see structure in 3D Viewer AISynGAP1 P318R is not reported in ClinVar and is absent from gnomAD. In silico predictors that classify the variant as benign: none. Those that predict pathogenicity include SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions from FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy tools give a consistent pathogenic signal: AlphaMissense‑Optimized reports pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; Foldetta remains inconclusive. Overall, the consensus of the majority of predictors supports a pathogenic effect. This conclusion is not contradicted by ClinVar status, which is currently unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.111485	Structured	0.400936	Uncertain	0.858	0.234	0.000											-14.132	Likely Pathogenic	0.987	Likely Pathogenic	Likely Pathogenic	1.20	Ambiguous	0.1	0.70	Ambiguous	0.95	Ambiguous	1.01	Destabilizing	0.643	Likely Pathogenic	-8.01	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.84	Pathogenic	0.01	Affected			0.1308	0.3310		0	-2	-2.9	59.07
c.953C>T	P318L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P318L is listed in ClinVar with an uncertain significance (ClinVar ID 956570.0) and is present in gnomAD (6‑33437858‑C‑T). Functional prediction tools that agree on a benign effect are Rosetta and premPS. The remaining tools—REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Taken together, the preponderance of evidence points to a pathogenic effect for P318L, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.111485	Structured	0.400936	Uncertain	0.858	0.234	0.000					Uncertain		3	6-33437858-C-T	3	1.86e-6	-10.090	Likely Pathogenic	0.958	Likely Pathogenic	Likely Pathogenic	1.33	Ambiguous	0.1	0.26	Likely Benign	0.80	Ambiguous	0.43	Likely Benign	0.624	Likely Pathogenic	-8.96	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.82	Pathogenic	0.03	Affected	3.38	23	0.2166	0.6941		-3	-3	5.4	16.04	228.6	-68.9	-0.7	0.7	-0.4	0.1						X		Potentially Benign	The cyclic five-membered pyrrolidine ring of Pro318, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Asp330-Ala322, res. Thr305-Asn315), packs against the hydrophobic side chain of Ile205 at the end of the anti-parallel β sheet in the PH domain. In the variant simulations, the iso-butyl side chain of Leu318 is unable to do the same, potentially weakening the PH and C2 domain association. Importantly, the residue swap could also affect loop formation during folding, as proline can make tighter turns than leucine. Because the residue swap could affect the C2 domain stability, it could also negatively impact the SynGAP-membrane association.
c.955G>A	A319T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict a pathogenic effect are polyPhen2_HumDiv and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of reliable predictors classify the variant as benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.179055	Structured	0.410405	Uncertain	0.879	0.254	0.125											-7.841	In-Between	0.098	Likely Benign	Likely Benign	0.55	Ambiguous	0.3	0.70	Ambiguous	0.63	Ambiguous	0.30	Likely Benign	0.116	Likely Benign	-1.35	Neutral	0.775	Possibly Damaging	0.306	Benign	1.92	Pathogenic	0.09	Tolerated			0.1274	0.6083		1	0	-2.5	30.03
c.955G>C	A319P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319P is catalogued in gnomAD (ID 6‑33437860‑G‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive are Rosetta, ESM1b, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.179055	Structured	0.410405	Uncertain	0.879	0.254	0.125								6-33437860-G-C	3	1.86e-6	-7.213	In-Between	0.109	Likely Benign	Likely Benign	-0.02	Likely Benign	0.9	-1.18	Ambiguous	-0.60	Ambiguous	0.22	Likely Benign	0.286	Likely Benign	0.11	Neutral	0.999	Probably Damaging	0.977	Probably Damaging	1.97	Pathogenic	1.00	Tolerated	3.38	23	0.1839	0.5067		-1	1	-3.4	26.04
c.955G>T	A319S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as benign. No prediction or stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.179055	Structured	0.410405	Uncertain	0.879	0.254	0.125											-7.109	In-Between	0.093	Likely Benign	Likely Benign	0.16	Likely Benign	0.2	0.02	Likely Benign	0.09	Likely Benign	0.13	Likely Benign	0.165	Likely Benign	-0.58	Neutral	0.978	Probably Damaging	0.754	Possibly Damaging	2.02	Pathogenic	0.12	Tolerated			0.2537	0.4703		1	1	-2.6	16.00
c.956C>A	A319D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A319D missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a likely pathogenic verdict (3/4 pathogenic votes). High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, whereas the SGM‑Consensus remains pathogenic. Foldetta, which integrates FoldX‑MD (benign) and Rosetta (uncertain), is considered unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.179055	Structured	0.410405	Uncertain	0.879	0.254	0.125											-11.144	Likely Pathogenic	0.752	Likely Pathogenic	Likely Benign	-0.02	Likely Benign	0.2	-0.84	Ambiguous	-0.43	Likely Benign	0.30	Likely Benign	0.373	Likely Benign	-2.38	Neutral	0.998	Probably Damaging	0.966	Probably Damaging	2.01	Pathogenic	0.20	Tolerated			0.1504	0.1360		0	-2	-5.3	44.01
c.956C>G	A319G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict benign or likely benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict pathogenicity, while Rosetta remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.179055	Structured	0.410405	Uncertain	0.879	0.254	0.125											-6.505	Likely Benign	0.148	Likely Benign	Likely Benign	0.11	Likely Benign	0.4	0.56	Ambiguous	0.34	Likely Benign	0.39	Likely Benign	0.219	Likely Benign	-1.83	Neutral	0.994	Probably Damaging	0.900	Possibly Damaging	1.89	Pathogenic	0.09	Tolerated			0.2345	0.4532		1	0	-2.2	-14.03
c.956C>T	A319V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A319V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is also inconclusive. Overall, the majority of evidence points to a benign effect, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.179055	Structured	0.410405	Uncertain	0.879	0.254	0.125											-8.179	Likely Pathogenic	0.141	Likely Benign	Likely Benign	0.58	Ambiguous	0.4	0.63	Ambiguous	0.61	Ambiguous	0.23	Likely Benign	0.329	Likely Benign	-2.32	Neutral	0.989	Probably Damaging	0.824	Possibly Damaging	1.88	Pathogenic	0.10	Tolerated			0.1094	0.6390		0	0	2.4	28.05
c.958G>A	V320I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta remains inconclusive. High‑accuracy assessments corroborate the benign trend: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the preponderance of evidence points to a benign effect for V320I, and this conclusion does not conflict with the current ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.185198	Structured	0.419626	Uncertain	0.905	0.266	0.125					Uncertain		1				-5.220	Likely Benign	0.111	Likely Benign	Likely Benign	-0.27	Likely Benign	0.2	0.66	Ambiguous	0.20	Likely Benign	0.01	Likely Benign	0.027	Likely Benign	-0.21	Neutral	0.198	Benign	0.114	Benign	1.77	Pathogenic	0.45	Tolerated	3.38	23	0.0514	0.3207		3	4	0.3	14.03
c.958G>C	V320L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437863‑G‑C). Functional prediction tools that agree on benign impact include REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Pathogenic predictions come from polyPhen‑2 HumDiv and FATHMM, while Rosetta, Foldetta, premPS, and AlphaMissense‑Default are inconclusive. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a benign verdict. AlphaMissense‑Optimized also predicts benign, whereas Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.185198	Structured	0.419626	Uncertain	0.905	0.266	0.125					Uncertain		2	6-33437863-G-C	6	3.72e-6	-6.207	Likely Benign	0.362	Ambiguous	Likely Benign	-0.26	Likely Benign	0.2	1.33	Ambiguous	0.54	Ambiguous	0.51	Ambiguous	0.096	Likely Benign	-1.02	Neutral	0.900	Possibly Damaging	0.373	Benign	1.78	Pathogenic	0.92	Tolerated	3.38	23	0.0661	0.3863		2	1	-0.4	14.03	245.8	-10.2	0.3	0.9	0.1	0.3						X		Potentially Benign	The isopropyl side chain of Val310, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Thr305-Asn315, res. Ala322-Asp330), hydrophobically packs with the side chains of nearby residues (e.g., Leu286, Val350, Pro318). The hydrophobic Leu320 side chain mostly forms the same interactions; hence, the residue swap does not seem to negatively affect the protein structure based on the variant simulations.
c.958G>T	V320F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant V320F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on benign impact include REVEL, premPS, and SIFT, whereas tools that agree on pathogenic impact include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as inconclusive. Because the majority of available predictions and the SGM‑Consensus favor pathogenicity, the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for V320F. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.185198	Structured	0.419626	Uncertain	0.905	0.266	0.125											-9.958	Likely Pathogenic	0.877	Likely Pathogenic	Ambiguous	1.49	Ambiguous	1.4	1.55	Ambiguous	1.52	Ambiguous	0.44	Likely Benign	0.237	Likely Benign	-3.26	Deleterious	0.994	Probably Damaging	0.944	Probably Damaging	1.79	Pathogenic	0.06	Tolerated			0.0473	0.3064		-1	-1	-1.4	48.04
c.959T>A	V320D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL and SIFT; pathogenic predictions from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Stability‑based methods FoldX and Rosetta returned uncertain results, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also yielded an uncertain prediction. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect, which is consistent with the lack of ClinVar annotation and gnomAD absence. Thus, the variant is most likely pathogenic, and this prediction does not contradict ClinVar status because ClinVar has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.185198	Structured	0.419626	Uncertain	0.905	0.266	0.125											-11.269	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	1.99	Ambiguous	1.0	1.67	Ambiguous	1.83	Ambiguous	1.50	Destabilizing	0.405	Likely Benign	-5.58	Deleterious	0.999	Probably Damaging	0.972	Probably Damaging	1.93	Pathogenic	0.07	Tolerated			0.1101	0.0482		-2	-3	-7.7	15.96
c.959T>C	V320A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V320A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Four tools (AlphaMissense‑Default, FoldX, Rosetta, Foldetta) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, more tools (five) predict pathogenicity than benign (four), and the high‑accuracy consensus leans toward pathogenic. Thus, the variant is most likely pathogenic, with no contradiction to ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.185198	Structured	0.419626	Uncertain	0.905	0.266	0.125											-5.488	Likely Benign	0.545	Ambiguous	Likely Benign	1.26	Ambiguous	0.7	1.48	Ambiguous	1.37	Ambiguous	1.27	Destabilizing	0.179	Likely Benign	-3.05	Deleterious	0.948	Possibly Damaging	0.761	Possibly Damaging	1.84	Pathogenic	0.35	Tolerated			0.2405	0.1903		0	0	-2.4	-28.05
c.959T>G	V320G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools cluster into two agreement groups: the single benign prediction comes from REVEL, while the pathogenic group includes FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain; the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—returns pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. Overall, the preponderance of evidence indicates that V320G is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.185198	Structured	0.419626	Uncertain	0.905	0.266	0.125											-9.043	Likely Pathogenic	0.816	Likely Pathogenic	Ambiguous	2.15	Destabilizing	1.1	1.87	Ambiguous	2.01	Destabilizing	1.48	Destabilizing	0.438	Likely Benign	-5.74	Deleterious	0.958	Probably Damaging	0.999	Probably Damaging	1.89	Pathogenic	0.02	Affected			0.1688	0.1949		-1	-3	-4.6	-42.08
c.95C>A	T32N 2D AIThe SynGAP1 missense variant T32N is catalogued in gnomAD (ID 6‑33423504‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.437154	Uncertain	0.349	0.879	0.375								6-33423504-C-A	2	1.24e-6	-3.466	Likely Benign	0.090	Likely Benign	Likely Benign										0.040	Likely Benign	-1.01	Neutral	0.604	Possibly Damaging	0.140	Benign	4.15	Benign	0.00	Affected	4.32	1	0.1681	0.5264		0	0	-2.8	13.00
c.95C>G	T32S 2D AIThe SynGAP1 missense variant T32S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.437154	Uncertain	0.349	0.879	0.375											-2.618	Likely Benign	0.072	Likely Benign	Likely Benign										0.024	Likely Benign	-0.39	Neutral	0.171	Benign	0.050	Benign	4.18	Benign	0.00	Affected			0.3603	0.5174		1	1	-0.1	-14.03
c.95C>T	T32I 2D AIThe SynGAP1 missense variant T32I is reported in gnomAD (ID 6‑33423504‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also reports likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for T32I, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.437154	Uncertain	0.349	0.879	0.375								6-33423504-C-T	1	6.20e-7	-3.689	Likely Benign	0.213	Likely Benign	Likely Benign										0.024	Likely Benign	-0.57	Neutral	0.049	Benign	0.026	Benign	4.26	Benign	0.00	Affected	4.32	1	0.1081	0.6403		-1	0	5.2	12.05
c.961C>A	R321S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Two tools—FoldX and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of predictions lean toward a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.175930	Structured	0.423273	Uncertain	0.931	0.297	0.125											-10.146	Likely Pathogenic	0.497	Ambiguous	Likely Benign	0.66	Ambiguous	0.1	-0.30	Likely Benign	0.18	Likely Benign	0.24	Likely Benign	0.379	Likely Benign	-2.27	Neutral	0.999	Probably Damaging	0.997	Probably Damaging	2.00	Pathogenic	0.10	Tolerated			0.2958	0.2785		0	-1	3.7	-69.11
c.961C>G	R321G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, AlphaMissense‑Default, AlphaMissense‑Optimized, and premPS. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, while the high‑accuracy subset is mixed, with one benign, one pathogenic, and one uncertain result. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.175930	Structured	0.423273	Uncertain	0.931	0.297	0.125											-10.554	Likely Pathogenic	0.293	Likely Benign	Likely Benign	0.90	Ambiguous	0.1	0.28	Likely Benign	0.59	Ambiguous	0.49	Likely Benign	0.430	Likely Benign	-3.70	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.92	Pathogenic	0.04	Affected			0.3224	0.2898		-3	-2	4.1	-99.14
c.961C>T	R321C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33437866‑C‑T). Prediction tools that agree on a benign effect include REVEL, premPS, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Five tools (SGM‑Consensus, FoldX, Rosetta, AlphaMissense‑Default, and Foldetta) report uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (six out of eleven) support a pathogenic impact, while three support benign and five are inconclusive. Thus, the variant is most likely pathogenic based on current computational evidence, and this does not contradict its ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.175930	Structured	0.423273	Uncertain	0.931	0.297	0.125					Conflicting		2	6-33437866-C-T	9	5.58e-6	-10.025	Likely Pathogenic	0.387	Ambiguous	Likely Benign	0.57	Ambiguous	0.1	0.56	Ambiguous	0.57	Ambiguous	0.18	Likely Benign	0.495	Likely Benign	-4.59	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.89	Pathogenic	0.01	Affected	3.38	23	0.3313	0.2516		-3	-4	7.0	-53.05
c.962G>A	R321H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R321H is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6‑33437867‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM, while premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions support a benign impact, and this consensus does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.175930	Structured	0.423273	Uncertain	0.931	0.297	0.125					Uncertain		1	6-33437867-G-A	8	4.96e-6	-8.751	Likely Pathogenic	0.136	Likely Benign	Likely Benign	0.48	Likely Benign	0.1	-0.36	Likely Benign	0.06	Likely Benign	0.59	Ambiguous	0.323	Likely Benign	-1.43	Neutral	1.000	Probably Damaging	0.998	Probably Damaging	1.92	Pathogenic	0.25	Tolerated	3.38	23	0.2930	0.0936		2	0	1.3	-19.05	218.5	86.9	1.1	0.0	0.3	0.0						X		Potentially Benign	The guanidinium group of Arg321, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Thr305-Asn315, res. Ala322-Asp330), faces outward without forming any stable interactions in the WT simulations. Similarly, in the variant simulations, the imidazole ring of His321 also points outward without making any stable intra-protein interactions. Thus, the residue swap does not seem to cause adverse effects on the protein structure based on the simulations. However, β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant.
c.962G>C	R321P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. FoldX and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools (8/12) predict pathogenicity, whereas 4/12 predict benign, with two high‑accuracy tools supporting benign and one supporting pathogenic. Thus, the variant is most likely pathogenic based on the preponderance of evidence, and this assessment does not contradict ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.175930	Structured	0.423273	Uncertain	0.931	0.297	0.125											-11.576	Likely Pathogenic	0.740	Likely Pathogenic	Likely Benign	1.22	Ambiguous	0.3	-0.77	Ambiguous	0.23	Likely Benign	0.41	Likely Benign	0.488	Likely Benign	-3.59	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.92	Pathogenic	0.03	Affected			0.2186	0.3661		0	-2	2.9	-59.07
c.962G>T	R321L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SIFT, polyPhen‑2 (HumDiv and HumVar), PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign; FoldX and Rosetta individually are inconclusive. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.175930	Structured	0.423273	Uncertain	0.931	0.297	0.125											-11.709	Likely Pathogenic	0.551	Ambiguous	Likely Benign	0.54	Ambiguous	0.0	-0.58	Ambiguous	-0.02	Likely Benign	0.18	Likely Benign	0.451	Likely Benign	-4.06	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.93	Pathogenic	0.03	Affected			0.1745	0.4048		-3	-2	8.3	-43.03
c.964G>A	A322T 2D AIThe SynGAP1 missense variant A322T is not reported in ClinVar and is absent from gnomAD. Consensus from most in silico predictors classifies the change as benign: SGM‑Consensus (Likely Benign), REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect. Only FATHMM indicates a pathogenic signal, while FoldX and premPS are inconclusive. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign impact on protein stability. Overall, the majority of evidence supports a benign effect for A322T, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.175930	Structured	0.425745	Uncertain	0.938	0.334	0.000											-2.252	Likely Benign	0.064	Likely Benign	Likely Benign	0.58	Ambiguous	0.9	0.22	Likely Benign	0.40	Likely Benign	-0.52	Ambiguous	0.112	Likely Benign	0.20	Neutral	0.010	Benign	0.005	Benign	1.95	Pathogenic	0.73	Tolerated			0.1367	0.6432		1	0	-2.5	30.03
c.964G>C	A322P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A322P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, and SIFT, while pathogenic calls are made by SGM‑Consensus, Rosetta, Foldetta, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: FoldX and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Thus, the variant is most likely pathogenic, with no ClinVar evidence to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.175930	Structured	0.425745	Uncertain	0.938	0.334	0.000											-10.558	Likely Pathogenic	0.878	Likely Pathogenic	Ambiguous	1.26	Ambiguous	1.3	5.43	Destabilizing	3.35	Destabilizing	0.40	Likely Benign	0.343	Likely Benign	-1.72	Neutral	0.784	Possibly Damaging	0.390	Benign	1.90	Pathogenic	0.18	Tolerated			0.2064	0.5400		1	-1	-3.4	26.04
c.964G>T	A322S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A322S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. Grouping by consensus, the benign‑predicting tools outnumber the single pathogenic prediction. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates a benign effect. No prediction or stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.175930	Structured	0.425745	Uncertain	0.938	0.334	0.000											-1.424	Likely Benign	0.058	Likely Benign	Likely Benign	0.41	Likely Benign	0.2	0.38	Likely Benign	0.40	Likely Benign	-0.44	Likely Benign	0.127	Likely Benign	1.09	Neutral	0.010	Benign	0.010	Benign	2.00	Pathogenic	0.67	Tolerated			0.2696	0.5253		1	1	-2.6	16.00
c.965C>A	A322D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A322D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The remaining tools—FoldX, Rosetta, ESM1b, and AlphaMissense‑Default—return uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta indicates no significant stability change (uncertain). Overall, the preponderance of evidence (seven benign predictions versus one pathogenic) suggests the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.175930	Structured	0.425745	Uncertain	0.938	0.334	0.000											-7.184	In-Between	0.411	Ambiguous	Likely Benign	0.65	Ambiguous	0.1	1.35	Ambiguous	1.00	Ambiguous	0.34	Likely Benign	0.246	Likely Benign	-0.95	Neutral	0.270	Benign	0.136	Benign	1.96	Pathogenic	0.32	Tolerated			0.1646	0.1660		0	-2	-5.3	44.01
c.965C>G	A322G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A322G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only FATHMM predicts a pathogenic outcome. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain or inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Based on the preponderance of benign predictions and the lack of contradictory evidence, the variant is most likely benign; this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.175930	Structured	0.425745	Uncertain	0.938	0.334	0.000											-5.230	Likely Benign	0.121	Likely Benign	Likely Benign	0.84	Ambiguous	0.1	1.43	Ambiguous	1.14	Ambiguous	0.64	Ambiguous	0.054	Likely Benign	-1.07	Neutral	0.139	Benign	0.088	Benign	1.94	Pathogenic	0.19	Tolerated			0.2513	0.4683		1	0	-2.2	-14.03
c.965C>T	A322V 2D AIThe SynGAP1 missense variant A322V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No predictions or stability results are missing or inconclusive. Based on the overwhelming consensus of the available tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.175930	Structured	0.425745	Uncertain	0.938	0.334	0.000											-4.905	Likely Benign	0.121	Likely Benign	Likely Benign	0.02	Likely Benign	1.0	-0.42	Likely Benign	-0.20	Likely Benign	0.19	Likely Benign	0.052	Likely Benign	-1.63	Neutral	0.270	Benign	0.136	Benign	1.96	Pathogenic	0.22	Tolerated			0.1279	0.6126		0	0	2.4	28.05
c.967C>A	L323M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L323M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—Foldetta, premPS, AlphaMissense‑Default, ESM1b, and Rosetta—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Taken together, the evidence leans toward a benign impact for the variant, and this assessment does not contradict any ClinVar annotation, as none exists for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.268042	Structured	0.428564	Uncertain	0.956	0.369	0.000											-7.065	In-Between	0.427	Ambiguous	Likely Benign	0.11	Likely Benign	0.1	1.82	Ambiguous	0.97	Ambiguous	0.93	Ambiguous	0.270	Likely Benign	-1.02	Neutral	0.997	Probably Damaging	0.939	Probably Damaging	0.64	Pathogenic	0.03	Affected			0.0637	0.3010		4	2	-1.9	18.03
c.967C>G	L323V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L323V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, premPS, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic predictions (FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM). The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Benign. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority of the four high‑accuracy tools) also indicates Likely Benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.268042	Structured	0.428564	Uncertain	0.956	0.369	0.000											-3.483	Likely Benign	0.107	Likely Benign	Likely Benign	2.18	Destabilizing	0.3	2.22	Destabilizing	2.20	Destabilizing	0.17	Likely Benign	0.227	Likely Benign	0.19	Neutral	0.898	Possibly Damaging	0.472	Possibly Damaging	0.80	Pathogenic	0.80	Tolerated			0.1277	0.2656		2	1	0.4	-14.03
c.968T>A	L323Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L323Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—return pathogenic or likely pathogenic calls. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.268042	Structured	0.428564	Uncertain	0.956	0.369	0.000											-14.487	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	3.19	Destabilizing	0.2	3.28	Destabilizing	3.24	Destabilizing	1.85	Destabilizing	0.728	Likely Pathogenic	-4.54	Deleterious	0.999	Probably Damaging	0.977	Probably Damaging	0.59	Pathogenic	0.00	Affected			0.0915	0.0758		-2	-2	-7.3	14.97
c.968T>C	L323P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L323P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.268042	Structured	0.428564	Uncertain	0.956	0.369	0.000					Uncertain		1				-12.507	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	3.39	Destabilizing	0.6	8.46	Destabilizing	5.93	Destabilizing	2.20	Destabilizing	0.762	Likely Pathogenic	-4.80	Deleterious	0.999	Probably Damaging	0.977	Probably Damaging	0.59	Pathogenic	0.01	Affected	4.29	398	0.3678	0.1221		-3	-3	-5.4	-16.04	201.9	68.2	0.0	0.1	0.6	0.3	X							Potentially Pathogenic	The iso-butyl side chain of Leu323, located at the beginning of an anti-parallel β sheet strand (res. Ala322-Asp330), packs against multiple hydrophobic leucine residues (e.g., Leu264, Leu266, Leu284, Leu286). In contrast, in the variant simulations, the less bulky cyclic five-membered pyrrolidine ring of Pro323 cannot fill the hydrophobic space as effectively as the branched hydrocarbon side chain of leucine. Notably, the backbone amide group of Leu323 forms a hydrogen bond with the backbone carbonyl group of Cys285. Pro323 cannot form this bond due to the absence of the backbone amide group, resulting in partial unfolding of the anti-parallel β sheet end in the variant simulations.
c.968T>G	L323R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L323R is listed in ClinVar (ID 978601.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Consequently, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.268042	Structured	0.428564	Uncertain	0.956	0.369	0.000					Likely Pathogenic		1				-14.568	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	3.75	Destabilizing	0.4	4.47	Destabilizing	4.11	Destabilizing	2.15	Destabilizing	0.692	Likely Pathogenic	-4.70	Deleterious	0.999	Probably Damaging	0.969	Probably Damaging	0.59	Pathogenic	0.01	Affected	3.39	22	0.1066	0.0600		-3	-2	-8.3	43.03	261.8	-61.6	-0.4	0.2	0.8	0.2	X		X				X	Potentially Pathogenic	The iso-butyl side chain of Leu323, located at the beginning of an anti-parallel β sheet strand (res. Ala322-Asp330), packs against multiple hydrophobic leucine residues (e.g., Leu264, Leu266, Leu284, Leu286). In contrast, in the variant simulations, the positively charged guanidinium group of the Arg323 side chain is unsuitable for the hydrophobic niche. Consequently, the side chain either rotates away from the center of the C2 domain or, if it remains within the C2 domain core, it reorients nearby residues to form hydrogen bonds. Regardless, the residue swap extensively disrupts the C2 domain structure.
c.970C>G	R324G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R324G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. With the majority of evidence pointing to deleterious impact and two of the three high‑accuracy methods supporting pathogenicity, the variant is most likely pathogenic. This conclusion does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.257454	Structured	0.426893	Uncertain	0.954	0.397	0.000											-12.266	Likely Pathogenic	0.708	Likely Pathogenic	Likely Benign	2.99	Destabilizing	0.1	3.18	Destabilizing	3.09	Destabilizing	1.27	Destabilizing	0.496	Likely Benign	-2.64	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.84	Pathogenic	0.39	Tolerated			0.3546	0.4135		-3	-2	4.1	-99.14
c.970C>T	R324W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R324W is listed in ClinVar with an uncertain significance (ClinVar ID 845180.0) and is present in gnomAD (ID 6‑33437875‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other stability or functional scores are available. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a leaning toward pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.257454	Structured	0.426893	Uncertain	0.954	0.397	0.000					Uncertain		1	6-33437875-C-T	2	1.24e-6	-12.906	Likely Pathogenic	0.694	Likely Pathogenic	Likely Benign	1.49	Ambiguous	0.3	0.56	Ambiguous	1.03	Ambiguous	0.66	Ambiguous	0.481	Likely Benign	-3.12	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.82	Pathogenic	0.16	Tolerated	3.39	22	0.1517	0.4361		2	-3	3.6	30.03	256.6	39.1	0.0	0.1	0.3	0.2		X						Potentially Pathogenic	The guanidinium group of Arg324, located at the end of an anti-parallel β sheet strand (res. Ala322-Asp330), faces outward and frequently forms a salt bridge with the carboxylate group of the Asp288 side chain, which is part of a β strand end (res. Met289-Pro298). In the variant simulations, the indole ring of the Trp324 side chain cannot maintain a similar interaction with the negatively charged carboxylate side chain of Asp288, potentially compromising the folding of the anti-parallel β sheet assembly. However, the residue swap does not appear to negatively impact the protein structure or its integrity based on the simulations.
c.971G>A	R324Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R324Q is listed in ClinVar with an uncertain significance (ClinVar ID 2572558.0) and is present in gnomAD (ID 6‑33437876‑G‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. Protein‑stability predictions from FoldX, Rosetta, and the combined Foldetta method are all uncertain. Overall, the consensus of available computational evidence points to a benign effect for R324Q, which is consistent with its ClinVar status of uncertain significance rather than a pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.257454	Structured	0.426893	Uncertain	0.954	0.397	0.000					Uncertain		3	6-33437876-G-A	3	1.86e-6	-5.001	Likely Benign	0.173	Likely Benign	Likely Benign	0.56	Ambiguous	0.1	0.63	Ambiguous	0.60	Ambiguous	1.02	Destabilizing	0.307	Likely Benign	-1.17	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	1.92	Pathogenic	0.41	Tolerated	3.39	22	0.3804	0.3214		1	1	1.0	-28.06
c.971G>C	R324P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R324P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, PROVEAN, and SIFT, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic” because three of the four contributing tools predict pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenic. Based on the preponderance of pathogenic predictions—including the high‑accuracy tools—the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.257454	Structured	0.426893	Uncertain	0.954	0.397	0.000											-14.533	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	4.61	Destabilizing	0.5	2.19	Destabilizing	3.40	Destabilizing	1.03	Destabilizing	0.486	Likely Benign	-2.15	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.83	Pathogenic	0.29	Tolerated			0.2291	0.5556		0	-2	2.9	-59.07
c.971G>T	R324L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R324L is catalogued in gnomAD (6-33437876‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, and SIFT; pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome, and Foldetta (integrating FoldX‑MD and Rosetta outputs) reports a benign stability change. Overall, the majority of evidence points toward a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.257454	Structured	0.426893	Uncertain	0.954	0.397	0.000								6-33437876-G-T	1	6.20e-7	-10.328	Likely Pathogenic	0.575	Likely Pathogenic	Likely Benign	-0.28	Likely Benign	0.0	-0.08	Likely Benign	-0.18	Likely Benign	0.29	Likely Benign	0.489	Likely Benign	-2.20	Neutral	0.999	Probably Damaging	0.997	Probably Damaging	1.86	Pathogenic	0.63	Tolerated	3.39	22	0.2310	0.5607		-2	-3	8.3	-43.03
c.973C>A	L325M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and premPS. Two tools give uncertain results: Foldetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. No prediction or folding stability result is missing or inconclusive. Overall, the majority of tools (six pathogenic vs five benign) lean toward pathogenicity, but the high‑accuracy methods and several benign predictions introduce uncertainty. Thus, the variant is most likely pathogenic based on the collective evidence, and this assessment is not contradicted by any ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.352862	Structured	0.424577	Uncertain	0.955	0.436	0.000											-6.725	Likely Benign	0.445	Ambiguous	Likely Benign	0.22	Likely Benign	0.0	2.04	Destabilizing	1.13	Ambiguous	1.05	Destabilizing	0.306	Likely Benign	-0.86	Neutral	0.997	Probably Damaging	0.939	Probably Damaging	1.36	Pathogenic	0.01	Affected			0.0934	0.3942		4	2	-1.9	18.03
c.973C>G	L325V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L325V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Rosetta and Foldetta give uncertain results. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.352862	Structured	0.424577	Uncertain	0.955	0.436	0.000											-3.104	Likely Benign	0.162	Likely Benign	Likely Benign	2.26	Destabilizing	0.1	1.27	Ambiguous	1.77	Ambiguous	-0.39	Likely Benign	0.183	Likely Benign	0.16	Neutral	0.898	Possibly Damaging	0.472	Possibly Damaging	1.68	Pathogenic	1.00	Tolerated			0.1571	0.3957		2	1	0.4	-14.03
c.974T>A	L325Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—return pathogenic or likely pathogenic calls. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.352862	Structured	0.424577	Uncertain	0.955	0.436	0.000											-17.005	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	3.23	Destabilizing	0.0	2.68	Destabilizing	2.96	Destabilizing	2.02	Destabilizing	0.547	Likely Pathogenic	-3.97	Deleterious	0.999	Probably Damaging	0.977	Probably Damaging	1.33	Pathogenic	0.00	Affected			0.1235	0.1405		-2	-2	-7.3	14.97
c.974T>C	L325P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325P is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.352862	Structured	0.424577	Uncertain	0.955	0.436	0.000											-16.130	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	5.49	Destabilizing	0.3	7.27	Destabilizing	6.38	Destabilizing	1.89	Destabilizing	0.607	Likely Pathogenic	-4.37	Deleterious	0.999	Probably Damaging	0.977	Probably Damaging	1.33	Pathogenic	0.00	Affected			0.3393	0.1903		-3	-3	-5.4	-16.04
c.974T>G	L325R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. No predictions or stability results are missing or inconclusive. **Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status (no ClinVar entry).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.352862	Structured	0.424577	Uncertain	0.955	0.436	0.000											-16.612	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	4.34	Destabilizing	0.3	4.11	Destabilizing	4.23	Destabilizing	1.94	Destabilizing	0.551	Likely Pathogenic	-4.39	Deleterious	0.999	Probably Damaging	0.969	Probably Damaging	1.33	Pathogenic	0.00	Affected			0.1405	0.1047		-3	-2	-8.3	43.03
c.976C>A	H326N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326N has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and SIFT, whereas a majority (seven) predict a pathogenic outcome: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the balance of evidence points to a pathogenic impact for H326N, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.342579	Structured	0.418150	Uncertain	0.944	0.455	0.000											-8.914	Likely Pathogenic	0.925	Likely Pathogenic	Ambiguous	0.81	Ambiguous	0.2	1.48	Ambiguous	1.15	Ambiguous	0.97	Ambiguous	0.409	Likely Benign	-5.63	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.95	Pathogenic	0.11	Tolerated			0.1929	0.2552		2	1	-0.3	-23.04
c.976C>G	H326D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H326D missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only SIFT, which scores the variant as benign. All other evaluated algorithms—REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome. Tools with inconclusive results are FoldX, Foldetta, and premPS, which are listed as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a pathogenic verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, reports an uncertain result. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.342579	Structured	0.418150	Uncertain	0.944	0.455	0.000											-13.000	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.87	Ambiguous	0.6	2.00	Destabilizing	1.44	Ambiguous	0.96	Ambiguous	0.561	Likely Pathogenic	-7.67	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	2.04	Pathogenic	0.10	Tolerated			0.2612	0.1611		1	-1	-0.3	-22.05
c.976C>T	H326Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas a majority of tools (REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic effect for H326Y, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.342579	Structured	0.418150	Uncertain	0.944	0.455	0.000											-10.896	Likely Pathogenic	0.855	Likely Pathogenic	Ambiguous	0.03	Likely Benign	0.4	0.25	Likely Benign	0.14	Likely Benign	0.07	Likely Benign	0.562	Likely Pathogenic	-5.32	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.92	Pathogenic	0.02	Affected			0.0796	0.4323		0	2	1.9	26.03
c.977A>C	H326P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; pathogenic predictions are reported by REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). The only inconclusive result is premPS, which is listed as Uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Pathogenic. Based on the consensus of these predictions, the variant is most likely pathogenic, and this conclusion is consistent with the absence of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.342579	Structured	0.418150	Uncertain	0.944	0.455	0.000											-18.452	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	2.67	Destabilizing	0.3	2.59	Destabilizing	2.63	Destabilizing	0.88	Ambiguous	0.711	Likely Pathogenic	-8.73	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.92	Pathogenic	0.03	Affected			0.2383	0.4492		0	-2	1.6	-40.02
c.977A>G	H326R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H326R missense variant is not listed in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include SIFT and Foldetta, whereas the remaining tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports it as likely pathogenic; Foldetta, a protein‑folding stability approach that integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. Because the majority of evidence points to a deleterious change, the variant is most likely pathogenic, and this assessment is not contradicted by the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.342579	Structured	0.418150	Uncertain	0.944	0.455	0.000											-12.369	Likely Pathogenic	0.980	Likely Pathogenic	Likely Pathogenic	-0.65	Ambiguous	0.1	1.40	Ambiguous	0.38	Likely Benign	0.83	Ambiguous	0.601	Likely Pathogenic	-6.89	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.97	Pathogenic	0.10	Tolerated			0.1832	0.2413		2	0	-1.3	19.05
c.977A>T	H326L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H326L missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect include SIFT, premPS, Rosetta, and Foldetta. Tools that agree on a pathogenic effect include REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) predicts benign. No evidence is available from FoldX or AlphaMissense‑Optimized to support either outcome. Overall, the majority of predictions (nine pathogenic vs. four benign) indicate that H326L is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.342579	Structured	0.418150	Uncertain	0.944	0.455	0.000											-10.421	Likely Pathogenic	0.888	Likely Pathogenic	Ambiguous	-0.85	Ambiguous	0.2	0.36	Likely Benign	-0.25	Likely Benign	0.44	Likely Benign	0.627	Likely Pathogenic	-9.64	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.95	Pathogenic	0.08	Tolerated			0.0992	0.5799		-2	-3	7.0	-23.98
c.978T>A	H326Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and SIFT, whereas a majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools, Foldetta (combining FoldX‑MD and Rosetta) and Rosetta alone, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for H326Q. This conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.342579	Structured	0.418150	Uncertain	0.944	0.455	0.000											-8.688	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	0.46	Likely Benign	0.1	1.67	Ambiguous	1.07	Ambiguous	1.00	Destabilizing	0.444	Likely Benign	-6.89	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	2.07	Pathogenic	0.10	Tolerated			0.1485	0.3500		3	0	-0.3	-9.01
c.978T>G	H326Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and SIFT, whereas a majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools, Foldetta (combining FoldX‑MD and Rosetta) and Rosetta alone, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also indicates likely pathogenic, while Foldetta remains uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for H326Q. This conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.342579	Structured	0.418150	Uncertain	0.944	0.455	0.000											-8.688	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	0.46	Likely Benign	0.1	1.67	Ambiguous	1.07	Ambiguous	1.00	Destabilizing	0.444	Likely Benign	-6.89	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	2.07	Pathogenic	0.10	Tolerated			0.1485	0.3500		3	0	-0.3	-9.01
c.979C>A	L327M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L327M missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, AlphaMissense‑Optimized, and Foldetta, whereas those that predict a pathogenic outcome are SGM‑Consensus, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta predicting a benign effect. Overall, the majority of tools indicate a pathogenic effect, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.409189	Uncertain	0.939	0.490	0.000											-10.320	Likely Pathogenic	0.727	Likely Pathogenic	Likely Benign	0.20	Likely Benign	0.0	0.72	Ambiguous	0.46	Likely Benign	1.07	Destabilizing	0.320	Likely Benign	-1.61	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.53	Pathogenic	0.01	Affected			0.0806	0.3807		4	2	-1.9	18.03
c.979C>G	L327V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L327V is reported in gnomAD (ID 6‑33437884‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.335645	Structured	0.409189	Uncertain	0.939	0.490	0.000								6-33437884-C-G	3	1.86e-6	-8.978	Likely Pathogenic	0.148	Likely Benign	Likely Benign	1.38	Ambiguous	0.1	0.67	Ambiguous	1.03	Ambiguous	1.31	Destabilizing	0.208	Likely Benign	-1.87	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	2.66	Benign	0.13	Tolerated	3.38	23	0.1648	0.4206		1	2	0.4	-14.03
c.97C>A	Q33K 2D AIThe SynGAP1 missense variant Q33K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.436712	Uncertain	0.342	0.860	0.375											-0.317	Likely Benign	0.217	Likely Benign	Likely Benign										0.026	Likely Benign	-0.53	Neutral	0.019	Benign	0.021	Benign	4.24	Benign	0.00	Affected			0.2366	0.4514		1	1	-0.4	0.04
c.97C>G	Q33E 2D AIThe SynGAP1 missense variant Q33E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign status: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.436712	Uncertain	0.342	0.860	0.375											0.191	Likely Benign	0.110	Likely Benign	Likely Benign										0.024	Likely Benign	-0.13	Neutral	0.017	Benign	0.014	Benign	4.25	Benign	0.00	Affected			0.1773	0.3326		2	2	0.0	0.98
c.980T>A	L327Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L327Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. With all available evidence pointing to a harmful impact and no ClinVar entry to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.409189	Uncertain	0.939	0.490	0.000											-14.243	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	3.03	Destabilizing	0.1	2.17	Destabilizing	2.60	Destabilizing	2.11	Destabilizing	0.605	Likely Pathogenic	-5.26	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.52	Pathogenic	0.00	Affected			0.1131	0.1042		-2	-2	-7.3	14.97
c.980T>C	L327P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L327P (ClinVar ID 660421) is classified as Pathogenic in ClinVar and is not reported in gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, leaving no tools in the benign category. High‑accuracy assessments further support this: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is Pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.409189	Uncertain	0.939	0.490	0.000					Pathogenic/Likely path.		4				-16.602	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	5.38	Destabilizing	0.1	4.00	Destabilizing	4.69	Destabilizing	2.62	Destabilizing	0.658	Likely Pathogenic	-5.97	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.52	Pathogenic	0.01	Affected	3.38	23	0.3921	0.1703		-3	-3	-5.4	-16.04	221.7	69.4	0.1	0.0	0.6	0.1	X							Potentially Pathogenic	The backbone amide group of Leu327, located in the middle of an anti-parallel β sheet strand (res. Ala322-Asp330), forms a hydrogen bond with the carbonyl group of Gly344 on a neighboring β strand (res. Lys336-Pro349) in the WT simulations. In contrast, in the variant simulations, the introduction of Pro327 destabilizes the hydrogen bonding between the two anti-parallel β strands because proline lacks the backbone amide group altogether. Additionally, in the WT simulations, the iso-butyl side chain of Leu327 packs against multiple hydrophobic residues (e.g., Leu274, V400, Val343), whereas the less bulky cyclic five-membered pyrrolidine ring of Pro327 cannot fill the same space as effectively. Thus, although no large-scale unfolding is observed during the variant simulations, the residue swap is likely to cause severe problems for the correct C2 domain folding, which could also affect the SynGAP-membrane association.	10.1016/j.ajhg.2020.11.011
c.980T>G	L327R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L327R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a destabilizing, pathogenic effect. All available predictions are concordant and indicate a likely pathogenic impact. Thus, based on the current computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.409189	Uncertain	0.939	0.490	0.000											-13.403	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	4.46	Destabilizing	0.3	4.75	Destabilizing	4.61	Destabilizing	1.95	Destabilizing	0.619	Likely Pathogenic	-5.28	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.52	Pathogenic	0.00	Affected			0.1281	0.1085		-3	-2	-8.3	43.03
c.982T>A	Y328N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.411940	Structured	0.392519	Uncertain	0.916	0.497	0.000											-13.778	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	2.72	Destabilizing	0.1	3.88	Destabilizing	3.30	Destabilizing	2.06	Destabilizing	0.548	Likely Pathogenic	-8.07	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.53	Pathogenic	0.01	Affected			0.2374	0.0703		-2	-2	-2.2	-49.07
c.982T>C	Y328H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.411940	Structured	0.392519	Uncertain	0.916	0.497	0.000											-10.885	Likely Pathogenic	0.983	Likely Pathogenic	Likely Pathogenic	2.08	Destabilizing	0.0	2.43	Destabilizing	2.26	Destabilizing	1.35	Destabilizing	0.516	Likely Pathogenic	-4.53	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.54	Pathogenic	0.02	Affected			0.2572	0.0703		0	2	-1.9	-26.03
c.982T>G	Y328D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328D is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classifies the substitution as pathogenic; no tool predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.411940	Structured	0.392519	Uncertain	0.916	0.497	0.000											-13.701	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.32	Destabilizing	0.2	4.97	Destabilizing	4.65	Destabilizing	1.87	Destabilizing	0.680	Likely Pathogenic	-8.93	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.52	Pathogenic	0.01	Affected			0.4233	0.0703		-4	-3	-2.2	-48.09
c.983A>C	Y328S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328S is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact on protein stability. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.411940	Structured	0.392519	Uncertain	0.916	0.497	0.000											-12.358	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	3.13	Destabilizing	0.1	4.55	Destabilizing	3.84	Destabilizing	1.80	Destabilizing	0.586	Likely Pathogenic	-8.01	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.54	Pathogenic	0.01	Affected			0.4924	0.2449		-3	-2	0.5	-76.10
c.983A>G	Y328C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (integrating FoldX‑MD and Rosetta outputs) also reports a pathogenic outcome. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.411940	Structured	0.392519	Uncertain	0.916	0.497	0.000											-12.385	Likely Pathogenic	0.975	Likely Pathogenic	Likely Pathogenic	2.52	Destabilizing	0.1	3.74	Destabilizing	3.13	Destabilizing	1.40	Destabilizing	0.523	Likely Pathogenic	-8.01	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.55	Pathogenic	0.01	Affected			0.3154	0.2882		0	-2	3.8	-60.04
c.983A>T	Y328F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.411940	Structured	0.392519	Uncertain	0.916	0.497	0.000											-6.770	Likely Benign	0.444	Ambiguous	Likely Benign	0.34	Likely Benign	0.1	0.43	Likely Benign	0.39	Likely Benign	0.37	Likely Benign	0.330	Likely Benign	-3.21	Deleterious	0.999	Probably Damaging	0.992	Probably Damaging	1.67	Pathogenic	0.16	Tolerated			0.2409	0.3643		7	3	4.1	-16.00
c.985C>A	R329S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R329S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the majority of available predictions support a pathogenic impact. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.376086	Uncertain	0.887	0.479	0.250											-10.731	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	1.80	Ambiguous	0.3	0.78	Ambiguous	1.29	Ambiguous	0.78	Ambiguous	0.192	Likely Benign	-3.36	Deleterious	0.653	Possibly Damaging	0.226	Benign	4.07	Benign	0.04	Affected			0.2886	0.3625		0	-1	3.7	-69.11
c.985C>G	R329G 2D 3DClick to see structure in 3D Viewer AISynGAP1 R329G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls are made by FoldX, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments give an overall pathogenic signal: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta is inconclusive. Taken together, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.376086	Uncertain	0.887	0.479	0.250											-12.426	Likely Pathogenic	0.927	Likely Pathogenic	Ambiguous	2.21	Destabilizing	0.3	1.58	Ambiguous	1.90	Ambiguous	0.92	Ambiguous	0.204	Likely Benign	-4.78	Deleterious	0.653	Possibly Damaging	0.293	Benign	4.03	Benign	0.04	Affected			0.3147	0.3037		-3	-2	4.1	-99.14
c.985C>T	R329C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R329C is reported in gnomAD (ID 6‑33437890‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, Rosetta, Foldetta, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools remain inconclusive: premPS and AlphaMissense‑Optimized. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta) as benign. Overall, six tools favor pathogenicity versus five favor benign, with one uncertain. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.376086	Uncertain	0.887	0.479	0.250								6-33437890-C-T	2	1.24e-6	-9.433	Likely Pathogenic	0.865	Likely Pathogenic	Ambiguous	0.44	Likely Benign	0.1	0.40	Likely Benign	0.42	Likely Benign	0.69	Ambiguous	0.313	Likely Benign	-5.70	Deleterious	0.999	Probably Damaging	0.825	Possibly Damaging	3.98	Benign	0.00	Affected	3.41	15	0.3553	0.2921		-3	-4	7.0	-53.05
c.986G>A	R329H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R329H is listed in ClinVar with an uncertain significance (ClinVar ID 2074400.0) and is present in gnomAD (ID 6‑33437891‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the balance of predictions favors a pathogenic impact, which does not contradict the ClinVar uncertain status but suggests the variant is more likely deleterious. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.376086	Uncertain	0.887	0.479	0.250					Uncertain		1	6-33437891-G-A	2	1.24e-6	-10.154	Likely Pathogenic	0.769	Likely Pathogenic	Likely Benign	2.53	Destabilizing	0.7	0.71	Ambiguous	1.62	Ambiguous	0.82	Ambiguous	0.155	Likely Benign	-3.17	Deleterious	0.995	Probably Damaging	0.778	Possibly Damaging	4.04	Benign	0.05	Affected	3.41	15	0.2955	0.1961		2	0	1.3	-19.05	220.4	81.4	0.1	0.1	0.2	0.3								Uncertain	The guanidinium group of Arg329, located at the end of an anti-parallel β sheet strand (res. Ala322-Asp330), faces the negatively charged lipid bilayer surface. While the residue swap does not cause any apparent negative effects on the protein structure in the variant simulations, it could adversely affect the SynGAP-membrane association in reality. The positively charged Arg329 side chain forms hydrogen bonds with other loop residues (e.g., Ser371, Asp338) that are expected to dynamically interact with the membrane head group region. However, this phenomenon is beyond the scope of the solvent-only simulations to unravel. Notably, histidine can also be double protonated and positively charged, but this alternative protonation state was not considered in the variant simulations.
c.986G>C	R329P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R329P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of algorithms predict a pathogenic outcome: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic,” and premPS is uncertain. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. Overall, the evidence overwhelmingly points to a pathogenic effect for R329P, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.376086	Uncertain	0.887	0.479	0.250											-14.528	Likely Pathogenic	0.965	Likely Pathogenic	Likely Pathogenic	3.06	Destabilizing	0.2	4.99	Destabilizing	4.03	Destabilizing	0.73	Ambiguous	0.350	Likely Benign	-4.28	Deleterious	0.902	Possibly Damaging	0.544	Possibly Damaging	4.00	Benign	0.01	Affected			0.2215	0.4099		0	-2	2.9	-59.07
c.986G>T	R329L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R329L has no ClinVar entry and is not reported in gnomAD. Consensus from standard prediction tools shows a split: benign calls come from REVEL, FoldX, FATHMM, and polyPhen‑2 HumVar, while pathogenic calls arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Predictions marked uncertain (Rosetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of tools lean toward pathogenicity, but the folding‑stability evidence suggests a benign effect. Given the lack of ClinVar annotation, there is no contradiction. The variant is most likely pathogenic based on the preponderance of pathogenic predictions, though the benign folding‑stability result introduces uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.376086	Uncertain	0.887	0.479	0.250											-10.186	Likely Pathogenic	0.907	Likely Pathogenic	Ambiguous	-0.09	Likely Benign	0.4	0.53	Ambiguous	0.22	Likely Benign	0.54	Ambiguous	0.219	Likely Benign	-4.81	Deleterious	0.653	Possibly Damaging	0.361	Benign	4.02	Benign	0.01	Affected			0.1827	0.4121		-3	-2	8.3	-43.03
c.988G>A	D330N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330N missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious interpretation: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic,” while AlphaMissense‑Optimized and Foldetta yield uncertain results and are treated as unavailable. No folding‑stability methods (FoldX, Rosetta, premPS) provide decisive evidence. Overall, the preponderance of pathogenic predictions strongly suggests that D330N is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.380708	Structured	0.360008	Uncertain	0.805	0.488	0.250											-12.993	Likely Pathogenic	0.909	Likely Pathogenic	Ambiguous	1.61	Ambiguous	0.2	0.59	Ambiguous	1.10	Ambiguous	0.59	Ambiguous	0.350	Likely Benign	-3.46	Deleterious	0.980	Probably Damaging	0.721	Possibly Damaging	1.01	Pathogenic	0.02	Affected			0.1252	0.4263		2	1	0.0	-0.98
c.988G>C	D330H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330H missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into three groups: benign predictions are limited to REVEL; pathogenic predictions include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, FoldX, and the SGM‑Consensus (Likely Pathogenic). Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Taken together, the overwhelming majority of evidence points to a pathogenic impact for D330H. This conclusion is not contradicted by any ClinVar annotation, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.380708	Structured	0.360008	Uncertain	0.805	0.488	0.250											-13.926	Likely Pathogenic	0.980	Likely Pathogenic	Likely Pathogenic	2.29	Destabilizing	0.6	1.32	Ambiguous	1.81	Ambiguous	0.61	Ambiguous	0.425	Likely Benign	-4.67	Deleterious	0.998	Probably Damaging	0.961	Probably Damaging	0.96	Pathogenic	0.01	Affected			0.1608	0.4843		1	-1	0.3	22.05
c.988G>T	D330Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D330Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and premPS, whereas the remaining tools—including SGM‑Consensus, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; FoldX is uncertain and therefore not counted. High‑accuracy methods all support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is pathogenic. Taken together, the overwhelming majority of evidence indicates that D330Y is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.380708	Structured	0.360008	Uncertain	0.805	0.488	0.250											-14.200	Likely Pathogenic	0.956	Likely Pathogenic	Likely Pathogenic	1.98	Ambiguous	0.6	2.90	Destabilizing	2.44	Destabilizing	0.35	Likely Benign	0.472	Likely Benign	-6.47	Deleterious	0.998	Probably Damaging	0.948	Probably Damaging	0.89	Pathogenic	0.00	Affected			0.0539	0.4689		-4	-3	2.2	48.09
c.989A>C	D330A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330A missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL and SIFT, while a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Tools with uncertain or inconclusive results—FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized—do not provide definitive evidence. High‑accuracy methods give the following: SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; AlphaMissense‑Optimized is uncertain; Foldetta is also uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for D330A. This conclusion is not contradicted by ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.380708	Structured	0.360008	Uncertain	0.805	0.488	0.250											-14.051	Likely Pathogenic	0.929	Likely Pathogenic	Ambiguous	1.75	Ambiguous	0.3	1.06	Ambiguous	1.41	Ambiguous	0.60	Ambiguous	0.399	Likely Benign	-5.49	Deleterious	0.961	Probably Damaging	0.655	Possibly Damaging	0.93	Pathogenic	0.11	Tolerated			0.4087	0.4476		0	-2	5.3	-44.01
c.989A>G	D330G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D330G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, whereas the majority of algorithms predict a pathogenic impact: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two predictors (AlphaMissense‑Optimized and premPS) give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, classifies the variant as pathogenic. Overall, the preponderance of evidence indicates that D330G is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.380708	Structured	0.360008	Uncertain	0.805	0.488	0.250											-13.064	Likely Pathogenic	0.950	Likely Pathogenic	Ambiguous	2.69	Destabilizing	0.2	2.17	Destabilizing	2.43	Destabilizing	0.63	Ambiguous	0.373	Likely Benign	-5.03	Deleterious	0.980	Probably Damaging	0.782	Possibly Damaging	0.94	Pathogenic	0.01	Affected			0.3935	0.5015		1	-1	3.1	-58.04
c.989A>T	D330V 2D 3DClick to see structure in 3D Viewer AISynGAP1 D330V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and premPS, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, and AlphaMissense‑Default. Uncertain predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are treated as unavailable. High‑accuracy assessments show that the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized and Foldetta provide inconclusive results and are therefore not considered evidence. Overall, the preponderance of evidence points to a pathogenic effect for D330V, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.380708	Structured	0.360008	Uncertain	0.805	0.488	0.250											-13.176	Likely Pathogenic	0.950	Likely Pathogenic	Ambiguous	2.06	Destabilizing	0.5	0.57	Ambiguous	1.32	Ambiguous	0.45	Likely Benign	0.428	Likely Benign	-6.40	Deleterious	0.994	Probably Damaging	0.892	Possibly Damaging	0.89	Pathogenic	0.01	Affected			0.0862	0.4633		-2	-3	7.7	-15.96
c.98A>C	Q33P 2D AIThe SynGAP1 missense variant Q33P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.436712	Uncertain	0.342	0.860	0.375											0.546	Likely Benign	0.049	Likely Benign	Likely Benign										0.098	Likely Benign	-0.75	Neutral	0.000	Benign	0.000	Benign	4.21	Benign	0.00	Affected			0.2445	0.5623		0	-1	1.9	-31.01
c.98A>G	Q33R 2D AIThe SynGAP1 missense variant Q33R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The predictions do not contradict ClinVar status, as ClinVar contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.436712	Uncertain	0.342	0.860	0.375											0.561	Likely Benign	0.171	Likely Benign	Likely Benign										0.035	Likely Benign	-0.82	Neutral	0.084	Benign	0.046	Benign	4.20	Benign	0.00	Affected			0.1936	0.2773		1	1	-1.0	28.06
c.98A>T	Q33L 2D AIThe SynGAP1 missense variant Q33L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.436712	Uncertain	0.342	0.860	0.375											0.253	Likely Benign	0.174	Likely Benign	Likely Benign										0.075	Likely Benign	-1.24	Neutral	0.084	Benign	0.033	Benign	4.18	Benign	0.00	Affected			0.1127	0.6214		-2	-2	7.3	-14.97
c.990C>A	D330E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are Rosetta and FATHMM. The remaining tools—FoldX, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.380708	Structured	0.360008	Uncertain	0.805	0.488	0.250											-3.427	Likely Benign	0.407	Ambiguous	Likely Benign	0.98	Ambiguous	0.2	2.31	Destabilizing	1.65	Ambiguous	0.39	Likely Benign	0.073	Likely Benign	-1.38	Neutral	0.122	Benign	0.030	Benign	0.97	Pathogenic	0.67	Tolerated			0.1464	0.4416		3	2	0.0	14.03
c.990C>G	D330E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are Rosetta and FATHMM. The remaining tools—FoldX, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.380708	Structured	0.360008	Uncertain	0.805	0.488	0.250											-3.427	Likely Benign	0.407	Ambiguous	Likely Benign	0.98	Ambiguous	0.2	2.31	Destabilizing	1.65	Ambiguous	0.39	Likely Benign	0.075	Likely Benign	-1.38	Neutral	0.122	Benign	0.030	Benign	0.97	Pathogenic	0.67	Tolerated			0.1464	0.4416		3	2	0.0	14.03
c.991T>A	S331T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while FoldX and premPS are inconclusive (Uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Taken together, the majority of evidence indicates that S331T is most likely benign, and this conclusion does not contradict the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.433034	Structured	0.346458	Uncertain	0.658	0.475	0.250											-2.474	Likely Benign	0.071	Likely Benign	Likely Benign	0.60	Ambiguous	0.2	-0.10	Likely Benign	0.25	Likely Benign	-0.72	Ambiguous	0.095	Likely Benign	1.13	Neutral	0.003	Benign	0.002	Benign	1.86	Pathogenic	0.98	Tolerated			0.1505	0.4552		1	1	0.1	14.03
c.991T>C	S331P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are Rosetta, polyPhen‑2 HumDiv, and FATHMM. Two tools give inconclusive results: AlphaMissense‑Default and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.433034	Structured	0.346458	Uncertain	0.658	0.475	0.250											-5.104	Likely Benign	0.409	Ambiguous	Likely Benign	0.33	Likely Benign	0.2	2.35	Destabilizing	1.34	Ambiguous	0.44	Likely Benign	0.186	Likely Benign	-1.81	Neutral	0.784	Possibly Damaging	0.390	Benign	1.83	Pathogenic	0.26	Tolerated			0.2306	0.4086		1	-1	-0.8	10.04
c.991T>G	S331A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign majority vote (3 benign vs. 1 pathogenic). High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote) is benign; and Foldetta, combining FoldX‑MD and Rosetta outputs, is benign. No prediction or folding‑stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.433034	Structured	0.346458	Uncertain	0.658	0.475	0.250											-2.199	Likely Benign	0.101	Likely Benign	Likely Benign	0.22	Likely Benign	0.1	-0.08	Likely Benign	0.07	Likely Benign	-0.15	Likely Benign	0.071	Likely Benign	-0.44	Neutral	0.139	Benign	0.060	Benign	1.89	Pathogenic	0.67	Tolerated			0.5314	0.3008	Weaken	1	1	2.6	-16.00
c.992C>T	S331L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only FATHMM predicts pathogenicity, while FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the consensus of the majority of tools supports a benign classification, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.433034	Structured	0.346458	Uncertain	0.658	0.475	0.250											-6.570	Likely Benign	0.219	Likely Benign	Likely Benign	0.54	Ambiguous	0.0	1.06	Ambiguous	0.80	Ambiguous	0.07	Likely Benign	0.090	Likely Benign	-1.72	Neutral	0.270	Benign	0.136	Benign	1.87	Pathogenic	0.58	Tolerated			0.0953	0.4124		-3	-2	4.6	26.08
c.994G>A	D332N 2D 3DClick to see structure in 3D Viewer AISynGAP1 D332N is not reported in ClinVar and is absent from gnomAD. Benign predictions come from REVEL, Rosetta, premPS, and SIFT, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default; SGM‑Consensus indicates a likely pathogenic outcome. FoldX and Foldetta give uncertain results. High‑accuracy tools show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, but the high‑accuracy AlphaMissense‑Optimized result is benign and Foldetta is inconclusive. Thus, the variant is most likely pathogenic based on the collective evidence, and this assessment does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.339168	Structured	0.336528	Uncertain	0.537	0.445	0.375											-10.931	Likely Pathogenic	0.771	Likely Pathogenic	Likely Benign	1.20	Ambiguous	0.1	-0.16	Likely Benign	0.52	Ambiguous	0.49	Likely Benign	0.396	Likely Benign	-4.14	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.32	Pathogenic	0.11	Tolerated			0.0785	0.3963		2	1	0.0	-0.98
c.994G>C	D332H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D332H has no ClinVar entry and is absent from gnomAD. Functional prediction tools that agree on a benign effect are Rosetta and premPS, whereas the majority of predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify the change as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Taken together, the preponderance of evidence indicates that D332H is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.339168	Structured	0.336528	Uncertain	0.537	0.445	0.375											-13.255	Likely Pathogenic	0.973	Likely Pathogenic	Likely Pathogenic	1.50	Ambiguous	0.4	-0.28	Likely Benign	0.61	Ambiguous	0.22	Likely Benign	0.505	Likely Pathogenic	-5.63	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.23	Pathogenic	0.01	Affected			0.1005	0.4542		1	-1	0.3	22.05
c.994G>T	D332Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D332Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and premPS, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a likely pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. Overall, the majority of evidence points to a pathogenic impact for D332Y, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.339168	Structured	0.336528	Uncertain	0.537	0.445	0.375											-14.210	Likely Pathogenic	0.966	Likely Pathogenic	Likely Pathogenic	1.15	Ambiguous	0.6	-0.07	Likely Benign	0.54	Ambiguous	0.41	Likely Benign	0.485	Likely Benign	-7.33	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.20	Pathogenic	0.00	Affected			0.0372	0.4018		-4	-3	2.2	48.09
c.995A>C	D332A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and Rosetta, while the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.339168	Structured	0.336528	Uncertain	0.537	0.445	0.375											-12.290	Likely Pathogenic	0.876	Likely Pathogenic	Ambiguous	1.19	Ambiguous	0.2	0.32	Likely Benign	0.76	Ambiguous	0.54	Ambiguous	0.458	Likely Benign	-6.45	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.24	Pathogenic	0.02	Affected			0.2998	0.4176		0	-2	5.3	-44.01
c.995A>G	D332G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. Predictions that are inconclusive or uncertain are given by FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for D332G, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.339168	Structured	0.336528	Uncertain	0.537	0.445	0.375											-10.844	Likely Pathogenic	0.860	Likely Pathogenic	Ambiguous	1.78	Ambiguous	0.3	0.69	Ambiguous	1.24	Ambiguous	0.63	Ambiguous	0.539	Likely Pathogenic	-5.98	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.31	Pathogenic	0.07	Tolerated			0.3052	0.4765		1	-1	3.1	-58.04
c.995A>T	D332V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, and premPS, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain results come from FoldX, Rosetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.339168	Structured	0.336528	Uncertain	0.537	0.445	0.375											-13.710	Likely Pathogenic	0.933	Likely Pathogenic	Ambiguous	1.39	Ambiguous	0.1	-0.52	Ambiguous	0.44	Likely Benign	0.50	Likely Benign	0.484	Likely Benign	-7.27	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.21	Pathogenic	0.03	Affected			0.0573	0.4132		-2	-3	7.7	-15.96
c.996C>A	D332E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332E missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Overall, the majority of evidence points to a benign effect. This conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.339168	Structured	0.336528	Uncertain	0.537	0.445	0.375											-4.915	Likely Benign	0.320	Likely Benign	Likely Benign	0.50	Ambiguous	0.2	0.04	Likely Benign	0.27	Likely Benign	0.35	Likely Benign	0.191	Likely Benign	-2.66	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.29	Pathogenic	0.24	Tolerated			0.0970	0.3915		3	2	0.0	14.03
c.996C>G	D332E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence supports a benign classification. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.339168	Structured	0.336528	Uncertain	0.537	0.445	0.375											-4.915	Likely Benign	0.320	Likely Benign	Likely Benign	0.50	Ambiguous	0.2	0.04	Likely Benign	0.27	Likely Benign	0.35	Likely Benign	0.188	Likely Benign	-2.66	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.29	Pathogenic	0.24	Tolerated			0.0970	0.3915		3	2	0.0	14.03
c.997A>C	K333Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K333Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and SIFT, while those that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Tools with inconclusive results are AlphaMissense‑Optimized, Foldetta, premPS, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign (combining FoldX‑MD and Rosetta outputs). Overall, the majority of evidence points toward a pathogenic classification, which does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.311707	Structured	0.330781	Uncertain	0.537	0.447	0.500											-11.647	Likely Pathogenic	0.866	Likely Pathogenic	Ambiguous	0.00	Likely Benign	0.1	0.51	Ambiguous	0.26	Likely Benign	0.76	Ambiguous	0.444	Likely Benign	-3.11	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.91	Pathogenic	0.08	Tolerated			0.4015	0.1219		1	1	0.4	-0.04
c.997A>G	K333E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K333E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and SIFT. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact for K333E. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.311707	Structured	0.330781	Uncertain	0.537	0.447	0.500											-14.059	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	-0.06	Likely Benign	0.2	0.30	Likely Benign	0.12	Likely Benign	0.89	Ambiguous	0.488	Likely Benign	-3.21	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.91	Pathogenic	0.09	Tolerated			0.3429	0.1039		0	1	0.4	0.94
c.998A>C	K333T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K333T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include Rosetta, Foldetta, premPS, and SIFT, whereas a larger set—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score—predict a pathogenic impact. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) reports a benign effect. Overall, the majority of evidence points to a pathogenic effect for K333T, and this conclusion does not conflict with any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.311707	Structured	0.330781	Uncertain	0.537	0.447	0.500											-11.358	Likely Pathogenic	0.949	Likely Pathogenic	Ambiguous	0.51	Ambiguous	0.0	-0.15	Likely Benign	0.18	Likely Benign	0.46	Likely Benign	0.506	Likely Pathogenic	-4.82	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.96	Pathogenic	0.08	Tolerated			0.1839	0.3354		0	-1	3.2	-27.07
c.998A>G	K333R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K333R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign”) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign stability. No prediction or folding result is missing or inconclusive. Overall, the majority of evidence points to a benign effect for K333R, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.311707	Structured	0.330781	Uncertain	0.537	0.447	0.500											-4.897	Likely Benign	0.120	Likely Benign	Likely Benign	-0.23	Likely Benign	0.0	0.15	Likely Benign	-0.04	Likely Benign	0.33	Likely Benign	0.232	Likely Benign	-2.02	Neutral	0.999	Probably Damaging	0.995	Probably Damaging	2.01	Pathogenic	0.14	Tolerated			0.4294	0.1134		3	2	-0.6	28.01
c.998A>T	K333I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K333I missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX and premPS, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta and Foldetta give uncertain results. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.311707	Structured	0.330781	Uncertain	0.537	0.447	0.500											-14.517	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	0.30	Likely Benign	0.0	0.95	Ambiguous	0.63	Ambiguous	0.43	Likely Benign	0.544	Likely Pathogenic	-6.49	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.89	Pathogenic	0.03	Affected			0.0931	0.3521		-2	-3	8.4	-15.01
c.999A>C	K333N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K333N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, FoldX, Rosetta, and SIFT, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). The high‑accuracy subset yields contrasting results: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus also indicates Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta stability outputs) predicts benign. premPS is inconclusive. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy predictions are not uniformly supportive of benign status. Therefore, K333N is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.311707	Structured	0.330781	Uncertain	0.537	0.447	0.500											-11.821	Likely Pathogenic	0.989	Likely Pathogenic	Likely Pathogenic	0.30	Likely Benign	0.1	0.42	Likely Benign	0.36	Likely Benign	0.55	Ambiguous	0.359	Likely Benign	-4.03	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.91	Pathogenic	0.13	Tolerated			0.3267	0.1315		1	0	0.4	-14.07
c.999A>T	K333N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K333N has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and SIFT, whereas a larger group predicts pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). The high‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) reports a benign stability change. premPS is inconclusive and is treated as unavailable. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.311707	Structured	0.330781	Uncertain	0.537	0.447	0.500											-11.821	Likely Pathogenic	0.989	Likely Pathogenic	Likely Pathogenic	0.30	Likely Benign	0.1	0.42	Likely Benign	0.36	Likely Benign	0.55	Ambiguous	0.366	Likely Benign	-4.03	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.91	Pathogenic	0.13	Tolerated			0.3267	0.1315		1	0	0.4	-14.07
c.99A>C	Q33H 2D AIThe SynGAP1 missense variant Q33H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.436712	Uncertain	0.342	0.860	0.375											-0.450	Likely Benign	0.133	Likely Benign	Likely Benign										0.054	Likely Benign	-0.95	Neutral	0.704	Possibly Damaging	0.198	Benign	4.16	Benign	0.00	Affected			0.1856	0.4509		3	0	0.3	9.01
c.99A>T	Q33H 2D AIThe SynGAP1 missense variant Q33H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.436712	Uncertain	0.342	0.860	0.375											-0.450	Likely Benign	0.133	Likely Benign	Likely Benign										0.054	Likely Benign	-0.95	Neutral	0.704	Possibly Damaging	0.198	Benign	4.16	Benign	0.00	Affected			0.1856	0.4509		3	0	0.3	9.01
c.9G>C	R3S 2D AIThe SynGAP1 missense variant R3S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect. The prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.550331	Binding	0.358	0.920	0.875											-2.296	Likely Benign	0.310	Likely Benign	Likely Benign										0.111	Likely Benign	-0.53	Neutral	0.115	Benign	0.013	Benign	4.02	Benign	0.00	Affected	4.32	1	0.3148	0.4732		-1	0	3.7	-69.11
c.9G>T	R3S 2D AIThe SynGAP1 missense variant R3S is reported in gnomAD (ID 6‑33420273‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus itself is benign; Foldetta results are not available. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.550331	Binding	0.358	0.920	0.875								6-33420273-G-T	1	6.50e-7	-2.296	Likely Benign	0.310	Likely Benign	Likely Benign										0.111	Likely Benign	-0.53	Neutral	0.115	Benign	0.013	Benign	4.02	Benign	0.00	Affected	4.32	1	0.3148	0.4732		-1	0	3.7	-69.11