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

c.dna	Variant	SGM Consensus	Domain	IUPred2		ANCHOR2		AlphaFold		MobiDB	ClinVar			gnomAD			ESM1b		AlphaMissense			REVEL		PSMutPred			FoldX			Rosetta		Foldetta		PremPS		PROVEAN		PolyPhen-2 HumDiv		PolyPhen-2 HumVar		FATHMM		SIFT				PAM		Physical		SASA		Normalized B-factor backbone		Normalized B-factor sidechain		SynGAP Structural Annotation									DOI
				Score	Prediction	Score	Prediction	pLDDT	disorder	disorder	Clinical Status	Review	Subm.	ID	Allele count	Allele freq.	LLR score	Prediction	Pathogenicity	Class	Optimized	Score	Prediction	IP RF	SP RF	Prediction	Average ΔΔG	Prediction	StdDev	ΔΔG	Prediction	ΔΔG	Prediction	ΔΔG	Prediction	Score	Prediction	pph2_prob	Prediction	pph2_prob	Prediction	Nervous System Score	Prediction	Prediction	Status	Conservation	Sequences	PAM250	PAM120	Hydropathy Δ	MW Δ	Average	Δ	Δ	StdDev	Δ	StdDev	Secondary	Tertiary bonds	Inside out	GAP-Ras interface	At membrane	No effect	MD Alert	Verdict	Description
c.1990T>A	L664M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664M 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 FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also uncertain due to a 2‑vs‑2 split; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of conventional tools predict a pathogenic impact, whereas the high‑accuracy methods do not provide a definitive verdict. Consequently, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.100716	Structured	0.089318	Uncertain	0.937	0.339	0.000							-11.819	Likely Pathogenic	0.807	Likely Pathogenic	Ambiguous	0.429	Likely Benign	0.0620	0.2541		0.49	Likely Benign	0.1	1.35	Ambiguous	0.92	Ambiguous	0.96	Ambiguous	-2.00	Neutral	1.000	Probably Damaging	0.996	Probably Damaging	2.92	Benign	0.01	Affected			4	2	-1.9	18.03
c.1990T>G	L664V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664V 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, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta and Foldetta are uncertain, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic (3 pathogenic vs 1 benign). Foldetta’s stability prediction is uncertain. Overall, the majority of reliable tools predict a pathogenic impact. Therefore, 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	GAP	0.100716	Structured	0.089318	Uncertain	0.937	0.339	0.000							-11.515	Likely Pathogenic	0.755	Likely Pathogenic	Likely Benign	0.378	Likely Benign	0.0984	0.2628		2.01	Destabilizing	0.1	1.13	Ambiguous	1.57	Ambiguous	1.37	Destabilizing	-2.99	Deleterious	0.993	Probably Damaging	0.776	Possibly Damaging	2.91	Benign	0.01	Affected			2	1	0.4	-14.03
c.1991T>C	L664S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664S is listed in ClinVar as Benign (ClinVar ID 2429773.0) and is present in gnomAD (ID 6‑33441250‑T‑C). Prediction tools that report a benign effect include only FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the overwhelming majority of pathogenic predictions—including the high‑accuracy tools—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	GAP	0.100716	Structured	0.089318	Uncertain	0.937	0.339	0.000	Likely Benign		1	6-33441250-T-C	1	6.20e-7	-16.498	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.543	Likely Pathogenic	0.2091	0.0896		3.75	Destabilizing	0.2	3.63	Destabilizing	3.69	Destabilizing	2.77	Destabilizing	-5.99	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	2.85	Benign	0.00	Affected	3.38	28	-3	-2	-4.6	-26.08	215.5	50.1	0.0	0.0	-0.2	0.2						X		Potentially Benign	The iso-butyl side chain of L664, located on an α-helix (res. Ser641-Glu666), hydrophobically interacts with residues in the inter-helix space between three helices (res. Glu617-Asn635, res. Glu582-Met603, and res. Ser641-Glu666), such as Ile589, Phe663, and Met660. In the variant simulations, the hydroxyl group of Ser664 forms hydrogen bonds with the backbone carbonyl oxygen of another helix residue, such as Met660 or Gln661. This interaction is known to destabilize hydrogen bonding in the α-helix, but this effect was not observed in the simulations. Additionally, Ser664 occasionally forms hydrogen bonds with the carboxylate group of Asp586 on another α-helix (res. Glu582-Met603), which could minimally influence the tertiary structure assembly. Despite these interactions, no major negative effects on the protein structure were observed during the simulations.
c.1991T>G	L664W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: benign calls are made only by REVEL and FATHMM, whereas the remaining 13 predictors—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a pathogenic 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	GAP	0.100716	Structured	0.089318	Uncertain	0.937	0.339	0.000							-17.438	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.479	Likely Benign	0.0543	0.2272		7.81	Destabilizing	0.5	3.17	Destabilizing	5.49	Destabilizing	1.57	Destabilizing	-5.99	Deleterious	1.000	Probably Damaging	0.984	Probably Damaging	2.84	Benign	0.00	Affected			-2	-2	-4.7	73.05
c.1992G>C	L664F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664F resides in the GAP domain. ClinVar lists no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Those that predict a pathogenic effect include SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are uncertain (FoldX, Rosetta, Foldetta, premPS) 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 the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.100716	Structured	0.089318	Uncertain	0.937	0.339	0.000							-12.834	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	0.355	Likely Benign	0.0537	0.2311		1.98	Ambiguous	0.3	1.03	Ambiguous	1.51	Ambiguous	0.55	Ambiguous	-3.99	Deleterious	0.999	Probably Damaging	0.895	Possibly Damaging	3.05	Benign	0.03	Affected			2	0	-1.0	34.02
c.1992G>T	L664F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664F resides in the GAP domain. ClinVar lists no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Those that predict a pathogenic effect include SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are uncertain (FoldX, Rosetta, Foldetta, premPS) 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 the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.100716	Structured	0.089318	Uncertain	0.937	0.339	0.000							-12.834	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	0.355	Likely Benign	0.0537	0.2311		1.98	Ambiguous	0.3	1.03	Ambiguous	1.51	Ambiguous	0.55	Ambiguous	-3.99	Deleterious	0.999	Probably Damaging	0.895	Possibly Damaging	3.05	Benign	0.03	Affected			2	0	-1.0	34.02
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	0.529	Likely Pathogenic	0.1366	0.2758		-0.28	Likely Benign	0.1	0.74	Ambiguous	0.23	Likely Benign	-0.13	Likely Benign	-0.44	Neutral	0.787	Possibly Damaging	0.351	Benign	5.89	Benign	0.13	Tolerated			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	0.474	Likely Benign	0.1055	0.1476		0.42	Likely Benign	0.1	-0.26	Likely Benign	0.08	Likely Benign	1.04	Destabilizing	-1.46	Neutral	0.128	Benign	0.039	Benign	5.80	Benign	0.03	Affected			2	2	0.0	0.98
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	0.770	Likely Pathogenic	0.1768	0.3631		3.43	Destabilizing	0.2	7.83	Destabilizing	5.63	Destabilizing	0.81	Ambiguous	-3.56	Deleterious	0.995	Probably Damaging	0.795	Possibly Damaging	5.69	Benign	0.02	Affected			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	0.471	Likely Benign	0.1196	0.1324		-0.38	Likely Benign	0.0	0.21	Likely Benign	-0.09	Likely Benign	-0.91	Ambiguous	1.22	Neutral	0.948	Possibly Damaging	0.533	Possibly Damaging	5.91	Benign	1.00	Tolerated			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	0.687	Likely Pathogenic	0.0573	0.4129		-0.86	Ambiguous	0.5	-1.14	Ambiguous	-1.00	Ambiguous	0.38	Likely Benign	-3.89	Deleterious	0.982	Probably Damaging	0.628	Possibly Damaging	5.70	Benign	0.02	Affected			-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	0.579	Likely Pathogenic	0.0932	0.2558		0.37	Likely Benign	0.2	0.02	Likely Benign	0.20	Likely Benign	0.58	Ambiguous	-2.10	Neutral	0.995	Probably Damaging	0.854	Possibly Damaging	5.71	Benign	0.02	Affected			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	0.579	Likely Pathogenic	0.0932	0.2558		0.37	Likely Benign	0.2	0.02	Likely Benign	0.20	Likely Benign	0.58	Ambiguous	-2.10	Neutral	0.995	Probably Damaging	0.854	Possibly Damaging	5.71	Benign	0.02	Affected			3	0	0.3	9.01
c.1951G>A	E651K 2D AIThe SynGAP1 E651K missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign calls (REVEL, FoldX, premPS, polyPhen‑2 HumVar, SIFT, FATHMM) and pathogenic calls (PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default). Three tools (Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is uncertain; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, 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	GAP	0.088832	Structured	0.365409	Uncertain	0.955	0.340	0.000							-8.714	Likely Pathogenic	0.818	Likely Pathogenic	Ambiguous	0.211	Likely Benign	0.2768	0.5803		0.11	Likely Benign	0.4	1.15	Ambiguous	0.63	Ambiguous	0.08	Likely Benign	-2.92	Deleterious	0.921	Possibly Damaging	0.303	Benign	3.39	Benign	0.17	Tolerated			0	1	-0.4	-0.94
c.1951G>C	E651Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E651Q 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, and FATHMM—all classifying the change as benign. No tool predicts a pathogenic outcome. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign result. Consequently, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.088832	Structured	0.365409	Uncertain	0.955	0.340	0.000							-6.308	Likely Benign	0.476	Ambiguous	Likely Benign	0.158	Likely Benign	0.1438	0.5893		0.13	Likely Benign	0.1	0.15	Likely Benign	0.14	Likely Benign	-0.13	Likely Benign	-1.23	Neutral	0.244	Benign	0.075	Benign	3.34	Benign	0.58	Tolerated			2	2	0.0	-0.98
c.1952A>C	E651A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E651A 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, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicting it as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign impact. Overall, the balance of evidence leans toward a benign classification, and this conclusion does not contradict the absence of a ClinVar record. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.088832	Structured	0.365409	Uncertain	0.955	0.340	0.000							-8.694	Likely Pathogenic	0.610	Likely Pathogenic	Likely Benign	0.396	Likely Benign	0.3926	0.5551		0.38	Likely Benign	0.1	0.52	Ambiguous	0.45	Likely Benign	0.23	Likely Benign	-4.54	Deleterious	0.986	Probably Damaging	0.875	Possibly Damaging	3.33	Benign	0.13	Tolerated			0	-1	5.3	-58.04
c.1952A>G	E651G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E651G 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, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Predictions that are uncertain or unavailable are FoldX, Rosetta, ESM1b, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as unavailable. Overall, the majority of tools (five benign vs. four pathogenic) lean toward a benign interpretation, and this does not contradict the lack of ClinVar annotation. Thus, based on the available predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.088832	Structured	0.365409	Uncertain	0.955	0.340	0.000							-7.596	In-Between	0.591	Likely Pathogenic	Likely Benign	0.444	Likely Benign	0.2908	0.4488		0.66	Ambiguous	0.1	1.61	Ambiguous	1.14	Ambiguous	0.32	Likely Benign	-4.78	Deleterious	0.999	Probably Damaging	0.935	Probably Damaging	3.31	Benign	0.06	Tolerated			0	-2	3.1	-72.06
c.1952A>T	E651V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E651V missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools split in their assessment: benign‑predicted scores include REVEL, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic‑predicted scores come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized and FoldX give uncertain results. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, leans pathogenic (3 pathogenic vs. 1 benign); Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the majority of tools (including the high‑accuracy SGM Consensus) suggest a pathogenic impact, whereas Foldetta and several other predictors indicate benign. 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	GAP	0.088832	Structured	0.365409	Uncertain	0.955	0.340	0.000							-10.025	Likely Pathogenic	0.865	Likely Pathogenic	Ambiguous	0.467	Likely Benign	0.0824	0.6136		0.63	Ambiguous	0.1	0.25	Likely Benign	0.44	Likely Benign	0.21	Likely Benign	-5.53	Deleterious	0.988	Probably Damaging	0.734	Possibly Damaging	3.27	Benign	0.05	Affected			-2	-2	7.7	-29.98
c.1953G>C	E651D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E651D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen2_HumDiv predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign prediction. No prediction tool or stability analysis is 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	GAP	0.088832	Structured	0.365409	Uncertain	0.955	0.340	0.000							-3.220	Likely Benign	0.231	Likely Benign	Likely Benign	0.153	Likely Benign	0.1813	0.3762		0.16	Likely Benign	0.1	0.33	Likely Benign	0.25	Likely Benign	-0.29	Likely Benign	-0.13	Neutral	0.906	Possibly Damaging	0.429	Benign	3.48	Benign	0.53	Tolerated			3	2	0.0	-14.03
c.1953G>T	E651D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E651D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only polyPhen2_HumDiv predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign prediction. No prediction tool or stability analysis is inconclusive or missing. 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	GAP	0.088832	Structured	0.365409	Uncertain	0.955	0.340	0.000							-3.220	Likely Benign	0.231	Likely Benign	Likely Benign	0.153	Likely Benign	0.1813	0.3762		0.16	Likely Benign	0.1	0.33	Likely Benign	0.25	Likely Benign	-0.29	Likely Benign	-0.13	Neutral	0.906	Possibly Damaging	0.429	Benign	3.48	Benign	0.53	Tolerated			3	2	0.0	-14.03
c.1606T>A	L536M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L536M 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, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, 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 uncertain. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.137348	Structured	0.042188	Uncertain	0.931	0.341	0.000							-10.124	Likely Pathogenic	0.462	Ambiguous	Likely Benign	0.571	Likely Pathogenic	0.0937	0.3299		0.37	Likely Benign	0.1	1.18	Ambiguous	0.78	Ambiguous	0.93	Ambiguous	-1.94	Neutral	1.000	Probably Damaging	1.000	Probably Damaging	-1.32	Pathogenic	0.01	Affected			4	2	-1.9	18.03
c.1606T>G	L536V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L536V is listed in ClinVar (ID 1690714.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic verdict. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. No evidence from FoldX or Rosetta alone is available. Overall, the majority of evidence points toward a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.137348	Structured	0.042188	Uncertain	0.931	0.341	0.000	Uncertain		1				-9.014	Likely Pathogenic	0.269	Likely Benign	Likely Benign	0.586	Likely Pathogenic	0.1591	0.3565		1.25	Ambiguous	0.3	1.22	Ambiguous	1.24	Ambiguous	1.20	Destabilizing	-2.81	Deleterious	0.998	Probably Damaging	0.992	Probably Damaging	-1.34	Pathogenic	0.09	Tolerated	3.37	34	2	1	0.4	-14.03	204.7	26.4	0.2	0.0	-0.2	0.2						X		Potentially Benign	Leu536 is located on an α-helix (res. Ala533-Val560) at the membrane interface. The iso-butyl group of Leu536 interacts with nearby hydrophobic residues in the preceding loop (e.g., Val526, Pro528, Cys531). In the variant simulations, the iso-propyl side chain of Val536 forms similar hydrophobic interactions as Leu536 in the WT, causing no negative structural effects.
c.1607T>C	L536S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L536S is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. The only inconclusive result is from FoldX, which is listed as 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, and PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenic. Consequently, the variant is most likely pathogenic 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 Pathogenic	GAP	0.137348	Structured	0.042188	Uncertain	0.931	0.341	0.000							-12.996	Likely Pathogenic	0.968	Likely Pathogenic	Likely Pathogenic	0.909	Likely Pathogenic	0.2849	0.0577		1.45	Ambiguous	0.3	3.08	Destabilizing	2.27	Destabilizing	1.51	Destabilizing	-5.78	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-1.47	Pathogenic	0.00	Affected			-3	-2	-4.6	-26.08
c.1607T>G	L536W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L536W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a deleterious effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; all of these classify the variant as pathogenic. Tools that are inconclusive (FoldX, Rosetta, Foldetta) do not provide evidence for or against pathogenicity. High‑accuracy assessments further support a damaging impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta’s stability analysis is 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	GAP	0.137348	Structured	0.042188	Uncertain	0.931	0.341	0.000							-14.169	Likely Pathogenic	0.970	Likely Pathogenic	Likely Pathogenic	0.897	Likely Pathogenic	0.0843	0.2577		1.07	Ambiguous	0.6	1.31	Ambiguous	1.19	Ambiguous	1.33	Destabilizing	-5.92	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	-1.50	Pathogenic	0.00	Affected			-2	-2	-4.7	73.05
c.1608G>C	L536F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L536F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only Rosetta. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus. Predictions that are uncertain or inconclusive are FoldX, 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 majority of reliable tools predict 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	GAP	0.137348	Structured	0.042188	Uncertain	0.931	0.341	0.000							-10.316	Likely Pathogenic	0.851	Likely Pathogenic	Ambiguous	0.724	Likely Pathogenic	0.0874	0.2804		1.31	Ambiguous	0.5	0.40	Likely Benign	0.86	Ambiguous	0.70	Ambiguous	-3.90	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	-1.36	Pathogenic	0.01	Affected			2	0	-1.0	34.02
c.1608G>T	L536F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L536F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only Rosetta. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus. Predictions that are uncertain or inconclusive are FoldX, 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 majority of reliable tools predict 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	GAP	0.137348	Structured	0.042188	Uncertain	0.931	0.341	0.000							-10.316	Likely Pathogenic	0.851	Likely Pathogenic	Ambiguous	0.722	Likely Pathogenic	0.0874	0.2804		1.31	Ambiguous	0.5	0.40	Likely Benign	0.86	Ambiguous	0.70	Ambiguous	-3.90	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	-1.36	Pathogenic	0.01	Affected			2	0	-1.0	34.02
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	0.859	Likely Pathogenic	0.4206	0.0771		0.85	Ambiguous	0.5	1.15	Ambiguous	1.00	Ambiguous	1.34	Destabilizing	-12.71	Deleterious	0.995	Probably Damaging	0.854	Possibly Damaging	1.52	Pathogenic	0.00	Affected	3.40	14	-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	0.858	Likely Pathogenic	0.4206	0.0771		0.85	Ambiguous	0.5	1.15	Ambiguous	1.00	Ambiguous	1.34	Destabilizing	-12.71	Deleterious	0.995	Probably Damaging	0.854	Possibly Damaging	1.52	Pathogenic	0.00	Affected	3.40	14	-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	0.883	Likely Pathogenic	0.4378	0.1851		2.70	Destabilizing	0.3	2.48	Destabilizing	2.59	Destabilizing	0.83	Ambiguous	-11.80	Deleterious	0.900	Possibly Damaging	0.452	Possibly Damaging	1.52	Pathogenic	0.00	Affected			-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	0.797	Likely Pathogenic	0.4424	0.1418		1.96	Ambiguous	0.2	1.97	Ambiguous	1.97	Ambiguous	0.83	Ambiguous	-12.71	Deleterious	0.900	Possibly Damaging	0.535	Possibly Damaging	1.52	Pathogenic	0.00	Affected			-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	0.799	Likely Pathogenic	0.2370	0.2986		-0.29	Likely Benign	0.3	0.12	Likely Benign	-0.09	Likely Benign	0.44	Likely Benign	-11.80	Deleterious	0.948	Possibly Damaging	0.533	Possibly Damaging	1.52	Pathogenic	0.01	Affected			-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	0.889	Likely Pathogenic	0.3626	0.1617		1.77	Ambiguous	0.4	1.62	Ambiguous	1.70	Ambiguous	0.63	Ambiguous	-11.80	Deleterious	0.999	Probably Damaging	0.887	Possibly Damaging	1.52	Pathogenic	0.00	Affected			-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	0.889	Likely Pathogenic	0.3626	0.1617		1.77	Ambiguous	0.4	1.62	Ambiguous	1.70	Ambiguous	0.63	Ambiguous	-11.80	Deleterious	0.999	Probably Damaging	0.887	Possibly Damaging	1.52	Pathogenic	0.00	Affected			-8	-2	3.4	-83.07
c.1051G>A	A351T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A351T missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Uncertain predictions come from Rosetta and Foldetta. 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 inconclusive. Overall, the majority of evidence supports a benign impact for A351T, 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	0.216401	Structured	0.362025	Uncertain	0.925	0.342	0.000							-6.863	Likely Benign	0.077	Likely Benign	Likely Benign	0.040	Likely Benign	0.1337	0.6713		0.22	Likely Benign	0.0	0.80	Ambiguous	0.51	Ambiguous	0.49	Likely Benign	-2.42	Neutral	0.524	Possibly Damaging	0.138	Benign	1.71	Pathogenic	0.06	Tolerated			1	0	-2.5	30.03
c.1051G>C	A351P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351P 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are Foldetta, PROVEAN, SIFT, FATHMM, and Rosetta. FoldX and premPS give uncertain results. 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‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the lack of ClinVar reporting; thus the variant is most likely benign rather than pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.216401	Structured	0.362025	Uncertain	0.925	0.342	0.000							-6.559	Likely Benign	0.147	Likely Benign	Likely Benign	0.051	Likely Benign	0.1862	0.5472		-0.89	Ambiguous	0.2	6.19	Destabilizing	2.65	Destabilizing	0.62	Ambiguous	-3.08	Deleterious	0.016	Benign	0.007	Benign	1.67	Pathogenic	0.03	Affected			1	-1	-3.4	26.04
c.1051G>T	A351S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351S 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. High‑accuracy methods—AlphaMissense‑Optimized, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (integrating FoldX‑MD and Rosetta)—all report benign or likely benign. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely benign; 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 Benign	C2	0.216401	Structured	0.362025	Uncertain	0.925	0.342	0.000							-4.823	Likely Benign	0.073	Likely Benign	Likely Benign	0.016	Likely Benign	0.2558	0.5334		0.24	Likely Benign	0.0	0.25	Likely Benign	0.25	Likely Benign	0.27	Likely Benign	-1.42	Neutral	0.080	Benign	0.023	Benign	1.88	Pathogenic	0.13	Tolerated			1	1	-2.6	16.00
c.1052C>A	A351D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A351D 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, SIFT, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and FATHMM; AlphaMissense‑Default and ESM1b are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward pathogenic due to two pathogenic and two uncertain calls. Overall, the majority of tools predict a benign outcome, and this does not contradict the lack of ClinVar annotation. Thus, based on the available predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.216401	Structured	0.362025	Uncertain	0.925	0.342	0.000							-7.917	In-Between	0.543	Ambiguous	Likely Benign	0.114	Likely Benign	0.1535	0.1386		-0.02	Likely Benign	0.0	-0.12	Likely Benign	-0.07	Likely Benign	0.49	Likely Benign	-3.61	Deleterious	0.842	Possibly Damaging	0.321	Benign	1.77	Pathogenic	0.11	Tolerated			0	-2	-5.3	44.01
c.1052C>G	A351G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A351G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign vs two pathogenic), and Foldetta is uncertain. Taken together, the majority of available predictions lean toward a benign impact, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.216401	Structured	0.362025	Uncertain	0.925	0.342	0.000							-4.983	Likely Benign	0.089	Likely Benign	Likely Benign	0.041	Likely Benign	0.2298	0.4737		0.39	Likely Benign	0.0	1.04	Ambiguous	0.72	Ambiguous	0.55	Ambiguous	-2.53	Deleterious	0.688	Possibly Damaging	0.138	Benign	1.77	Pathogenic	0.04	Affected			1	0	-2.2	-14.03
c.1052C>T	A351V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351V is not reported in ClinVar and is absent from gnomAD. Computational predictions cluster into two groups: benign (REVEL, FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen2_HumVar) and pathogenic (PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, FATHMM, SGM‑Consensus). High‑accuracy tools give a mixed signal: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the balance of evidence leans toward a benign effect, but the presence of several pathogenic predictions introduces uncertainty. The variant is most likely benign based on the current computational data, 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	0.216401	Structured	0.362025	Uncertain	0.925	0.342	0.000							-9.002	Likely Pathogenic	0.124	Likely Benign	Likely Benign	0.052	Likely Benign	0.1140	0.6565		0.09	Likely Benign	0.0	0.19	Likely Benign	0.14	Likely Benign	0.29	Likely Benign	-2.84	Deleterious	0.915	Possibly Damaging	0.321	Benign	1.66	Pathogenic	0.03	Affected			0	0	2.4	28.05
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	0.487	Likely Benign	0.2828	0.5591		2.82	Destabilizing	0.5	0.73	Ambiguous	1.78	Ambiguous	0.72	Ambiguous	-5.52	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.73	Pathogenic	0.07	Tolerated			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	0.572	Likely Pathogenic	0.0964	0.5097		1.99	Ambiguous	0.5	0.52	Ambiguous	1.26	Ambiguous	0.55	Ambiguous	-7.35	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.70	Pathogenic	0.04	Affected			-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	0.656	Likely Pathogenic	0.1378	0.4574		2.60	Destabilizing	0.4	1.09	Ambiguous	1.85	Ambiguous	0.67	Ambiguous	-8.27	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.66	Pathogenic	0.00	Affected			-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	0.523	Likely Pathogenic	0.1889	0.2678		2.89	Destabilizing	0.5	-0.03	Likely Benign	1.43	Ambiguous	0.75	Ambiguous	-6.43	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.88	Pathogenic	0.06	Tolerated			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	0.373	Likely Benign	0.3949	0.4974		2.44	Destabilizing	0.4	0.30	Likely Benign	1.37	Ambiguous	0.71	Ambiguous	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.69	Pathogenic	0.09	Tolerated			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	0.531	Likely Pathogenic	0.1256	0.3910		4.55	Destabilizing	0.5	3.61	Destabilizing	4.08	Destabilizing	0.76	Ambiguous	-8.27	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.67	Pathogenic	0.00	Affected			-1	-3	4.6	42.08
c.1603A>C	S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R is not reported in ClinVar and is present in gnomAD (ID 6‑33438846‑A‑C). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results come from AlphaMissense‑Optimized, Foldetta, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the balance of evidence, especially the SGM Consensus, points to a pathogenic interpretation. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.236433	Structured	0.041365	Uncertain	0.918	0.343	0.000				6-33438846-A-C	3	1.86e-6	-9.363	Likely Pathogenic	0.913	Likely Pathogenic	Ambiguous	0.390	Likely Benign	0.1086	0.3743		-0.37	Likely Benign	0.0	-0.97	Ambiguous	-0.67	Ambiguous	0.64	Ambiguous	-1.99	Neutral	0.830	Possibly Damaging	0.274	Benign	-1.23	Pathogenic	0.19	Tolerated	3.37	35	-1	0	-3.7	69.11
c.1603A>G	S535G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535G 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, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Uncertain or inconclusive 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 benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for S535G, 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 Benign	GAP	0.236433	Structured	0.041365	Uncertain	0.918	0.343	0.000							-4.619	Likely Benign	0.143	Likely Benign	Likely Benign	0.247	Likely Benign	0.2858	0.4644		0.19	Likely Benign	0.0	0.93	Ambiguous	0.56	Ambiguous	0.64	Ambiguous	-1.75	Neutral	0.606	Possibly Damaging	0.114	Benign	-1.30	Pathogenic	0.19	Tolerated			1	0	0.4	-30.03
c.1603A>T	S535C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535C 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 Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. Two tools, FoldX and ESM1b, return uncertain results. 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 predictions lean toward a benign effect, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.236433	Structured	0.041365	Uncertain	0.918	0.343	0.000							-7.526	In-Between	0.165	Likely Benign	Likely Benign	0.500	Likely Pathogenic	0.1139	0.5633		0.57	Ambiguous	0.1	0.25	Likely Benign	0.41	Likely Benign	0.47	Likely Benign	-2.96	Deleterious	0.933	Possibly Damaging	0.419	Benign	-1.33	Pathogenic	0.02	Affected			0	-1	3.3	16.06
c.1604G>A	S535N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Across the broad panel of in‑silico predictors, 13 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign”) uniformly predict a benign effect, whereas only FATHMM assigns a pathogenic label. High‑accuracy assessments corroborate 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) predicts benign stability. Thus, the variant is most likely benign based on the available predictions, 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 Benign	GAP	0.236433	Structured	0.041365	Uncertain	0.918	0.343	0.000							-4.957	Likely Benign	0.196	Likely Benign	Likely Benign	0.176	Likely Benign	0.1390	0.4784		-0.46	Likely Benign	0.2	-0.26	Likely Benign	-0.36	Likely Benign	0.18	Likely Benign	-0.05	Neutral	0.070	Benign	0.032	Benign	-1.25	Pathogenic	0.29	Tolerated			1	1	-2.7	27.03
c.1604G>C	S535T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535T is catalogued in ClinVar as benign (ClinVar ID 537005.0) and is observed in gnomAD (variant ID 6‑33438847‑G‑C). In silico 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 return benign scores. Only FATHMM predicts 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 confirm this: AlphaMissense‑Optimized is benign; the SGM Consensus is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Overall, the consensus of predictive tools and high‑accuracy methods indicates that the variant is most likely benign, consistent with its ClinVar classification and presence in gnomAD. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.236433	Structured	0.041365	Uncertain	0.918	0.343	0.000	Benign		1	6-33438847-G-C	14	8.67e-6	-3.886	Likely Benign	0.069	Likely Benign	Likely Benign	0.177	Likely Benign	0.1456	0.6291		0.45	Likely Benign	0.1	-0.27	Likely Benign	0.09	Likely Benign	0.17	Likely Benign	-0.81	Neutral	0.000	Benign	0.001	Benign	-1.25	Pathogenic	0.25	Tolerated	3.37	35	1	1	0.1	14.03	201.3	-17.3	-0.1	0.7	-0.2	0.1						X		Potentially Benign	Ser535 is located near the terminal end of an α-helix (res. Ala533-Val560) close to the membrane interface. In the WT simulations, the hydroxyl side chain of Ser535 forms hydrogen bonds with nearby residues (e.g., His539, Glu538) without any specific interactions. These hydrogen bonds disrupt the structure of the terminal end of the α-helix (Ala533-Ser535), causing it to weaken or unfold during the WT simulations. In the variant simulations, Thr535, a hydrophilic residue with a hydroxyl group of almost the same size as Ser, interacts more frequently with the preceding loop residues (e.g., Thr532, Cys531) due to its longer side chain. Regardless, the residue swap is tolerated in the simulations with no negative effects. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations.	10.1016/j.ajhg.2020.11.011
c.1604G>T	S535I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the preponderance of evidence points to a benign impact for S535I, 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.		GAP	0.236433	Structured	0.041365	Uncertain	0.918	0.343	0.000							-8.073	Likely Pathogenic	0.330	Likely Benign	Likely Benign	0.246	Likely Benign	0.1123	0.5571		0.50	Ambiguous	0.0	-0.42	Likely Benign	0.04	Likely Benign	0.14	Likely Benign	-2.49	Neutral	0.004	Benign	0.004	Benign	-1.25	Pathogenic	0.07	Tolerated			-1	-2	5.3	26.08
c.1605T>A	S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, and SIFT, while pathogenic calls come from polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is also inconclusive. Overall, the balance of evidence, particularly the SGM Consensus, points to a pathogenic effect. 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	GAP	0.236433	Structured	0.041365	Uncertain	0.918	0.343	0.000							-9.363	Likely Pathogenic	0.913	Likely Pathogenic	Ambiguous	0.432	Likely Benign	0.1086	0.3743		-0.37	Likely Benign	0.0	-0.97	Ambiguous	-0.67	Ambiguous	0.64	Ambiguous	-1.99	Neutral	0.830	Possibly Damaging	0.274	Benign	-1.23	Pathogenic	0.19	Tolerated	3.37	35	-1	0	-3.7	69.11
c.1605T>G	S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, and SIFT, while pathogenic calls come from polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is also inconclusive. Overall, the balance of evidence, particularly the SGM Consensus, points to a pathogenic effect. 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	GAP	0.236433	Structured	0.041365	Uncertain	0.918	0.343	0.000							-9.363	Likely Pathogenic	0.913	Likely Pathogenic	Ambiguous	0.432	Likely Benign	0.1086	0.3743		-0.37	Likely Benign	0.0	-0.97	Ambiguous	-0.67	Ambiguous	0.64	Ambiguous	-1.99	Neutral	0.830	Possibly Damaging	0.274	Benign	-1.23	Pathogenic	0.19	Tolerated	3.37	35	-1	0	-3.7	69.11
c.1936C>A	L646M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646M 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. Predictions that are inconclusive are FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, while Foldetta’s stability analysis remains uncertain. Overall, the evidence overwhelmingly supports a benign classification for this variant, 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 Benign	GAP	0.048328	Structured	0.303751	Uncertain	0.941	0.344	0.000							-1.911	Likely Benign	0.152	Likely Benign	Likely Benign	0.106	Likely Benign	0.2041	0.3427		0.70	Ambiguous	0.1	1.66	Ambiguous	1.18	Ambiguous	-1.10	Stabilizing	1.86	Neutral	0.211	Benign	0.055	Benign	3.57	Benign	1.00	Tolerated			4	2	-1.9	18.03
c.1936C>G	L646V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and FATHMM, whereas pathogenic predictions arise from FoldX, Rosetta, premPS, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (3 benign vs 1 pathogenic votes). High‑accuracy assessments further indicate AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools, including the high‑accuracy methods, lean toward 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	GAP	0.048328	Structured	0.303751	Uncertain	0.941	0.344	0.000							-8.995	Likely Pathogenic	0.332	Likely Benign	Likely Benign	0.125	Likely Benign	0.2200	0.3767		3.82	Destabilizing	0.2	2.01	Destabilizing	2.92	Destabilizing	1.41	Destabilizing	-1.40	Neutral	0.040	Benign	0.021	Benign	3.21	Benign	0.03	Affected			2	1	0.4	-14.03
c.1937T>A	L646Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L646Q lies in the GAP domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect are REVEL, FATHMM, and AlphaMissense‑Optimized. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Taken together, the overwhelming majority of evidence indicates that 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	GAP	0.048328	Structured	0.303751	Uncertain	0.941	0.344	0.000							-12.735	Likely Pathogenic	0.752	Likely Pathogenic	Likely Benign	0.462	Likely Benign	0.2090	0.1963		3.23	Destabilizing	0.1	3.04	Destabilizing	3.14	Destabilizing	2.12	Destabilizing	-2.78	Deleterious	0.994	Probably Damaging	0.790	Possibly Damaging	3.17	Benign	0.00	Affected			-2	-2	-7.3	14.97
c.1937T>C	L646P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646P 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 all other evaluated algorithms—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 further support a deleterious impact: 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) 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 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	GAP	0.048328	Structured	0.303751	Uncertain	0.941	0.344	0.000							-12.956	Likely Pathogenic	0.970	Likely Pathogenic	Likely Pathogenic	0.604	Likely Pathogenic	0.3481	0.1874		7.34	Destabilizing	0.5	12.08	Destabilizing	9.71	Destabilizing	2.72	Destabilizing	-4.55	Deleterious	0.999	Probably Damaging	0.926	Probably Damaging	3.17	Benign	0.00	Affected			-3	-3	-5.4	-16.04
c.1937T>G	L646R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic calls are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, 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 further support a deleterious effect: AlphaMissense‑Optimized is uncertain, SGM Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the preponderance of evidence points to a pathogenic effect for L646R, 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	GAP	0.048328	Structured	0.303751	Uncertain	0.941	0.344	0.000							-12.393	Likely Pathogenic	0.920	Likely Pathogenic	Ambiguous	0.455	Likely Benign	0.2304	0.1405		4.44	Destabilizing	0.2	3.94	Destabilizing	4.19	Destabilizing	2.75	Destabilizing	-3.56	Deleterious	0.014	Benign	0.002	Benign	3.17	Benign	0.03	Affected			-3	-2	-8.3	43.03
c.1945A>C	M649L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M649L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN and AlphaMissense‑Default, while premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta predicts benign stability. Overall, the preponderance of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar assertion, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.051831	Structured	0.360413	Uncertain	0.962	0.345	0.000							-5.210	Likely Benign	0.745	Likely Pathogenic	Likely Benign	0.294	Likely Benign	0.1361	0.4025		0.19	Likely Benign	0.4	0.26	Likely Benign	0.23	Likely Benign	0.64	Ambiguous	-2.99	Deleterious	0.009	Benign	0.007	Benign	3.73	Benign	0.15	Tolerated			4	2	1.9	-18.03
c.1945A>G	M649V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M649V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. With 8 pathogenic versus 3 benign predictions, the overall evidence favors a deleterious effect. Therefore, the variant is most likely pathogenic, and this conclusion 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	GAP	0.051831	Structured	0.360413	Uncertain	0.962	0.345	0.000							-9.907	Likely Pathogenic	0.887	Likely Pathogenic	Ambiguous	0.370	Likely Benign	0.2389	0.3121		2.84	Destabilizing	0.3	2.55	Destabilizing	2.70	Destabilizing	1.05	Destabilizing	-3.99	Deleterious	0.997	Probably Damaging	0.735	Possibly Damaging	3.40	Benign	0.06	Tolerated			2	1	2.3	-32.06
c.1945A>T	M649L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M649L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and AlphaMissense‑Default, while premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta (combining FoldX‑MD and Rosetta outputs) 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 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.		GAP	0.051831	Structured	0.360413	Uncertain	0.962	0.345	0.000							-5.210	Likely Benign	0.745	Likely Pathogenic	Likely Benign	0.294	Likely Benign	0.1361	0.4025		0.19	Likely Benign	0.4	0.26	Likely Benign	0.23	Likely Benign	0.64	Ambiguous	-2.99	Deleterious	0.009	Benign	0.007	Benign	3.73	Benign	0.15	Tolerated			4	2	1.9	-18.03
c.1946T>A	M649K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M649K is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign calls are limited to polyPhen‑2 (HumVar) and FATHMM. High‑accuracy methods reinforce the pathogenic consensus: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. 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 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	GAP	0.051831	Structured	0.360413	Uncertain	0.962	0.345	0.000							-14.533	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	0.614	Likely Pathogenic	0.1438	0.1079		3.42	Destabilizing	0.0	6.19	Destabilizing	4.81	Destabilizing	1.79	Destabilizing	-5.98	Deleterious	0.968	Probably Damaging	0.382	Benign	3.34	Benign	0.01	Affected			0	-1	-5.8	-3.02
c.1946T>C	M649T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M649T 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 all other evaluated algorithms—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 scores the variant as pathogenic; 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 classifies the variant as pathogenic. Based on the collective evidence, 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	GAP	0.051831	Structured	0.360413	Uncertain	0.962	0.345	0.000							-11.916	Likely Pathogenic	0.988	Likely Pathogenic	Likely Pathogenic	0.531	Likely Pathogenic	0.1732	0.1615		3.19	Destabilizing	0.2	3.45	Destabilizing	3.32	Destabilizing	1.92	Destabilizing	-5.98	Deleterious	0.999	Probably Damaging	0.779	Possibly Damaging	3.35	Benign	0.00	Affected			-1	-1	-2.6	-30.09
c.1946T>G	M649R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M649R 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 all other evaluated algorithms—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 assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a pathogenic effect. Based on the collective 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	GAP	0.051831	Structured	0.360413	Uncertain	0.962	0.345	0.000							-14.827	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.595	Likely Pathogenic	0.1635	0.1228		5.02	Destabilizing	0.1	5.97	Destabilizing	5.50	Destabilizing	2.09	Destabilizing	-5.98	Deleterious	0.985	Probably Damaging	0.464	Possibly Damaging	3.33	Benign	0.00	Affected			0	-1	-6.4	24.99
c.1947G>A	M649I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M649I has no ClinVar entry and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas the majority of tools (SGM‑Consensus, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta is inconclusive and is not counted. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Taken together, the preponderance of evidence supports a pathogenic classification for M649I, and this conclusion does not conflict with ClinVar status, which is currently unavailable. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.051831	Structured	0.360413	Uncertain	0.962	0.345	0.000							-9.361	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	0.449	Likely Benign	0.1215	0.2980		2.42	Destabilizing	0.2	1.96	Ambiguous	2.19	Destabilizing	1.01	Destabilizing	-3.99	Deleterious	0.672	Possibly Damaging	0.093	Benign	3.40	Benign	0.02	Affected	3.38	27	2	1	2.6	-18.03	243.7	21.5	0.0	0.1	0.0	0.1							X	Potentially Benign	The thioether side chain of Met649, located on an α helix (res. Ser641-Glu666), bridges Phe652, Phe648, and Phe639 in an inter-helix hydrophobic cavity in the WT simulations. In the variant simulations, the sec-butyl side chain of Ile649 maintains hydrophobic interactions with nearby residues, with no significant effects on the protein structure.However, methionine is known as a bridging motif for aromatic residues, and these Met-aromatic interactions are lost in the variant. Indeed, in the second variant simulation,the bridging of Phe652, Phe648 and Phe639 is completely lost. In reality, the effect could be more severe on the structure during the protein folding.
c.1947G>C	M649I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M649I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas the majority of other in silico predictors (FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) report a pathogenic outcome; Rosetta is inconclusive. High‑accuracy assessments further support a deleterious impact: 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. Overall, the preponderance of evidence points to a pathogenic effect for M649I, which 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 Pathogenic	GAP	0.051831	Structured	0.360413	Uncertain	0.962	0.345	0.000	Uncertain		1				-9.361	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	0.449	Likely Benign	0.1215	0.2980		2.42	Destabilizing	0.2	1.96	Ambiguous	2.19	Destabilizing	1.01	Destabilizing	-3.99	Deleterious	0.672	Possibly Damaging	0.093	Benign	3.40	Benign	0.02	Affected	3.38	27	2	1	2.6	-18.03	243.7	21.5	0.0	0.1	0.0	0.1							X	Potentially Benign	The thioether side chain of Met649, located on an α helix (res. Ser641-Glu666), bridges Phe652, Phe648, and Phe639 in an inter-helix hydrophobic cavity in the WT simulations. In the variant simulations, the sec-butyl side chain of Ile649 maintains hydrophobic interactions with nearby residues, with no significant effects on the protein structure.However, methionine is known as a bridging motif for aromatic residues, and these Met-aromatic interactions are lost in the variant. Indeed, in the second variant simulation,the bridging of Phe652, Phe648 and Phe639 is completely lost. In reality, the effect could be more severe on the structure during the protein folding.
c.1947G>T	M649I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M649I 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, whereas pathogenic calls are made by FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, votes strongly for pathogenicity (3/4 pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) is likely pathogenic, and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. Rosetta alone is uncertain and is treated as unavailable. Overall, the majority of evidence points to a pathogenic impact, 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	GAP	0.051831	Structured	0.360413	Uncertain	0.962	0.345	0.000							-9.361	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	0.449	Likely Benign	0.1215	0.2980		2.42	Destabilizing	0.2	1.96	Ambiguous	2.19	Destabilizing	1.01	Destabilizing	-3.99	Deleterious	0.672	Possibly Damaging	0.093	Benign	3.40	Benign	0.02	Affected	3.38	27	2	1	2.6	-18.03	243.7	21.5	0.0	0.1	0.0	0.1							X	Potentially Benign	The thioether side chain of Met649, located on an α helix (res. Ser641-Glu666), bridges Phe652, Phe648, and Phe639 in an inter-helix hydrophobic cavity in the WT simulations. In the variant simulations, the sec-butyl side chain of Ile649 maintains hydrophobic interactions with nearby residues, with no significant effects on the protein structure.However, methionine is known as a bridging motif for aromatic residues, and these Met-aromatic interactions are lost in the variant. Indeed, in the second variant simulation,the bridging of Phe652, Phe648 and Phe639 is completely lost. In reality, the effect could be more severe on the structure during the protein folding.
c.2101C>A	P701T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P701T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a tolerated change. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive, and FoldX alone is uncertain, so these results are treated as unavailable. Overall, the evidence strongly supports a benign effect for P701T, 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 Benign	GAP	0.074921	Structured	0.404318	Uncertain	0.918	0.345	0.000							-6.920	Likely Benign	0.272	Likely Benign	Likely Benign	0.144	Likely Benign	0.1398	0.4160		1.61	Ambiguous	0.0	0.11	Likely Benign	0.86	Ambiguous	-0.18	Likely Benign	-0.43	Neutral	0.084	Benign	0.050	Benign	3.44	Benign	0.70	Tolerated			0	-1	0.9	3.99
c.2101C>G	P701A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P701A 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; all of these classify the substitution as benign. No tool predicts a pathogenic outcome. Predictions that are inconclusive are FoldX (uncertain) and Foldetta (uncertain). High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta remains uncertain. Based on the collective evidence, the variant is most likely benign, and this conclusion 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	GAP	0.074921	Structured	0.404318	Uncertain	0.918	0.345	0.000							-6.836	Likely Benign	0.217	Likely Benign	Likely Benign	0.058	Likely Benign	0.3143	0.3765		1.35	Ambiguous	0.0	0.23	Likely Benign	0.79	Ambiguous	-0.16	Likely Benign	-0.55	Neutral	0.002	Benign	0.011	Benign	3.50	Benign	0.82	Tolerated			1	-1	3.4	-26.04
c.2101C>T	P701S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P701S (ClinVar ID 2995856.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (ID 6‑33441360‑C‑T). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). No tool in the dataset predicts a pathogenic outcome; all remaining predictions are either benign or uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.074921	Structured	0.404318	Uncertain	0.918	0.345	0.000	Uncertain		1	6-33441360-C-T	3	1.86e-6	-4.375	Likely Benign	0.221	Likely Benign	Likely Benign	0.132	Likely Benign	0.3149	0.3782		1.33	Ambiguous	0.0	0.12	Likely Benign	0.73	Ambiguous	-0.36	Likely Benign	0.78	Neutral	0.044	Benign	0.025	Benign	3.48	Benign	1.00	Tolerated	3.47	10	-1	1	0.8	-10.04																10.1016/j.ajhg.2020.11.011
c.2102C>A	P701H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P701H 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, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. 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 benign, and Foldetta as uncertain. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict the ClinVar status, which contains no pathogenic assertion for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.074921	Structured	0.404318	Uncertain	0.918	0.345	0.000							-8.786	Likely Pathogenic	0.553	Ambiguous	Likely Benign	0.141	Likely Benign	0.1495	0.3495		1.40	Ambiguous	0.0	-0.41	Likely Benign	0.50	Ambiguous	0.62	Ambiguous	-2.12	Neutral	0.936	Possibly Damaging	0.539	Possibly Damaging	3.38	Benign	0.03	Affected			0	-2	-1.6	40.02
c.2102C>G	P701R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P701R 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, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Two tools (FoldX and premPS) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta (combining FoldX‑MD and Rosetta outputs) as benign, while 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 points to a benign impact, and this conclusion 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.		GAP	0.074921	Structured	0.404318	Uncertain	0.918	0.345	0.000							-11.060	Likely Pathogenic	0.779	Likely Pathogenic	Likely Benign	0.088	Likely Benign	0.1365	0.2500		0.54	Ambiguous	0.0	-0.19	Likely Benign	0.18	Likely Benign	0.65	Ambiguous	-2.09	Neutral	0.784	Possibly Damaging	0.278	Benign	3.41	Benign	0.08	Tolerated			0	-2	-2.9	59.07
c.2102C>T	P701L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P701L 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, premPS, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and ESM1b. The remaining tools (FoldX, Rosetta, 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 benign. Overall, the majority of predictions (7 benign vs. 3 pathogenic) and the two high‑accuracy benign calls suggest that the variant is most likely benign. This conclusion does not contradict any ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.074921	Structured	0.404318	Uncertain	0.918	0.345	0.000							-10.185	Likely Pathogenic	0.515	Ambiguous	Likely Benign	0.116	Likely Benign	0.2018	0.5546		1.15	Ambiguous	0.0	-0.68	Ambiguous	0.24	Likely Benign	0.12	Likely Benign	-3.04	Deleterious	0.642	Possibly Damaging	0.087	Benign	3.50	Benign	0.09	Tolerated			-3	-3	5.4	16.04
c.2104C>A	Q702K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q702K 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and Foldetta as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence supports a benign 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.		GAP	0.074921	Structured	0.397258	Uncertain	0.907	0.345	0.000							-8.750	Likely Pathogenic	0.338	Likely Benign	Likely Benign	0.224	Likely Benign	0.1346	0.2524		-0.23	Likely Benign	0.0	0.26	Likely Benign	0.02	Likely Benign	0.08	Likely Benign	-2.86	Deleterious	0.863	Possibly Damaging	0.773	Possibly Damaging	3.46	Benign	0.08	Tolerated			1	1	-0.4	0.04
c.2104C>G	Q702E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q702E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Rosetta and Foldetta give uncertain results. High‑accuracy methods further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign; Foldetta remains inconclusive. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.074921	Structured	0.397258	Uncertain	0.907	0.345	0.000							-10.974	Likely Pathogenic	0.230	Likely Benign	Likely Benign	0.196	Likely Benign	0.1021	0.1609		0.48	Likely Benign	0.0	0.72	Ambiguous	0.60	Ambiguous	0.27	Likely Benign	-2.27	Neutral	0.989	Probably Damaging	0.930	Probably Damaging	3.55	Benign	0.15	Tolerated			2	2	0.0	0.98
c.2105A>C	Q702P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q702P 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; FoldX is uncertain and therefore not counted. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, more tools predict pathogenicity (7) than benignity (5), and the high‑accuracy pathogenic prediction from Foldetta further supports this. Consequently, the variant is most likely pathogenic, 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.		GAP	0.074921	Structured	0.397258	Uncertain	0.907	0.345	0.000							-10.361	Likely Pathogenic	0.324	Likely Benign	Likely Benign	0.369	Likely Benign	0.1877	0.3371		1.76	Ambiguous	0.1	7.05	Destabilizing	4.41	Destabilizing	-0.04	Likely Benign	-4.71	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	3.42	Benign	0.05	Affected			0	-1	1.9	-31.01
c.2105A>G	Q702R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q702R 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, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Predictions that remain inconclusive are Rosetta, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to equal benign and pathogenic signals. Overall, the majority of available predictions lean toward 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.		GAP	0.074921	Structured	0.397258	Uncertain	0.907	0.345	0.000	Uncertain		1				-7.894	In-Between	0.348	Ambiguous	Likely Benign	0.294	Likely Benign	0.1225	0.0605		-0.31	Likely Benign	0.1	0.63	Ambiguous	0.16	Likely Benign	0.13	Likely Benign	-3.14	Deleterious	0.909	Possibly Damaging	0.889	Possibly Damaging	3.43	Benign	0.02	Affected	3.47	10	1	1	-1.0	28.06	270.3	-52.9	0.0	0.0	0.0	0.1		X						Potentially Pathogenic	The carboxamide side chain of Gln702 is located at the end and outer surface of an α-helix (res. Leu685-Gln702), where it does not directly form hydrogen bonds with any residues in the WT simulations. In the variant simulations, the positively charged guanidinium group of Arg702 forms a salt bridge with the negatively charged carboxylate group of Glu698 on the same helix and/or hydrogen bonds with the backbone carbonyl group of Ala438 on an opposite α-helix (res. Tyr428-Glu436). Consequently, the residue swap could strengthen the tertiary structure assembly, which could have either positive or negative effects on its function.
c.2105A>T	Q702L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q702L 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, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. 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 balance of evidence leans toward a benign 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.		GAP	0.074921	Structured	0.397258	Uncertain	0.907	0.345	0.000							-9.954	Likely Pathogenic	0.149	Likely Benign	Likely Benign	0.392	Likely Benign	0.0584	0.3628		-0.13	Likely Benign	0.0	0.09	Likely Benign	-0.02	Likely Benign	0.16	Likely Benign	-5.66	Deleterious	0.939	Possibly Damaging	0.838	Possibly Damaging	3.42	Benign	0.00	Affected			-2	-2	7.3	-14.97
c.2106G>C	Q702H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q702H 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, Rosetta, Foldetta, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain results come from FoldX and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign outcome (2 benign vs. 1 pathogenic vote), and Foldetta predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely benign, 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.		GAP	0.074921	Structured	0.397258	Uncertain	0.907	0.345	0.000							-7.966	In-Between	0.211	Likely Benign	Likely Benign	0.233	Likely Benign	0.0811	0.2555		0.55	Ambiguous	0.0	0.13	Likely Benign	0.34	Likely Benign	0.12	Likely Benign	-4.11	Deleterious	0.982	Probably Damaging	0.947	Probably Damaging	3.45	Benign	0.00	Affected			3	0	0.3	9.01
c.2106G>T	Q702H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q702H 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, Rosetta, Foldetta, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain results come from FoldX and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign outcome (2 benign vs. 1 pathogenic vote), and Foldetta predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely benign, 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.		GAP	0.074921	Structured	0.397258	Uncertain	0.907	0.345	0.000							-7.966	In-Between	0.211	Likely Benign	Likely Benign	0.233	Likely Benign	0.0811	0.2555		0.55	Ambiguous	0.0	0.13	Likely Benign	0.34	Likely Benign	0.12	Likely Benign	-4.11	Deleterious	0.982	Probably Damaging	0.947	Probably Damaging	3.45	Benign	0.00	Affected			3	0	0.3	9.01
c.622C>A	P208T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P208T 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta; premPS and Rosetta are uncertain. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta also predicts pathogenic. With the majority of tools, including the high‑accuracy ones, indicating pathogenicity, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.271506	Structured	0.399506	Uncertain	0.864	0.345	0.125							-9.016	Likely Pathogenic	0.727	Likely Pathogenic	Likely Benign	0.270	Likely Benign	0.1857	0.5197		3.20	Destabilizing	0.5	1.27	Ambiguous	2.24	Destabilizing	0.94	Ambiguous	-6.80	Deleterious	1.000	Probably Damaging	0.994	Probably Damaging	3.76	Benign	0.01	Affected			0	-1	0.9	3.99
c.622C>G	P208A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P208A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. Predictions that are inconclusive are Rosetta and Foldetta. 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 uncertain. Overall, the majority of evidence points toward a benign effect, and this 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	PH	0.271506	Structured	0.399506	Uncertain	0.864	0.345	0.125							-5.623	Likely Benign	0.172	Likely Benign	Likely Benign	0.245	Likely Benign	0.3727	0.4390		2.19	Destabilizing	0.3	1.31	Ambiguous	1.75	Ambiguous	1.03	Destabilizing	-6.80	Deleterious	0.999	Probably Damaging	0.991	Probably Damaging	3.80	Benign	0.04	Affected			1	-1	3.4	-26.04
c.622C>T	P208S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P208S 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, FATHMM, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta. Rosetta’s output is uncertain and therefore not counted as evidence. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to pathogenic, and Foldetta also predicts pathogenic. With no ClinVar annotation to contradict, the overall evidence strongly favors a pathogenic classification for P208S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.271506	Structured	0.399506	Uncertain	0.864	0.345	0.125							-8.363	Likely Pathogenic	0.587	Likely Pathogenic	Likely Benign	0.270	Likely Benign	0.3808	0.4537		2.68	Destabilizing	0.3	1.53	Ambiguous	2.11	Destabilizing	1.21	Destabilizing	-6.78	Deleterious	1.000	Probably Damaging	0.994	Probably Damaging	3.79	Benign	0.02	Affected			1	-1	0.8	-10.04
c.623C>A	P208Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P208Q 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 are REVEL and FATHMM. The majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta. Two tools give uncertain results (AlphaMissense‑Optimized and Rosetta) and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as Pathogenic, reinforcing a deleterious prediction. Overall, the evidence strongly favors a pathogenic 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 Pathogenic	PH	0.271506	Structured	0.399506	Uncertain	0.864	0.345	0.125							-9.746	Likely Pathogenic	0.906	Likely Pathogenic	Ambiguous	0.411	Likely Benign	0.1570	0.4663		3.30	Destabilizing	0.7	0.75	Ambiguous	2.03	Destabilizing	1.23	Destabilizing	-6.78	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	3.78	Benign	0.00	Affected			0	-1	-1.9	31.01
c.623C>G	P208R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P208R 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 are REVEL and FATHMM. The majority of other in silico predictors (FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score (Likely Pathogenic) all indicate a pathogenic impact, while Rosetta remains uncertain. 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 the preponderance of pathogenic predictions and the absence of any benign consensus, 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.	Likely Pathogenic	PH	0.271506	Structured	0.399506	Uncertain	0.864	0.345	0.125							-11.929	Likely Pathogenic	0.966	Likely Pathogenic	Likely Pathogenic	0.472	Likely Benign	0.1676	0.3118		5.25	Destabilizing	1.6	1.39	Ambiguous	3.32	Destabilizing	1.16	Destabilizing	-7.50	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	3.75	Benign	0.00	Affected			0	-2	-2.9	59.07
c.623C>T	P208L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P208L has no ClinVar entry and is present in gnomAD (ID 6‑33435265‑C‑T). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, while those that agree on a pathogenic effect include FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions that are inconclusive are Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall distribution of 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	0.271506	Structured	0.399506	Uncertain	0.864	0.345	0.125				6-33435265-C-T	1	6.20e-7	-10.013	Likely Pathogenic	0.889	Likely Pathogenic	Ambiguous	0.466	Likely Benign	0.2219	0.6191		2.35	Destabilizing	0.5	0.04	Likely Benign	1.20	Ambiguous	0.67	Ambiguous	-8.49	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	3.75	Benign	0.01	Affected	3.44	12	-3	-3	5.4	16.04
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	0.770	Likely Pathogenic	0.3011	0.3385		2.23	Destabilizing	0.7	2.67	Destabilizing	2.45	Destabilizing	1.33	Destabilizing	-6.07	Deleterious	0.958	Probably Damaging	0.502	Possibly Damaging	5.70	Benign	0.00	Affected			-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	0.699	Likely Pathogenic	0.1124	0.4037		1.17	Ambiguous	0.3	-0.20	Likely Benign	0.49	Likely Benign	0.89	Ambiguous	-6.98	Deleterious	1.000	Probably Damaging	0.948	Probably Damaging	5.62	Benign	0.00	Affected	3.41	14	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	0.739	Likely Pathogenic	0.2572	0.2549		0.45	Likely Benign	0.2	1.67	Ambiguous	1.06	Ambiguous	1.05	Destabilizing	-3.34	Deleterious	0.999	Probably Damaging	0.715	Possibly Damaging	5.74	Benign	0.01	Affected	3.41	14	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	0.848	Likely Pathogenic	0.1943	0.4528		3.09	Destabilizing	0.6	8.87	Destabilizing	5.98	Destabilizing	1.21	Destabilizing	-5.97	Deleterious	0.998	Probably Damaging	0.878	Possibly Damaging	5.64	Benign	0.00	Affected	3.41	14	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	0.825	Likely Pathogenic	0.1616	0.4741		1.13	Ambiguous	0.5	0.01	Likely Benign	0.57	Ambiguous	0.67	Ambiguous	-6.06	Deleterious	0.979	Probably Damaging	0.680	Possibly Damaging	5.66	Benign	0.03	Affected			-3	-2	8.3	-43.03
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	0.767	Likely Pathogenic	0.4225	0.1527		0.33	Likely Benign	0.0	0.46	Likely Benign	0.40	Likely Benign	0.63	Ambiguous	-3.33	Deleterious	0.995	Probably Damaging	0.914	Probably Damaging	5.83	Benign	0.04	Affected			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	0.878	Likely Pathogenic	0.3610	0.1179		0.75	Ambiguous	0.1	1.36	Ambiguous	1.06	Ambiguous	0.68	Ambiguous	-3.43	Deleterious	0.982	Probably Damaging	0.679	Possibly Damaging	6.00	Benign	0.10	Tolerated			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	0.853	Likely Pathogenic	0.2021	0.3951		2.00	Destabilizing	0.4	0.06	Likely Benign	1.03	Ambiguous	0.60	Ambiguous	-5.14	Deleterious	0.995	Probably Damaging	0.747	Possibly Damaging	5.74	Benign	0.03	Affected			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	0.602	Likely Pathogenic	0.4571	0.1242		-0.23	Likely Benign	0.5	-0.03	Likely Benign	-0.13	Likely Benign	0.43	Likely Benign	-2.12	Neutral	0.982	Probably Damaging	0.679	Possibly Damaging	5.89	Benign	0.14	Tolerated			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	0.852	Likely Pathogenic	0.1176	0.3868		1.31	Ambiguous	0.5	0.28	Likely Benign	0.80	Ambiguous	0.41	Likely Benign	-6.96	Deleterious	0.985	Probably Damaging	0.704	Possibly Damaging	5.71	Benign	0.01	Affected			-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	0.663	Likely Pathogenic	0.3426	0.1872		0.92	Ambiguous	0.1	1.13	Ambiguous	1.03	Ambiguous	0.89	Ambiguous	-4.23	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	5.81	Benign	0.03	Affected			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	0.663	Likely Pathogenic	0.3426	0.1872		0.92	Ambiguous	0.1	1.13	Ambiguous	1.03	Ambiguous	0.89	Ambiguous	-4.23	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	5.81	Benign	0.03	Affected			1	0	0.4	-14.07
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	0.380	Likely Benign	0.0626	0.2891		-0.03	Likely Benign	0.2	-0.35	Likely Benign	-0.19	Likely Benign	0.32	Likely Benign	-0.33	Neutral	0.048	Benign	0.039	Benign	5.74	Benign	0.19	Tolerated			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	0.445	Likely Benign	0.1019	0.2591		1.09	Ambiguous	0.1	0.19	Likely Benign	0.64	Ambiguous	0.39	Likely Benign	-0.39	Neutral	0.617	Possibly Damaging	0.140	Benign	5.71	Benign	0.15	Tolerated			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	0.793	Likely Pathogenic	0.0409	0.2205		2.92	Destabilizing	2.5	0.53	Ambiguous	1.73	Ambiguous	0.42	Likely Benign	-2.21	Neutral	0.985	Probably Damaging	0.724	Possibly Damaging	5.53	Benign	0.02	Affected			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	0.811	Likely Pathogenic	0.0899	0.0212		1.90	Ambiguous	0.2	1.43	Ambiguous	1.67	Ambiguous	1.76	Destabilizing	-4.46	Deleterious	0.995	Probably Damaging	0.854	Possibly Damaging	5.49	Benign	0.00	Affected			-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	0.816	Likely Pathogenic	0.1027	0.0541		2.15	Destabilizing	0.2	1.52	Ambiguous	1.84	Ambiguous	1.72	Destabilizing	-3.06	Deleterious	0.982	Probably Damaging	0.702	Possibly Damaging	5.55	Benign	0.01	Affected			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	0.802	Likely Pathogenic	0.2658	0.0600		2.52	Destabilizing	0.2	2.22	Destabilizing	2.37	Destabilizing	1.71	Destabilizing	-3.55	Deleterious	0.995	Probably Damaging	0.795	Possibly Damaging	5.52	Benign	0.00	Affected			-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	0.474	Likely Benign	0.0553	0.2200		0.09	Likely Benign	0.1	0.16	Likely Benign	0.13	Likely Benign	-0.01	Likely Benign	0.58	Neutral	0.985	Probably Damaging	0.798	Possibly Damaging	5.61	Benign	0.94	Tolerated			2	1	-2.6	18.03
c.1561G>A	E521K 2D 3DClick to see structure in 3D Viewer AISynGAP1 E521K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give mixed results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. Overall, the majority of conventional tools lean toward a benign interpretation, while the high‑accuracy methods are split. Thus, 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.	Likely Pathogenic	GAP	0.086953	Structured	0.062387	Uncertain	0.865	0.349	0.000							-9.596	Likely Pathogenic	0.911	Likely Pathogenic	Ambiguous	0.379	Likely Benign	0.2895	0.6513		-0.48	Likely Benign	0.2	0.14	Likely Benign	-0.17	Likely Benign	-0.10	Likely Benign	-3.05	Deleterious	0.994	Probably Damaging	0.994	Probably Damaging	3.57	Benign	0.45	Tolerated			0	1	-0.4	-0.94
c.1561G>C	E521Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E521Q 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, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta predicts a benign stability change. Overall, the majority of evidence (9 benign vs. 4 pathogenic predictions) supports a benign 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.		GAP	0.086953	Structured	0.062387	Uncertain	0.865	0.349	0.000							-8.310	Likely Pathogenic	0.777	Likely Pathogenic	Likely Benign	0.262	Likely Benign	0.1580	0.6552		-0.28	Likely Benign	0.2	0.19	Likely Benign	-0.05	Likely Benign	-0.06	Likely Benign	-2.15	Neutral	0.992	Probably Damaging	0.993	Probably Damaging	3.30	Benign	0.11	Tolerated			2	2	0.0	-0.98
c.1562A>C	E521A 2D 3DClick to see structure in 3D Viewer AISynGAP1 E521A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign calls (REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM) and pathogenic calls (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). AlphaMissense‑Optimized is uncertain. High‑accuracy assessments give conflicting results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. No prediction or stability result is missing. Overall, the evidence is evenly split, with six benign and six pathogenic calls, and the two high‑accuracy tools disagree. Therefore, the variant’s impact remains uncertain; it is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.086953	Structured	0.062387	Uncertain	0.865	0.349	0.000							-8.997	Likely Pathogenic	0.892	Likely Pathogenic	Ambiguous	0.395	Likely Benign	0.4041	0.5918		0.18	Likely Benign	0.1	0.40	Likely Benign	0.29	Likely Benign	0.11	Likely Benign	-4.12	Deleterious	0.998	Probably Damaging	0.999	Probably Damaging	3.28	Benign	0.13	Tolerated			0	-1	5.3	-58.04
c.1562A>G	E521G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E521G 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it is a 2‑vs‑2 split and is treated as unavailable. Overall, the majority of evidence points to a benign impact. The variant is most likely benign based on current 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.		GAP	0.086953	Structured	0.062387	Uncertain	0.865	0.349	0.000							-6.636	Likely Benign	0.767	Likely Pathogenic	Likely Benign	0.289	Likely Benign	0.2932	0.5455		0.18	Likely Benign	0.1	0.58	Ambiguous	0.38	Likely Benign	0.14	Likely Benign	-3.64	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	3.31	Benign	0.07	Tolerated			0	-2	3.1	-72.06
c.1562A>T	E521V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E521V missense change 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, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized score is pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the majority of evidence points to a pathogenic impact for E521V, 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	GAP	0.086953	Structured	0.062387	Uncertain	0.865	0.349	0.000							-10.297	Likely Pathogenic	0.978	Likely Pathogenic	Likely Pathogenic	0.413	Likely Benign	0.0913	0.7104		0.31	Likely Benign	0.1	0.49	Likely Benign	0.40	Likely Benign	0.21	Likely Benign	-5.15	Deleterious	0.995	Probably Damaging	0.996	Probably Damaging	3.26	Benign	0.05	Affected			-2	-2	7.7	-29.98
c.1563G>C	E521D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change E521D 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, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). 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) yields Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, 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 is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.086953	Structured	0.062387	Uncertain	0.865	0.349	0.000							-4.963	Likely Benign	0.372	Ambiguous	Likely Benign	0.227	Likely Benign	0.2026	0.3721		0.13	Likely Benign	0.0	0.17	Likely Benign	0.15	Likely Benign	-0.29	Likely Benign	1.07	Neutral	0.986	Probably Damaging	0.989	Probably Damaging	3.40	Benign	0.92	Tolerated			3	2	0.0	-14.03
c.1563G>T	E521D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E521D missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. Only two tools—polyPhen‑2 HumDiv and HumVar—predict a pathogenic outcome. The high‑accuracy methods give a consistent benign signal: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, 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 Benign	GAP	0.086953	Structured	0.062387	Uncertain	0.865	0.349	0.000							-4.963	Likely Benign	0.372	Ambiguous	Likely Benign	0.227	Likely Benign	0.2026	0.3721		0.13	Likely Benign	0.0	0.17	Likely Benign	0.15	Likely Benign	-0.29	Likely Benign	1.07	Neutral	0.986	Probably Damaging	0.989	Probably Damaging	3.40	Benign	0.92	Tolerated			3	2	0.0	-14.03
c.2020A>C	T674P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T674P missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The high‑accuracy AlphaMissense‑Optimized predicts benign, while Foldetta predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. No other high‑accuracy tool provides a definitive call. Consequently, the evidence is evenly split between benign and pathogenic, leaving the variant’s clinical significance uncertain. This uncertainty does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.129801	Structured	0.109297	Uncertain	0.521	0.349	0.000							-8.661	Likely Pathogenic	0.109	Likely Benign	Likely Benign	0.143	Likely Benign	0.2039	0.6103		0.91	Ambiguous	0.6	4.12	Destabilizing	2.52	Destabilizing	0.12	Likely Benign	-2.69	Deleterious	0.995	Probably Damaging	0.891	Possibly Damaging	3.50	Benign	0.16	Tolerated			0	-1	-0.9	-3.99
c.2020A>G	T674A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly favor a benign effect: AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, SIFT, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, REVEL, FoldX, premPS, Foldetta, and the SGM‑Consensus score all indicate benign or likely benign. No tool predicts pathogenicity; the only inconclusive result comes from Rosetta, which is listed as uncertain. High‑accuracy methods corroborate the benign assessment: 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 aggregate predictions, 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.	Likely Benign	GAP	0.129801	Structured	0.109297	Uncertain	0.521	0.349	0.000							-5.915	Likely Benign	0.099	Likely Benign	Likely Benign	0.052	Likely Benign	0.4042	0.4845		-0.13	Likely Benign	0.0	0.89	Ambiguous	0.38	Likely Benign	0.29	Likely Benign	-1.48	Neutral	0.398	Benign	0.045	Benign	3.45	Benign	0.28	Tolerated			1	0	2.5	-30.03
c.2020A>T	T674S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, and AlphaMissense‑Default all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. With all available evidence pointing to a benign outcome and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.129801	Structured	0.109297	Uncertain	0.521	0.349	0.000							-5.320	Likely Benign	0.082	Likely Benign	Likely Benign	0.084	Likely Benign	0.3329	0.4938		-0.23	Likely Benign	0.0	0.44	Likely Benign	0.11	Likely Benign	-0.14	Likely Benign	0.47	Neutral	0.107	Benign	0.033	Benign	3.47	Benign	1.00	Tolerated			1	1	-0.1	-14.03
c.2021C>A	T674N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674N 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, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome; ESM1b is uncertain and does not influence the consensus. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports 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. No contradictory evidence is present. **Based on the aggregate predictions, the variant is most likely benign, and this conclusion does not conflict with the ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.129801	Structured	0.109297	Uncertain	0.521	0.349	0.000							-7.839	In-Between	0.135	Likely Benign	Likely Benign	0.119	Likely Benign	0.1263	0.4979		-0.21	Likely Benign	0.0	0.15	Likely Benign	-0.03	Likely Benign	0.19	Likely Benign	-0.71	Neutral	0.958	Probably Damaging	0.671	Possibly Damaging	3.44	Benign	0.17	Tolerated			0	0	-2.8	13.00
c.2021C>G	T674S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, and AlphaMissense‑Default all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. With all available evidence pointing to a benign outcome and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.129801	Structured	0.109297	Uncertain	0.521	0.349	0.000							-5.320	Likely Benign	0.082	Likely Benign	Likely Benign	0.088	Likely Benign	0.3329	0.4938		-0.23	Likely Benign	0.0	0.44	Likely Benign	0.11	Likely Benign	-0.14	Likely Benign	0.47	Neutral	0.107	Benign	0.033	Benign	3.47	Benign	1.00	Tolerated			1	1	-0.1	-14.03
c.2021C>T	T674I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674I is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (ID 6‑33441280‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and ESM1b (polyPhen‑2 HumVar is benign). 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 pathogenic. Overall, the majority of evidence points to 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.		GAP	0.129801	Structured	0.109297	Uncertain	0.521	0.349	0.000				6-33441280-C-T	2	1.24e-6	-8.951	Likely Pathogenic	0.522	Ambiguous	Likely Benign	0.289	Likely Benign	0.0898	0.6945		-0.05	Likely Benign	0.1	0.28	Likely Benign	0.12	Likely Benign	-0.04	Likely Benign	-3.18	Deleterious	0.981	Probably Damaging	0.444	Benign	3.46	Benign	0.11	Tolerated	3.40	24	-1	0	5.2	12.05
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	0.825	Likely Pathogenic	0.1437	0.7271		0.23	Likely Benign	0.1	-0.20	Likely Benign	0.02	Likely Benign	0.55	Ambiguous	-4.15	Deleterious	0.995	Probably Damaging	0.880	Possibly Damaging	5.84	Benign	0.01	Affected			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	0.712	Likely Pathogenic	0.1953	0.4599		0.27	Likely Benign	0.0	0.09	Likely Benign	0.18	Likely Benign	0.79	Ambiguous	-3.62	Deleterious	0.982	Probably Damaging	0.679	Possibly Damaging	5.84	Benign	0.13	Tolerated			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	0.855	Likely Pathogenic	0.0706	0.6771		-0.36	Likely Benign	0.1	0.11	Likely Benign	-0.13	Likely Benign	0.59	Ambiguous	-6.68	Deleterious	0.995	Probably Damaging	0.880	Possibly Damaging	5.86	Benign	0.00	Affected			-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	0.794	Likely Pathogenic	0.1397	0.7734		0.52	Ambiguous	0.1	0.04	Likely Benign	0.28	Likely Benign	0.76	Ambiguous	-4.79	Deleterious	0.948	Possibly Damaging	0.588	Possibly Damaging	5.87	Benign	0.01	Affected			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	0.524	Likely Pathogenic	0.3557	0.7229		0.46	Likely Benign	0.1	-0.16	Likely Benign	0.15	Likely Benign	0.42	Likely Benign	-3.75	Deleterious	0.787	Possibly Damaging	0.404	Benign	5.90	Benign	0.07	Tolerated			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	0.831	Likely Pathogenic	0.0672	0.6999		-0.56	Ambiguous	0.1	0.04	Likely Benign	-0.26	Likely Benign	0.60	Ambiguous	-7.46	Deleterious	0.995	Probably Damaging	0.832	Possibly Damaging	5.88	Benign	0.00	Affected			-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	0.474	Likely Benign	0.2271	0.5645		-0.32	Likely Benign	0.1	0.01	Likely Benign	-0.16	Likely Benign	0.83	Ambiguous	-4.86	Deleterious	0.948	Possibly Damaging	0.588	Possibly Damaging	5.88	Benign	0.01	Affected			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	0.474	Likely Benign	0.2271	0.5645		-0.32	Likely Benign	0.1	0.01	Likely Benign	-0.16	Likely Benign	0.83	Ambiguous	-4.86	Deleterious	0.948	Possibly Damaging	0.588	Possibly Damaging	5.88	Benign	0.01	Affected			1	0	-0.4	14.07
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	0.539	Likely Pathogenic	0.0975	0.5737		0.74	Ambiguous	0.3	0.55	Ambiguous	0.65	Ambiguous	0.71	Ambiguous	-2.66	Deleterious	0.900	Possibly Damaging	0.348	Benign	5.80	Benign	0.06	Tolerated			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	0.752	Likely Pathogenic	0.1593	0.3724		0.10	Likely Benign	0.5	4.20	Destabilizing	2.15	Destabilizing	1.04	Destabilizing	-3.68	Deleterious	0.995	Probably Damaging	0.832	Possibly Damaging	5.77	Benign	0.03	Affected			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	0.421	Likely Benign	0.2209	0.4357		0.48	Likely Benign	0.6	0.34	Likely Benign	0.41	Likely Benign	0.61	Ambiguous	-1.41	Neutral	0.259	Benign	0.048	Benign	5.82	Benign	0.31	Tolerated			1	1	-2.6	16.00
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	0.769	Likely Pathogenic	0.1419	0.2302		1.23	Ambiguous	0.4	3.49	Destabilizing	2.36	Destabilizing	1.20	Destabilizing	-3.97	Deleterious	0.969	Probably Damaging	0.704	Possibly Damaging	5.88	Benign	0.05	Affected			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	0.538	Likely Pathogenic	0.1809	0.2910		1.00	Ambiguous	0.0	2.01	Destabilizing	1.51	Ambiguous	1.14	Destabilizing	-2.91	Deleterious	0.900	Possibly Damaging	0.430	Benign	5.81	Benign	0.05	Affected			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	0.565	Likely Pathogenic	0.0771	0.4853		0.87	Ambiguous	0.4	0.97	Ambiguous	0.92	Ambiguous	0.18	Likely Benign	-3.26	Deleterious	0.900	Possibly Damaging	0.430	Benign	5.87	Benign	0.10	Tolerated			0	0	2.4	28.05
c.2107C>A	L703I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and Rosetta. Predictions that are uncertain or inconclusive (FoldX, Foldetta, premPS, AlphaMissense‑Default) are treated as unavailable. 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 high‑confidence tools predict a benign impact, and this conclusion does not contradict the ClinVar status, which has no pathogenic classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.144935	Structured	0.388282	Uncertain	0.929	0.353	0.000							-9.332	Likely Pathogenic	0.345	Ambiguous	Likely Benign	0.108	Likely Benign	0.0909	0.3079		1.44	Ambiguous	0.1	2.21	Destabilizing	1.83	Ambiguous	0.61	Ambiguous	-1.50	Neutral	0.982	Probably Damaging	0.758	Possibly Damaging	3.38	Benign	0.00	Affected			2	2	0.7	0.00
c.2107C>G	L703V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703V 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 SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Because the variant is not present in ClinVar or gnomAD, there is no existing clinical classification to contradict. Overall, the majority of predictions and the two high‑accuracy benign assessments suggest the variant is most likely benign, although the Foldetta result indicates a potential pathogenic effect that warrants further functional investigation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.144935	Structured	0.388282	Uncertain	0.929	0.353	0.000							-10.086	Likely Pathogenic	0.301	Likely Benign	Likely Benign	0.080	Likely Benign	0.1383	0.2621		2.32	Destabilizing	0.1	2.61	Destabilizing	2.47	Destabilizing	1.07	Destabilizing	-2.22	Neutral	0.789	Possibly Damaging	0.352	Benign	3.19	Benign	0.00	Affected			2	1	0.4	-14.03
c.2107C>T	L703F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703F is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized, while those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta provide 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, and PROVEAN) as pathogenic, and Foldetta remains unavailable. Overall, the majority of reliable predictions lean toward pathogenicity, 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	GAP	0.144935	Structured	0.388282	Uncertain	0.929	0.353	0.000							-10.929	Likely Pathogenic	0.768	Likely Pathogenic	Likely Benign	0.247	Likely Benign	0.0600	0.2555		1.03	Ambiguous	0.1	0.59	Ambiguous	0.81	Ambiguous	0.50	Likely Benign	-3.25	Deleterious	0.994	Probably Damaging	0.806	Possibly Damaging	3.12	Benign	0.00	Affected			2	0	-1.0	34.02
c.2108T>A	L703H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703H 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 FATHMM, whereas pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, 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, classifies the variant as Likely Pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM‑Consensus itself is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts Pathogenic. Taken together, the overwhelming majority 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	GAP	0.144935	Structured	0.388282	Uncertain	0.929	0.353	0.000							-12.886	Likely Pathogenic	0.957	Likely Pathogenic	Likely Pathogenic	0.420	Likely Benign	0.1038	0.0288		2.52	Destabilizing	0.0	2.29	Destabilizing	2.41	Destabilizing	1.75	Destabilizing	-5.71	Deleterious	1.000	Probably Damaging	0.993	Probably Damaging	3.09	Benign	0.00	Affected			-2	-3	-7.0	23.98
c.2108T>C	L703P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic, while only FATHMM predicts it benign. The SGM‑Consensus, which is a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Pathogenic” result (3 pathogenic vs. 1 benign). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus is likely pathogenic; and Foldetta, integrating 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 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	GAP	0.144935	Structured	0.388282	Uncertain	0.929	0.353	0.000							-13.766	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	0.559	Likely Pathogenic	0.3698	0.1186		4.44	Destabilizing	0.1	9.38	Destabilizing	6.91	Destabilizing	1.54	Destabilizing	-5.70	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	3.11	Benign	0.00	Affected			-3	-3	-5.4	-16.04
c.2108T>G	L703R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703R 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 other in silico predictors (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus) all classify the change as pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. The preponderance of pathogenic predictions, together with the high‑accuracy tools’ positive results, suggests that L703R is most likely pathogenic. 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	GAP	0.144935	Structured	0.388282	Uncertain	0.929	0.353	0.000							-13.244	Likely Pathogenic	0.935	Likely Pathogenic	Ambiguous	0.459	Likely Benign	0.1223	0.0488		2.85	Destabilizing	0.0	3.74	Destabilizing	3.30	Destabilizing	1.79	Destabilizing	-4.92	Deleterious	0.994	Probably Damaging	0.806	Possibly Damaging	3.13	Benign	0.00	Affected			-3	-2	-8.3	43.03
c.1063G>A	G355R 2D AIThe SynGAP1 missense variant G355R 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, and Foldetta. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 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 predict a pathogenic impact, whereas a minority predict benign. 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	0.155435	Structured	0.388832	Uncertain	0.810	0.354	0.125							-11.022	Likely Pathogenic	0.922	Likely Pathogenic	Ambiguous	0.340	Likely Benign	0.1041	0.4567		0.61	Ambiguous	1.4	0.10	Likely Benign	0.36	Likely Benign	0.60	Ambiguous	-6.74	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.80	Pathogenic	0.02	Affected			-3	-2	-4.1	99.14
c.1063G>C	G355R 2D AIThe SynGAP1 missense variant G355R 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, and Foldetta. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 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 predict a pathogenic impact, whereas a minority predict benign. 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	0.155435	Structured	0.388832	Uncertain	0.810	0.354	0.125							-11.022	Likely Pathogenic	0.922	Likely Pathogenic	Ambiguous	0.340	Likely Benign	0.1041	0.4567		0.61	Ambiguous	1.4	0.10	Likely Benign	0.36	Likely Benign	0.60	Ambiguous	-6.74	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.80	Pathogenic	0.02	Affected			-3	-2	-4.1	99.14
c.1063G>T	G355W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G355W is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL and premPS, and pathogenic predictions from SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, SGM‑Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with 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	0.155435	Structured	0.388832	Uncertain	0.810	0.354	0.125							-12.316	Likely Pathogenic	0.938	Likely Pathogenic	Ambiguous	0.455	Likely Benign	0.0796	0.4360		1.16	Ambiguous	0.5	0.88	Ambiguous	1.02	Ambiguous	0.18	Likely Benign	-6.92	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.73	Pathogenic	0.00	Affected			-7	-2	-0.5	129.16
c.1064G>A	G355E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G355E is catalogued in gnomAD (6‑33437969‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining evaluated algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic impact. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is uncertain. Overall, the preponderance of evidence from standard pathogenicity predictors points to a deleterious effect, and this conclusion is not contradicted by any ClinVar classification (none is available). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.155435	Structured	0.388832	Uncertain	0.810	0.354	0.125				6-33437969-G-A	2	1.24e-6	-9.395	Likely Pathogenic	0.891	Likely Pathogenic	Ambiguous	0.349	Likely Benign	0.1590	0.4271		0.72	Ambiguous	0.6	0.63	Ambiguous	0.68	Ambiguous	0.54	Ambiguous	-6.69	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.80	Pathogenic	0.04	Affected	3.38	24	-2	0	-3.1	72.06
c.1064G>C	G355A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G355A 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, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. FoldX and Foldetta are uncertain and therefore not counted as evidence. 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 uncertain. Consequently, the overall prediction leans toward a benign 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.		C2	0.155435	Structured	0.388832	Uncertain	0.810	0.354	0.125							-5.431	Likely Benign	0.245	Likely Benign	Likely Benign	0.286	Likely Benign	0.4111	0.5045		0.88	Ambiguous	0.6	0.46	Likely Benign	0.67	Ambiguous	0.49	Likely Benign	-4.80	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.80	Pathogenic	0.03	Affected			1	0	2.2	14.03
c.1064G>T	G355V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G355V is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or unavailable results are reported for FoldX, premPS, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect. Foldetta’s stability prediction is unavailable. Overall, the majority of evidence points to a pathogenic impact, 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	0.155435	Structured	0.388832	Uncertain	0.810	0.354	0.125							-10.111	Likely Pathogenic	0.675	Likely Pathogenic	Likely Benign	0.346	Likely Benign	0.1221	0.4685		1.78	Ambiguous	0.6	0.14	Likely Benign	0.96	Ambiguous	0.53	Ambiguous	-7.59	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.78	Pathogenic	0.04	Affected			-1	-3	4.6	42.08
c.1210G>A	A404T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: SGM‑Consensus (Likely Benign), REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FoldX and premPS are inconclusive, so they are treated as unavailable. High‑accuracy methods corroborate this: 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) is benign. Overall, the evidence strongly supports a benign classification, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.232838	Structured	0.415505	Uncertain	0.965	0.355	0.000							-6.674	Likely Benign	0.279	Likely Benign	Likely Benign	0.060	Likely Benign	0.1710	0.7367		0.74	Ambiguous	0.1	-0.01	Likely Benign	0.37	Likely Benign	0.56	Ambiguous	-1.74	Neutral	0.049	Benign	0.011	Benign	4.12	Benign	0.09	Tolerated			1	0	-2.5	30.03
c.1210G>C	A404P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A404P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, both polyPhen‑2 versions, and FATHMM, while pathogenic calls arise from FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic verdict. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion 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	0.232838	Structured	0.415505	Uncertain	0.965	0.355	0.000							-11.819	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.227	Likely Benign	0.2271	0.6366		3.03	Destabilizing	0.1	0.24	Likely Benign	1.64	Ambiguous	1.17	Destabilizing	-3.16	Deleterious	0.433	Benign	0.080	Benign	4.02	Benign	0.03	Affected			1	-1	-3.4	26.04
c.1210G>T	A404S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a pathogenic outcome. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a benign effect. No inconclusive or missing predictions are present. Based on the unanimous benign predictions and the lack of ClinVar evidence, 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	0.232838	Structured	0.415505	Uncertain	0.965	0.355	0.000							-1.937	Likely Benign	0.194	Likely Benign	Likely Benign	0.078	Likely Benign	0.2970	0.6178		0.13	Likely Benign	0.0	0.83	Ambiguous	0.48	Likely Benign	0.28	Likely Benign	-0.07	Neutral	0.000	Benign	0.001	Benign	4.18	Benign	0.22	Tolerated			1	1	-2.6	16.00
c.1211C>A	A404E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404E 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments further support a deleterious effect: 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 outputs, also predicts pathogenicity. Based on the preponderance of pathogenic 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	0.232838	Structured	0.415505	Uncertain	0.965	0.355	0.000							-13.639	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	0.163	Likely Benign	0.1423	0.2383		2.16	Destabilizing	0.1	3.04	Destabilizing	2.60	Destabilizing	1.51	Destabilizing	-2.77	Deleterious	0.179	Benign	0.033	Benign	4.02	Benign	0.02	Affected			0	-1	-5.3	58.04
c.1211C>G	A404G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404G 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. Tools that predict a pathogenic effect are premPS and SIFT. FoldX, Rosetta, and Foldetta give uncertain or inconclusive results and are treated as unavailable. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the majority of evidence points to a benign impact for A404G, 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 Benign	C2	0.232838	Structured	0.415505	Uncertain	0.965	0.355	0.000							-5.277	Likely Benign	0.137	Likely Benign	Likely Benign	0.099	Likely Benign	0.2370	0.5054		0.92	Ambiguous	0.0	1.88	Ambiguous	1.40	Ambiguous	1.18	Destabilizing	-2.34	Neutral	0.045	Benign	0.013	Benign	4.03	Benign	0.00	Affected			1	0	-2.2	-14.03
c.1211C>T	A404V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A404V missense variant is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438116‑C‑T). Prediction tools that agree on a benign effect include REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and ESM1b. Four tools (FoldX, Rosetta, AlphaMissense‑Default, Foldetta) give uncertain or inconclusive results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of predictions lean toward a benign impact, though a key consensus method suggests pathogenicity, leaving the variant’s effect unresolved. **The variant is most likely benign based on the prevailing predictions, and this assessment does not contradict ClinVar status, as no ClinVar classification exists.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.232838	Structured	0.415505	Uncertain	0.965	0.355	0.000				6-33438116-C-T	1	6.20e-7	-8.219	Likely Pathogenic	0.343	Ambiguous	Likely Benign	0.118	Likely Benign	0.1288	0.6842		0.56	Ambiguous	0.3	-1.55	Ambiguous	-0.50	Ambiguous	-0.05	Likely Benign	-2.96	Deleterious	0.345	Benign	0.018	Benign	4.20	Benign	0.47	Tolerated	3.38	28	0	0	2.4	28.05
c.1987T>A	F663I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663I 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 all other evaluated algorithms—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 further support a deleterious impact: 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) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, 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	GAP	0.056825	Structured	0.093963	Uncertain	0.944	0.355	0.000							-15.006	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	0.641	Likely Pathogenic	0.1740	0.1955		2.63	Destabilizing	0.1	4.51	Destabilizing	3.57	Destabilizing	1.60	Destabilizing	-5.99	Deleterious	0.999	Probably Damaging	0.989	Probably Damaging	3.06	Benign	0.00	Affected			1	0	1.7	-34.02
c.1987T>C	F663L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663L is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, which scores the variant as benign. All other evaluated algorithms—SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity, while Foldetta’s stability analysis is inconclusive and therefore unavailable. FoldX and Foldetta are treated as unavailable due to uncertain outputs. Based on the overwhelming agreement among pathogenic predictors and the lack of benign evidence, the variant is most likely pathogenic, and this conclusion 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	GAP	0.056825	Structured	0.093963	Uncertain	0.944	0.355	0.000							-11.996	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.540	Likely Pathogenic	0.1973	0.2936		0.91	Ambiguous	0.1	2.01	Destabilizing	1.46	Ambiguous	1.51	Destabilizing	-5.99	Deleterious	0.999	Probably Damaging	0.976	Probably Damaging	3.07	Benign	0.01	Affected			2	0	1.0	-34.02
c.1987T>G	F663V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all indicate pathogenicity, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change 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 calculations, also predicts a pathogenic effect. No predictions are missing or inconclusive. 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	GAP	0.056825	Structured	0.093963	Uncertain	0.944	0.355	0.000							-14.196	Likely Pathogenic	0.988	Likely Pathogenic	Likely Pathogenic	0.655	Likely Pathogenic	0.1844	0.1983		3.04	Destabilizing	0.1	3.31	Destabilizing	3.18	Destabilizing	1.75	Destabilizing	-6.98	Deleterious	0.998	Probably Damaging	0.993	Probably Damaging	3.02	Benign	0.00	Affected			-1	-1	1.4	-48.04
c.1988T>A	F663Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663Y 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, and FATHMM. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. 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 and the SGM‑Consensus lean toward pathogenicity, while a minority suggest benign impact. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.056825	Structured	0.093963	Uncertain	0.944	0.355	0.000							-12.749	Likely Pathogenic	0.853	Likely Pathogenic	Ambiguous	0.424	Likely Benign	0.1243	0.1584		0.37	Likely Benign	0.1	0.19	Likely Benign	0.28	Likely Benign	1.03	Destabilizing	-2.99	Deleterious	0.984	Probably Damaging	0.913	Probably Damaging	3.11	Benign	0.05	Affected			7	3	-4.1	16.00
c.1988T>C	F663S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663S 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 all other evaluated algorithms—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 further support a deleterious impact: 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) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy predictors, 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	GAP	0.056825	Structured	0.093963	Uncertain	0.944	0.355	0.000							-14.800	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.800	Likely Pathogenic	0.3965	0.0200		4.15	Destabilizing	0.0	4.69	Destabilizing	4.42	Destabilizing	2.50	Destabilizing	-7.98	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.98	Benign	0.00	Affected			-3	-2	-3.6	-60.10
c.1988T>G	F663C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663C 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 all other evaluated algorithms—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 assessments further support a deleterious impact: 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) 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 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	GAP	0.056825	Structured	0.093963	Uncertain	0.944	0.355	0.000							-13.544	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.772	Likely Pathogenic	0.2343	0.0783		3.83	Destabilizing	0.1	4.54	Destabilizing	4.19	Destabilizing	1.91	Destabilizing	-7.98	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	2.96	Benign	0.00	Affected			-4	-2	-0.3	-44.04
c.1989T>A	F663L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (PolyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM Consensus, premPS, and Rosetta) indicate a pathogenic impact. FoldX‑MD and Rosetta‑based stability calculations are inconclusive, yielding an uncertain Foldetta result. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence from consensus and high‑accuracy tools points to a pathogenic effect for F663L. This conclusion is not contradicted by 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	GAP	0.056825	Structured	0.093963	Uncertain	0.944	0.355	0.000							-11.996	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.423	Likely Benign	0.1973	0.2936		0.91	Ambiguous	0.1	2.01	Destabilizing	1.46	Ambiguous	1.51	Destabilizing	-5.99	Deleterious	0.999	Probably Damaging	0.976	Probably Damaging	3.07	Benign	0.01	Affected			2	0	1.0	-34.02
c.1989T>G	F663L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (PolyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, premPS, and the SGM Consensus) indicate a pathogenic impact. FoldX‑MD and Rosetta give conflicting stability results, with FoldX uncertain and Rosetta pathogenic; Foldetta, which integrates both, is also uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for F663L. 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	GAP	0.056825	Structured	0.093963	Uncertain	0.944	0.355	0.000							-11.996	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.423	Likely Benign	0.1973	0.2936		0.91	Ambiguous	0.1	2.01	Destabilizing	1.46	Ambiguous	1.51	Destabilizing	-5.99	Deleterious	0.999	Probably Damaging	0.976	Probably Damaging	3.07	Benign	0.01	Affected			2	0	1.0	-34.02
c.1939G>A	G647S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G647S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, 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 Rosetta and premPS, which are treated as unavailable. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the evidence strongly favors a benign classification, and this is consistent with its absence from ClinVar. The variant 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	GAP	0.048328	Structured	0.325524	Uncertain	0.936	0.356	0.000							-2.175	Likely Benign	0.082	Likely Benign	Likely Benign	0.037	Likely Benign	0.2409	0.3959		0.05	Likely Benign	0.1	-0.75	Ambiguous	-0.35	Likely Benign	-0.56	Ambiguous	0.65	Neutral	0.002	Benign	0.004	Benign	3.48	Benign	0.89	Tolerated			1	0	-0.4	30.03
c.1939G>C	G647R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G647R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. In contrast, AlphaMissense‑Default and polyPhen‑2 HumDiv predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) is inconclusive. No evidence from FoldX or Rosetta alone is available. Overall, the preponderance of evidence supports a benign classification, and this is consistent with the lack of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.048328	Structured	0.325524	Uncertain	0.936	0.356	0.000							-6.590	Likely Benign	0.636	Likely Pathogenic	Likely Benign	0.097	Likely Benign	0.1020	0.3712		-0.51	Ambiguous	0.1	-0.97	Ambiguous	-0.74	Ambiguous	0.29	Likely Benign	-1.81	Neutral	0.787	Possibly Damaging	0.349	Benign	3.49	Benign	0.17	Tolerated			-3	-2	-4.1	99.14
c.1939G>T	G647C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G647C is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, the majority (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign”) uniformly predict a benign effect, whereas only SIFT classifies the change as pathogenic. High‑accuracy tools give consistent benign results: 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) reports a benign stability change. 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 (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.048328	Structured	0.325524	Uncertain	0.936	0.356	0.000							-2.955	Likely Benign	0.112	Likely Benign	Likely Benign	0.112	Likely Benign	0.1194	0.3250		0.41	Likely Benign	0.0	-0.20	Likely Benign	0.11	Likely Benign	0.05	Likely Benign	-1.63	Neutral	0.003	Benign	0.004	Benign	3.44	Benign	0.02	Affected			-3	-3	2.9	46.09
c.1940G>A	G647D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G647D is reported in ClinVar as having no entry and is present in gnomAD (6‑33441199‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized all predict benign. Only AlphaMissense‑Default predicts pathogenic, while FoldX, Foldetta, premPS, and ESM1b are uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the consensus of most tools and the high‑accuracy predictions indicate that G647D is most likely benign, and this is consistent with the absence of a pathogenic ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.048328	Structured	0.325524	Uncertain	0.936	0.356	0.000				6-33441199-G-A	1	6.20e-7	-7.643	In-Between	0.582	Likely Pathogenic	Likely Benign	0.098	Likely Benign	0.1630	0.1372		0.68	Ambiguous	0.1	0.33	Likely Benign	0.51	Ambiguous	0.56	Ambiguous	-1.63	Neutral	0.282	Benign	0.128	Benign	3.45	Benign	0.24	Tolerated	3.37	30	-1	1	-3.1	58.04
c.1940G>C	G647A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G647A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. Predictions that are inconclusive are 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 as Uncertain. Taken together, the overwhelming majority of evidence indicates a benign effect for G647A, 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	GAP	0.048328	Structured	0.325524	Uncertain	0.936	0.356	0.000							-0.266	Likely Benign	0.078	Likely Benign	Likely Benign	0.037	Likely Benign	0.3558	0.4136		-0.18	Likely Benign	0.0	-0.99	Ambiguous	-0.59	Ambiguous	-0.69	Ambiguous	0.48	Neutral	0.000	Benign	0.002	Benign	3.55	Benign	0.81	Tolerated			1	0	2.2	14.03
c.1940G>T	G647V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G647V 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 benign: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a tolerated change. No tool predicts pathogenicity; only FoldX and Rosetta report uncertain stability effects, which are treated as unavailable evidence. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a benign effect. Therefore, 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.	Likely Benign	GAP	0.048328	Structured	0.325524	Uncertain	0.936	0.356	0.000							-4.713	Likely Benign	0.126	Likely Benign	Likely Benign	0.115	Likely Benign	0.1318	0.3946		0.85	Ambiguous	0.1	-0.59	Ambiguous	0.13	Likely Benign	-0.13	Likely Benign	-1.77	Neutral	0.178	Benign	0.073	Benign	3.52	Benign	0.12	Tolerated			-1	-3	4.6	42.08
c.1948A>C	N650H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650H lies in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, FoldX, and the SGM‑Consensus (majority vote). Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments: AlphaMissense‑Optimized predicts pathogenicity; the SGM‑Consensus also indicates likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Based on the preponderance of pathogenic predictions and the high‑accuracy tools’ results, the variant is most likely pathogenic. This conclusion 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	GAP	0.086953	Structured	0.361944	Uncertain	0.961	0.357	0.000							-14.187	Likely Pathogenic	0.986	Likely Pathogenic	Likely Pathogenic	0.465	Likely Benign	0.1990	0.4784		2.14	Destabilizing	0.3	1.79	Ambiguous	1.97	Ambiguous	0.55	Ambiguous	-4.98	Deleterious	0.999	Probably Damaging	0.929	Probably Damaging	3.01	Benign	0.05	Affected			2	1	0.3	23.04
c.1948A>G	N650D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650D 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, polyPhen‑2 HumVar, and FATHMM. Tools 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, premPS, Foldetta) 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. The variant is most likely pathogenic based on the consensus of predictive tools, 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	GAP	0.086953	Structured	0.361944	Uncertain	0.961	0.357	0.000							-14.267	Likely Pathogenic	0.971	Likely Pathogenic	Likely Pathogenic	0.389	Likely Benign	0.2320	0.2973		1.14	Ambiguous	0.3	0.61	Ambiguous	0.88	Ambiguous	0.91	Ambiguous	-4.98	Deleterious	0.591	Possibly Damaging	0.185	Benign	2.99	Benign	0.03	Affected			2	1	0.0	0.98
c.1948A>T	N650Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650Y 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 inconclusive. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta remains uncertain. Overall, the evidence strongly favors a pathogenic classification for the variant, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this mutation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.086953	Structured	0.361944	Uncertain	0.961	0.357	0.000							-16.923	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	0.587	Likely Pathogenic	0.0852	0.3865		1.56	Ambiguous	0.3	1.32	Ambiguous	1.44	Ambiguous	0.16	Likely Benign	-7.98	Deleterious	1.000	Probably Damaging	0.984	Probably Damaging	3.03	Benign	0.03	Affected			-2	-2	2.2	49.07
c.1949A>C	N650T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650T 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, and FATHMM, whereas a larger group predicts pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results come from Foldetta, premPS, and Rosetta. 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 inconclusive. Overall, the majority of evidence points to a pathogenic effect. 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	GAP	0.086953	Structured	0.361944	Uncertain	0.961	0.357	0.000							-13.626	Likely Pathogenic	0.978	Likely Pathogenic	Likely Pathogenic	0.471	Likely Benign	0.1700	0.4843		0.31	Likely Benign	0.1	0.73	Ambiguous	0.52	Ambiguous	0.69	Ambiguous	-5.98	Deleterious	0.986	Probably Damaging	0.710	Possibly Damaging	3.04	Benign	0.01	Affected			0	0	2.8	-13.00
c.1949A>G	N650S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650S lies in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain or inconclusive results come from AlphaMissense‑Optimized, FoldX, Rosetta, Foldetta, and premPS. For high‑accuracy methods, AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta is uncertain. Overall, the majority of available predictions support a pathogenic effect. The variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.086953	Structured	0.361944	Uncertain	0.961	0.357	0.000							-11.291	Likely Pathogenic	0.916	Likely Pathogenic	Ambiguous	0.395	Likely Benign	0.3791	0.5090		0.79	Ambiguous	0.2	1.43	Ambiguous	1.11	Ambiguous	0.77	Ambiguous	-4.98	Deleterious	0.996	Probably Damaging	0.606	Possibly Damaging	3.06	Benign	0.02	Affected			1	1	2.7	-27.03
c.1949A>T	N650I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N650I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX reports an uncertain outcome. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the balance of evidence favors a pathogenic effect for the variant, 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	GAP	0.086953	Structured	0.361944	Uncertain	0.961	0.357	0.000							-15.940	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.485	Likely Benign	0.0907	0.4339		0.50	Ambiguous	0.2	0.21	Likely Benign	0.36	Likely Benign	0.21	Likely Benign	-8.97	Deleterious	0.999	Probably Damaging	0.955	Probably Damaging	3.02	Benign	0.00	Affected			-2	-3	8.0	-0.94
c.1950T>A	N650K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N650K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, Foldetta, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and premPS. High‑accuracy assessments give a pathogenic verdict from AlphaMissense‑Optimized and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), while Foldetta predicts a benign effect on protein stability. Overall, the majority of evidence points to a pathogenic impact, and 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	GAP	0.086953	Structured	0.361944	Uncertain	0.961	0.357	0.000							-13.078	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.269	Likely Benign	0.3028	0.3360		-0.33	Likely Benign	0.1	0.66	Ambiguous	0.17	Likely Benign	0.92	Ambiguous	-5.98	Deleterious	0.995	Probably Damaging	0.807	Possibly Damaging	3.02	Benign	0.03	Affected	3.37	30	0	1	-0.4	14.07
c.1950T>G	N650K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650K is not reported in ClinVar and is present in gnomAD (ID 6‑33441209‑T‑G). Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, and Foldetta, whereas a majority of tools predict pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (premPS and Rosetta) give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of predictions lean toward pathogenicity, indicating the variant is most likely pathogenic, and this is consistent with the lack of a ClinVar entry; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.086953	Structured	0.361944	Uncertain	0.961	0.357	0.000				6-33441209-T-G			-13.078	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.269	Likely Benign	0.3028	0.3360		-0.33	Likely Benign	0.1	0.66	Ambiguous	0.17	Likely Benign	0.92	Ambiguous	-5.98	Deleterious	0.995	Probably Damaging	0.807	Possibly Damaging	3.02	Benign	0.03	Affected	3.37	30	0	1	-0.4	14.07
c.1612G>A	E538K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E538K has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment indicates that AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) supports a pathogenic outcome, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Overall, the majority of tools lean toward a benign effect, but the consensus of high‑accuracy predictors and several individual pathogenic scores suggest uncertainty. The variant is most likely benign based on the bulk of evidence, 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	GAP	0.122885	Structured	0.033501	Uncertain	0.938	0.359	0.000							-11.345	Likely Pathogenic	0.922	Likely Pathogenic	Ambiguous	0.215	Likely Benign	0.2257	0.3818		-0.03	Likely Benign	0.0	-0.16	Likely Benign	-0.10	Likely Benign	-0.22	Likely Benign	-2.97	Deleterious	0.848	Possibly Damaging	0.294	Benign	3.46	Benign	0.16	Tolerated			0	1	-0.4	-0.94
c.1612G>C	E538Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E538Q 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, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, 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, and PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of evidence supports a benign impact. This conclusion 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.		GAP	0.122885	Structured	0.033501	Uncertain	0.938	0.359	0.000							-10.380	Likely Pathogenic	0.733	Likely Pathogenic	Likely Benign	0.188	Likely Benign	0.1127	0.3952		0.07	Likely Benign	0.0	0.07	Likely Benign	0.07	Likely Benign	-0.08	Likely Benign	-2.14	Neutral	0.890	Possibly Damaging	0.436	Benign	3.37	Benign	0.11	Tolerated			2	2	0.0	-0.98
c.1613A>C	E538A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E538A 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, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote). High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts likely pathogenic, and Foldetta predicts benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of tools (7 pathogenic vs 6 benign) lean toward a pathogenic interpretation, and this 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	GAP	0.122885	Structured	0.033501	Uncertain	0.938	0.359	0.000							-9.888	Likely Pathogenic	0.770	Likely Pathogenic	Likely Benign	0.269	Likely Benign	0.3995	0.4187		0.33	Likely Benign	0.0	-0.06	Likely Benign	0.14	Likely Benign	0.16	Likely Benign	-4.66	Deleterious	0.944	Possibly Damaging	0.761	Possibly Damaging	3.36	Benign	0.05	Affected			0	-1	5.3	-58.04
c.1613A>G	E538G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E538G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from 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, is labeled 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 folding‑stability result is definitive. Overall, the balance of evidence, including the majority‑vote SGM Consensus and the higher number of pathogenic predictions, points to a pathogenic effect for E538G. This conclusion 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	GAP	0.122885	Structured	0.033501	Uncertain	0.938	0.359	0.000							-9.258	Likely Pathogenic	0.701	Likely Pathogenic	Likely Benign	0.285	Likely Benign	0.3173	0.3713		0.91	Ambiguous	0.0	1.07	Ambiguous	0.99	Ambiguous	0.31	Likely Benign	-5.10	Deleterious	0.993	Probably Damaging	0.700	Possibly Damaging	3.33	Benign	0.03	Affected			0	-2	3.1	-72.06
c.1613A>T	E538V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E538V missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, premPS, and FATHMM. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized and FoldX give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of evidence points to a pathogenic effect. Based on the aggregate predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.122885	Structured	0.033501	Uncertain	0.938	0.359	0.000							-11.537	Likely Pathogenic	0.885	Likely Pathogenic	Ambiguous	0.310	Likely Benign	0.0722	0.4436		0.67	Ambiguous	0.0	-0.49	Likely Benign	0.09	Likely Benign	0.23	Likely Benign	-5.53	Deleterious	0.929	Possibly Damaging	0.641	Possibly Damaging	3.30	Benign	0.04	Affected			-2	-2	7.7	-29.98
c.1614G>C	E538D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E538D is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and FATHMM. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports benign. Consequently, the variant is most likely benign, and this prediction does not contradict the ClinVar status (no ClinVar entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.122885	Structured	0.033501	Uncertain	0.938	0.359	0.000							-2.355	Likely Benign	0.112	Likely Benign	Likely Benign	0.122	Likely Benign	0.1801	0.2352		0.32	Likely Benign	0.0	0.09	Likely Benign	0.21	Likely Benign	0.16	Likely Benign	-0.88	Neutral	0.002	Benign	0.005	Benign	3.35	Benign	0.30	Tolerated			3	2	0.0	-14.03
c.1614G>T	E538D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E538D is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and FATHMM. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports benign. Consequently, the variant is most likely benign, and this prediction does not contradict the ClinVar status (no ClinVar entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.122885	Structured	0.033501	Uncertain	0.938	0.359	0.000							-2.355	Likely Benign	0.112	Likely Benign	Likely Benign	0.122	Likely Benign	0.1801	0.2352		0.32	Likely Benign	0.0	0.09	Likely Benign	0.21	Likely Benign	0.16	Likely Benign	-0.88	Neutral	0.002	Benign	0.005	Benign	3.35	Benign	0.30	Tolerated			3	2	0.0	-14.03
c.619A>C	K207Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K207Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give a mixed picture: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; AlphaMissense‑Optimized is uncertain; Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. Folding‑stability scores from FoldX and Rosetta are inconclusive, and premPS is unavailable. Overall, the preponderance of evidence points to a pathogenic 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.	Likely Pathogenic	PH	0.374039	Structured	0.406823	Uncertain	0.847	0.359	0.125							-9.544	Likely Pathogenic	0.874	Likely Pathogenic	Ambiguous	0.250	Likely Benign	0.4010	0.1797		0.57	Ambiguous	0.1	-0.57	Ambiguous	0.00	Likely Benign	0.61	Ambiguous	-2.95	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	4.00	Benign	0.10	Tolerated			1	1	0.4	-0.04
c.619A>G	K207E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K207E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a larger group predicts pathogenicity: premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. The remaining stability predictions (FoldX and Rosetta) are uncertain. Overall, the majority of evidence points to a pathogenic effect for K207E, 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	0.374039	Structured	0.406823	Uncertain	0.847	0.359	0.125							-14.387	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	0.265	Likely Benign	0.3504	0.1557		1.39	Ambiguous	0.1	1.21	Ambiguous	1.30	Ambiguous	1.09	Destabilizing	-3.00	Deleterious	0.982	Probably Damaging	0.679	Possibly Damaging	4.02	Benign	0.07	Tolerated			0	1	0.4	0.94
c.620A>C	K207T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K207T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from 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 also pathogenic; Foldetta’s stability analysis is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for K207T, 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	PH	0.374039	Structured	0.406823	Uncertain	0.847	0.359	0.125							-11.002	Likely Pathogenic	0.974	Likely Pathogenic	Likely Pathogenic	0.239	Likely Benign	0.1636	0.4031		2.15	Destabilizing	0.8	0.57	Ambiguous	1.36	Ambiguous	0.78	Ambiguous	-4.57	Deleterious	0.982	Probably Damaging	0.747	Possibly Damaging	3.99	Benign	0.07	Tolerated			0	-1	3.2	-27.07
c.620A>G	K207R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change K207R is not listed in ClinVar and has no reported allele in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign or likely benign outcome. In contrast, polyPhen‑2 HumDiv and HumVar classify the variant as pathogenic. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, providing no definitive support for either outcome. 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, 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	PH	0.374039	Structured	0.406823	Uncertain	0.847	0.359	0.125							-5.157	Likely Benign	0.217	Likely Benign	Likely Benign	0.140	Likely Benign	0.4640	0.1704		-0.58	Ambiguous	0.1	-1.07	Ambiguous	-0.83	Ambiguous	0.37	Likely Benign	-1.77	Neutral	0.982	Probably Damaging	0.679	Possibly Damaging	4.09	Benign	0.20	Tolerated			3	2	-0.6	28.01
c.620A>T	K207M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K207M 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 FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict a pathogenic impact; premPS is uncertain. High‑accuracy methods give mixed results: 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) predicts benign. Overall, the balance of evidence favors a pathogenic classification, 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	0.374039	Structured	0.406823	Uncertain	0.847	0.359	0.125							-12.596	Likely Pathogenic	0.977	Likely Pathogenic	Likely Pathogenic	0.336	Likely Benign	0.0982	0.4705		-0.22	Likely Benign	0.0	-0.47	Likely Benign	-0.35	Likely Benign	0.59	Ambiguous	-4.67	Deleterious	0.985	Probably Damaging	0.832	Possibly Damaging	3.94	Benign	0.03	Affected			0	-1	5.8	3.02
c.621G>C	K207N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K207N 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, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable. 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, while Foldetta’s stability prediction is unavailable. Overall, the preponderance of evidence points to a pathogenic effect for K207N, 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	0.374039	Structured	0.406823	Uncertain	0.847	0.359	0.125							-12.881	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.123	Likely Benign	0.3184	0.2335		0.72	Ambiguous	0.1	1.48	Ambiguous	1.10	Ambiguous	1.00	Destabilizing	-3.54	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	3.98	Benign	0.07	Tolerated			1	0	0.4	-14.07
c.621G>T	K207N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K207N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions arise from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, and the SGM Consensus (majority vote) also predicts Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence indicates that K207N 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	PH	0.374039	Structured	0.406823	Uncertain	0.847	0.359	0.125							-12.881	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.124	Likely Benign	0.3184	0.2335		0.72	Ambiguous	0.1	1.48	Ambiguous	1.10	Ambiguous	1.00	Destabilizing	-3.54	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	3.98	Benign	0.07	Tolerated			1	0	0.4	-14.07
c.1615C>A	H539N 2D 3DClick to see structure in 3D Viewer AISynGAP1 H539N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Foldetta, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further clarify the variant’s impact: AlphaMissense‑Optimized predicts a benign effect, 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 calculations, reports a benign change. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence points toward a pathogenic effect, which 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	GAP	0.060549	Structured	0.031398	Uncertain	0.948	0.360	0.000							-8.685	Likely Pathogenic	0.751	Likely Pathogenic	Likely Benign	0.647	Likely Pathogenic	0.1234	0.1281		0.12	Likely Benign	0.1	0.78	Ambiguous	0.45	Likely Benign	0.72	Ambiguous	-5.93	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-0.89	Pathogenic	0.26	Tolerated			2	1	-0.3	-23.04
c.1615C>G	H539D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H539D 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, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the only 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, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is consistent with the absence of any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.060549	Structured	0.031398	Uncertain	0.948	0.360	0.000							-16.450	Likely Pathogenic	0.989	Likely Pathogenic	Likely Pathogenic	0.889	Likely Pathogenic	0.2008	0.0708		1.22	Ambiguous	0.2	3.27	Destabilizing	2.25	Destabilizing	1.08	Destabilizing	-8.05	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-1.25	Pathogenic	0.02	Affected			1	-1	-0.3	-22.05
c.1615C>T	H539Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H539Y has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include only premPS, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default) all predict a pathogenic impact. Predictions marked as uncertain are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for H539Y. This conclusion is not contradicted by 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	GAP	0.060549	Structured	0.031398	Uncertain	0.948	0.360	0.000							-13.177	Likely Pathogenic	0.923	Likely Pathogenic	Ambiguous	0.906	Likely Pathogenic	0.0776	0.2552		-1.22	Ambiguous	0.0	-1.12	Ambiguous	-1.17	Ambiguous	0.34	Likely Benign	-5.60	Deleterious	0.998	Probably Damaging	0.990	Probably Damaging	-1.26	Pathogenic	0.01	Affected			0	2	1.9	26.03
c.1616A>C	H539P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H539P missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include only FoldX, whereas all other evaluated algorithms—REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, 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 likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. 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	GAP	0.060549	Structured	0.031398	Uncertain	0.948	0.360	0.000							-15.182	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.913	Likely Pathogenic	0.1900	0.2794		0.22	Likely Benign	0.3	9.08	Destabilizing	4.65	Destabilizing	1.03	Destabilizing	-9.18	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-1.29	Pathogenic	0.01	Affected			0	-2	1.6	-40.02
c.1616A>G	H539R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H539R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from SIFT and the protein‑folding stability method Foldetta, whereas the remaining tools (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) suggests a benign impact. Overall, the preponderance of evidence points to a pathogenic effect for H539R, and 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	GAP	0.060549	Structured	0.031398	Uncertain	0.948	0.360	0.000							-14.979	Likely Pathogenic	0.982	Likely Pathogenic	Likely Pathogenic	0.832	Likely Pathogenic	0.1497	0.1112		-0.83	Ambiguous	0.1	0.66	Ambiguous	-0.09	Likely Benign	1.02	Destabilizing	-7.19	Deleterious	0.997	Probably Damaging	0.989	Probably Damaging	-1.16	Pathogenic	0.07	Tolerated			2	0	-1.3	19.05
c.1616A>T	H539L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H539L is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, the SGM Consensus is likely pathogenic, and Foldetta’s stability prediction is uncertain. No evidence from the available data contradicts the ClinVar status, which is currently unreported. Overall, the preponderance of computational evidence indicates that H539L is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.060549	Structured	0.031398	Uncertain	0.948	0.360	0.000							-14.161	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	0.879	Likely Pathogenic	0.0758	0.3680		-1.76	Ambiguous	0.1	-0.17	Likely Benign	-0.97	Ambiguous	0.35	Likely Benign	-10.17	Deleterious	0.999	Probably Damaging	0.993	Probably Damaging	-1.29	Pathogenic	0.01	Affected			-2	-3	7.0	-23.98
c.1617C>A	H539Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H539Q 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 SIFT, FoldX, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain predictions come from AlphaMissense‑Optimized, Rosetta, and premPS. 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. Overall, the majority of tools (nine pathogenic vs. three benign) indicate a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.060549	Structured	0.031398	Uncertain	0.948	0.360	0.000							-9.133	Likely Pathogenic	0.942	Likely Pathogenic	Ambiguous	0.597	Likely Pathogenic	0.1052	0.2008		-0.42	Likely Benign	0.0	0.92	Ambiguous	0.25	Likely Benign	0.89	Ambiguous	-7.05	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	-1.21	Pathogenic	0.07	Tolerated			3	0	-0.3	-9.01
c.1617C>G	H539Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H539Q missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include SIFT, FoldX, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain predictions come from AlphaMissense‑Optimized, Rosetta, and premPS. 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. Overall, the majority of tools (nine pathogenic vs. three benign) and the SGM‑Consensus result support a pathogenic classification, while Foldetta suggests benign. No ClinVar entry exists to contradict these predictions, so the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.060549	Structured	0.031398	Uncertain	0.948	0.360	0.000							-9.133	Likely Pathogenic	0.942	Likely Pathogenic	Ambiguous	0.597	Likely Pathogenic	0.1052	0.2008		-0.42	Likely Benign	0.0	0.92	Ambiguous	0.25	Likely Benign	0.89	Ambiguous	-7.05	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	-1.21	Pathogenic	0.07	Tolerated			3	0	-0.3	-9.01
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	0.841	Likely Pathogenic	0.1887	0.6177		0.40	Likely Benign	1.0	0.45	Likely Benign	0.43	Likely Benign	0.80	Ambiguous	-3.37	Deleterious	0.990	Probably Damaging	0.760	Possibly Damaging	5.82	Benign	0.07	Tolerated			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	0.695	Likely Pathogenic	0.1016	0.5610		0.23	Likely Benign	0.9	-0.77	Ambiguous	-0.27	Likely Benign	0.40	Likely Benign	-2.49	Neutral	0.990	Probably Damaging	0.815	Possibly Damaging	5.78	Benign	0.05	Affected			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	0.865	Likely Pathogenic	0.2672	0.4926		0.39	Likely Benign	0.1	-0.45	Likely Benign	-0.03	Likely Benign	0.82	Ambiguous	-4.99	Deleterious	0.970	Probably Damaging	0.584	Possibly Damaging	5.74	Benign	0.01	Affected			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	0.900	Likely Pathogenic	0.2266	0.5252		1.28	Ambiguous	0.0	0.74	Ambiguous	1.01	Ambiguous	1.01	Destabilizing	-5.67	Deleterious	0.990	Probably Damaging	0.815	Possibly Damaging	5.73	Benign	0.01	Affected			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	0.925	Likely Pathogenic	0.0636	0.6073		1.04	Ambiguous	0.1	1.02	Ambiguous	1.03	Ambiguous	0.56	Ambiguous	-5.90	Deleterious	0.997	Probably Damaging	0.879	Possibly Damaging	5.68	Benign	0.00	Affected			-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	0.730	Likely Pathogenic	0.1740	0.3783		0.46	Likely Benign	0.1	1.61	Ambiguous	1.04	Ambiguous	0.93	Ambiguous	-2.53	Deleterious	0.976	Probably Damaging	0.675	Possibly Damaging	5.78	Benign	0.03	Affected			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	0.730	Likely Pathogenic	0.1740	0.3783		0.46	Likely Benign	0.1	1.61	Ambiguous	1.04	Ambiguous	0.93	Ambiguous	-2.53	Deleterious	0.976	Probably Damaging	0.675	Possibly Damaging	5.78	Benign	0.03	Affected			3	2	0.0	-14.03
c.1993T>A	Y665N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 Y665N 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, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) give uncertain results and are treated as unavailable evidence. 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 conventional predictors lean toward a benign impact, and this assessment does not contradict ClinVar status (none). Thus, the variant is most likely benign based on the prevailing predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.098513	Structured	0.086641	Uncertain	0.922	0.361	0.000							-11.189	Likely Pathogenic	0.470	Ambiguous	Likely Benign	0.219	Likely Benign	0.1929	0.0573		1.11	Ambiguous	0.1	1.43	Ambiguous	1.27	Ambiguous	0.50	Likely Benign	-3.03	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	3.50	Benign	0.88	Tolerated			-2	-2	-2.2	-49.07
c.1993T>C	Y665H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y665H is not reported in ClinVar (ClinVar status: not reported) but is present in gnomAD (gnomAD ID: 6‑33441252‑T‑C). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools with uncertain or inconclusive results are FoldX, Foldetta, and AlphaMissense‑Default. High‑accuracy methods give a benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta remains uncertain. Overall, the majority of predictions (7 benign vs. 4 pathogenic) and the high‑accuracy consensus support a benign classification. 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.		GAP	0.098513	Structured	0.086641	Uncertain	0.922	0.361	0.000				6-33441252-T-C	2	1.24e-6	-9.303	Likely Pathogenic	0.389	Ambiguous	Likely Benign	0.129	Likely Benign	0.2122	0.0513		0.85	Ambiguous	0.0	0.28	Likely Benign	0.57	Ambiguous	1.12	Destabilizing	-2.00	Neutral	1.000	Probably Damaging	0.996	Probably Damaging	3.45	Benign	0.48	Tolerated	3.38	28	2	0	-1.9	-26.03
c.1993T>G	Y665D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y665D is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as Uncertain. No evidence from these tools contradicts the ClinVar status, which is currently unreported. Overall, the balance of evidence—seven pathogenic versus four benign predictions, with a pathogenic consensus from SGM‑Consensus—suggests the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.098513	Structured	0.086641	Uncertain	0.922	0.361	0.000							-10.101	Likely Pathogenic	0.737	Likely Pathogenic	Likely Benign	0.227	Likely Benign	0.3838	0.0573		1.15	Ambiguous	0.2	1.30	Ambiguous	1.23	Ambiguous	0.15	Likely Benign	-3.67	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	3.75	Benign	1.00	Tolerated			-4	-3	-2.2	-48.09
c.1994A>C	Y665S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y665S 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, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic, and Foldetta is uncertain (treated as unavailable). Overall, the balance of evidence, particularly the pathogenic signal from the SGM Consensus and the equal split among standard predictors, indicates that the variant is most likely 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.		GAP	0.098513	Structured	0.086641	Uncertain	0.922	0.361	0.000							-9.110	Likely Pathogenic	0.453	Ambiguous	Likely Benign	0.202	Likely Benign	0.3995	0.1793		1.24	Ambiguous	0.2	1.40	Ambiguous	1.32	Ambiguous	0.87	Ambiguous	-2.50	Deleterious	1.000	Probably Damaging	0.994	Probably Damaging	3.55	Benign	0.62	Tolerated			-3	-2	0.5	-76.10
c.1994A>G	Y665C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y665C is listed in ClinVar with no assertion (status: None) and is present in gnomAD (ID 6‑33441253‑A‑G). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. 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 unavailable. Overall, the evidence is mixed, but the majority of high‑confidence tools lean toward a benign interpretation. Thus, the variant is most likely benign based on current predictions, and this does not contradict the ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.098513	Structured	0.086641	Uncertain	0.922	0.361	0.000				6-33441253-A-G	1	6.20e-7	-9.007	Likely Pathogenic	0.261	Likely Benign	Likely Benign	0.210	Likely Benign	0.2562	0.2019		1.05	Ambiguous	0.1	1.60	Ambiguous	1.33	Ambiguous	1.12	Destabilizing	-3.22	Deleterious	1.000	Probably Damaging	0.981	Probably Damaging	3.45	Benign	0.14	Tolerated	3.38	28	-2	0	3.8	-60.04
c.1994A>T	Y665F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y665F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only ESM1b predicts a pathogenic outcome, while Rosetta and Foldetta are uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar claim; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.098513	Structured	0.086641	Uncertain	0.922	0.361	0.000							-8.460	Likely Pathogenic	0.100	Likely Benign	Likely Benign	0.106	Likely Benign	0.2277	0.3076		0.07	Likely Benign	0.1	1.03	Ambiguous	0.55	Ambiguous	0.38	Likely Benign	-1.23	Neutral	0.159	Benign	0.036	Benign	3.45	Benign	0.47	Tolerated			7	3	4.1	-16.00
c.1600T>A	S534T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534T 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, 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) predicts benign stability. Thus, the overall evidence strongly supports a benign classification, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.167087	Structured	0.032173	Uncertain	0.860	0.362	0.000							-4.925	Likely Benign	0.104	Likely Benign	Likely Benign	0.200	Likely Benign	0.1238	0.5064		0.10	Likely Benign	0.1	0.46	Likely Benign	0.28	Likely Benign	0.19	Likely Benign	-2.42	Neutral	0.676	Possibly Damaging	0.933	Probably Damaging	3.32	Benign	0.07	Tolerated			1	1	0.1	14.03
c.1600T>C	S534P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534P is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438843‑T‑C). Functional prediction tools that report a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy assessments are consistent with a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the aggregate predictions, the variant is most likely benign, which does not contradict the ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.167087	Structured	0.032173	Uncertain	0.860	0.362	0.000	Uncertain		1	6-33438843-T-C	3	1.86e-6	-5.056	Likely Benign	0.265	Likely Benign	Likely Benign	0.203	Likely Benign	0.2071	0.4650		-0.40	Likely Benign	0.2	0.35	Likely Benign	-0.03	Likely Benign	0.47	Likely Benign	-3.81	Deleterious	0.993	Probably Damaging	0.993	Probably Damaging	3.32	Benign	0.05	Affected	3.37	35	-1	1	-0.8	10.04
c.1600T>G	S534A 2D 3DClick to see structure in 3D Viewer AISynGAP1 S534A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenicity. High‑accuracy methods reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. No evidence suggests a deleterious effect. Therefore, the variant is most likely benign, 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 Benign	GAP	0.167087	Structured	0.032173	Uncertain	0.860	0.362	0.000							-4.691	Likely Benign	0.082	Likely Benign	Likely Benign	0.163	Likely Benign	0.5042	0.3131	Weaken	0.01	Likely Benign	0.0	-0.01	Likely Benign	0.00	Likely Benign	0.11	Likely Benign	-1.70	Neutral	0.880	Possibly Damaging	0.994	Probably Damaging	3.36	Benign	0.42	Tolerated			1	1	2.6	-16.00
c.1601C>A	S534Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534Y has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, FATHMM, premPS, AlphaMissense‑Optimized, and Foldetta, while those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, SIFT, ESM1b, and AlphaMissense‑Default. 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 as benign. Overall, the majority of tools (seven versus six) lean toward a pathogenic effect, and the high‑accuracy consensus is split, leaving the variant’s impact uncertain. Based on the aggregate predictions, the variant is most likely pathogenic, which 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	GAP	0.167087	Structured	0.032173	Uncertain	0.860	0.362	0.000							-11.540	Likely Pathogenic	0.575	Likely Pathogenic	Likely Benign	0.314	Likely Benign	0.0629	0.5073		-0.01	Likely Benign	0.1	0.66	Ambiguous	0.33	Likely Benign	0.46	Likely Benign	-5.02	Deleterious	0.998	Probably Damaging	0.998	Probably Damaging	3.27	Benign	0.00	Affected			-3	-2	-0.5	76.10
c.1601C>G	S534C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is uncertain, so both are treated as unavailable. No other high‑accuracy predictions are available. Overall, the evidence is evenly split between benign and pathogenic predictions, leaving the variant’s clinical significance inconclusive. There is no ClinVar status to contradict this balanced prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.167087	Structured	0.032173	Uncertain	0.860	0.362	0.000							-8.077	Likely Pathogenic	0.247	Likely Benign	Likely Benign	0.308	Likely Benign	0.0984	0.4861		0.18	Likely Benign	0.1	0.90	Ambiguous	0.54	Ambiguous	0.56	Ambiguous	-4.05	Deleterious	0.998	Probably Damaging	0.997	Probably Damaging	3.25	Benign	0.00	Affected			0	-1	3.3	16.06
c.1601C>T	S534F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534F 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, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Tools with uncertain results are AlphaMissense‑Default and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this is consistent with the lack of ClinVar evidence; thus the variant is most likely benign and does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.167087	Structured	0.032173	Uncertain	0.860	0.362	0.000							-10.948	Likely Pathogenic	0.492	Ambiguous	Likely Benign	0.313	Likely Benign	0.0621	0.5379		-0.03	Likely Benign	0.1	0.88	Ambiguous	0.43	Likely Benign	0.43	Likely Benign	-5.09	Deleterious	0.998	Probably Damaging	0.998	Probably Damaging	3.26	Benign	0.00	Affected			-3	-2	3.6	60.10
c.1609G>A	A537T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537T is catalogued in gnomAD (6‑33438852‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome 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 further support a benign interpretation: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus (majority vote) is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also 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 conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.116183	Structured	0.037313	Uncertain	0.928	0.362	0.000				6-33438852-G-A	2	1.24e-6	-4.704	Likely Benign	0.097	Likely Benign	Likely Benign	0.210	Likely Benign	0.1520	0.5440		0.35	Likely Benign	0.0	0.29	Likely Benign	0.32	Likely Benign	0.37	Likely Benign	-1.41	Neutral	0.953	Possibly Damaging	0.602	Possibly Damaging	-1.27	Pathogenic	0.44	Tolerated	3.37	35	0	1	-2.5	30.03
c.1609G>C	A537P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FATHMM and Rosetta; FoldX and Foldetta are inconclusive. The high‑accuracy consensus (SGM‑Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN indicates a likely benign outcome, while AlphaMissense‑Optimized also predicts benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the majority of evidence points to a benign impact for A537P, 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 Benign	GAP	0.116183	Structured	0.037313	Uncertain	0.928	0.362	0.000							0.404	Likely Benign	0.102	Likely Benign	Likely Benign	0.218	Likely Benign	0.2152	0.3807		-0.61	Ambiguous	0.6	2.43	Destabilizing	0.91	Ambiguous	-0.18	Likely Benign	0.67	Neutral	0.020	Benign	0.022	Benign	-1.29	Pathogenic	0.35	Tolerated			1	-1	-3.4	26.04
c.1609G>T	A537S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537S is reported in gnomAD (6-33438852-G-T) and has no ClinVar entry. Consensus from multiple in silico predictors indicates a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while polyPhen‑2 (HumDiv and HumVar) and FATHMM predict pathogenicity. When predictions are grouped, the majority of tools (ten) support benign, whereas three tools support pathogenic. High‑accuracy assessments further reinforce the 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 outputs, also predicts benign. Consequently, 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	GAP	0.116183	Structured	0.037313	Uncertain	0.928	0.362	0.000				6-33438852-G-T	1	6.20e-7	-3.602	Likely Benign	0.095	Likely Benign	Likely Benign	0.206	Likely Benign	0.2729	0.4431		0.28	Likely Benign	0.0	0.46	Likely Benign	0.37	Likely Benign	0.28	Likely Benign	-0.66	Neutral	0.528	Possibly Damaging	0.592	Possibly Damaging	-1.25	Pathogenic	0.60	Tolerated	3.37	35	1	1	-2.6	16.00
c.1610C>A	A537E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537E 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, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are 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 benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or stability 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 annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.116183	Structured	0.037313	Uncertain	0.928	0.362	0.000							-5.120	Likely Benign	0.450	Ambiguous	Likely Benign	0.378	Likely Benign	0.1347	0.1566		-0.14	Likely Benign	0.1	0.00	Likely Benign	-0.07	Likely Benign	0.23	Likely Benign	-1.78	Neutral	0.987	Probably Damaging	0.838	Possibly Damaging	-1.04	Pathogenic	1.00	Tolerated			0	-1	-5.3	58.04
c.1610C>G	A537G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict pathogenic. Uncertain results come from Rosetta, Foldetta, and premPS. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized reports benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Benign, and Foldetta’s stability prediction is inconclusive. Overall, the majority of evidence supports a benign impact for A537G, 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	GAP	0.116183	Structured	0.037313	Uncertain	0.928	0.362	0.000							-4.302	Likely Benign	0.126	Likely Benign	Likely Benign	0.290	Likely Benign	0.2289	0.3387		0.40	Likely Benign	0.0	0.88	Ambiguous	0.64	Ambiguous	0.68	Ambiguous	-1.85	Neutral	0.977	Probably Damaging	0.672	Possibly Damaging	-1.30	Pathogenic	0.36	Tolerated			1	0	-2.2	-14.03
c.1610C>T	A537V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A537V is listed in ClinVar as Benign (ClinVar ID 766762.0) and is present in gnomAD (ID 6‑33438853‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is benign. FoldX alone is uncertain and therefore not considered evidence. Overall, the consensus of available predictions indicates that the variant is most likely benign, in agreement with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.116183	Structured	0.037313	Uncertain	0.928	0.362	0.000	Likely Benign		1	6-33438853-C-T	7	4.34e-6	-6.888	Likely Benign	0.120	Likely Benign	Likely Benign	0.382	Likely Benign	0.1328	0.4748		0.54	Ambiguous	0.0	-0.05	Likely Benign	0.25	Likely Benign	0.41	Likely Benign	-1.97	Neutral	0.977	Probably Damaging	0.469	Possibly Damaging	-1.26	Pathogenic	0.24	Tolerated	3.37	35	0	0	2.4	28.05	220.3	-45.1	0.0	0.0	-0.7	0.1						X		Potentially Benign	Ala537 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala537 is on the surface and does not form any interactions. In the variant simulations, the iso-propyl side chain of Val537 is also on the surface, similar to Ala537 in the WT, causing no negative structural effects.
c.2014A>C	T672P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T672P 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain results come from 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 pathogenic. No predictions are missing or inconclusive. Overall, the majority of evidence points to a pathogenic impact for T672P. This conclusion is not contradicted by ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.116183	Structured	0.102069	Uncertain	0.586	0.362	0.000							-11.022	Likely Pathogenic	0.346	Ambiguous	Likely Benign	0.087	Likely Benign	0.1988	0.5532		2.22	Destabilizing	0.2	5.54	Destabilizing	3.88	Destabilizing	0.55	Ambiguous	-4.20	Deleterious	0.968	Probably Damaging	0.824	Possibly Damaging	3.40	Benign	0.01	Affected			0	-1	-0.9	-3.99
c.2014A>G	T672A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T672A is listed in ClinVar as Benign (ClinVar ID 2154412.0) and is present in gnomAD (variant ID 6‑33441273‑A‑G). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only PROVEAN predicts a pathogenic outcome. Uncertain results are reported for FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a benign effect, and this conclusion is consistent with the ClinVar designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.116183	Structured	0.102069	Uncertain	0.586	0.362	0.000	Benign		1	6-33441273-A-G	3	1.86e-6	-6.524	Likely Benign	0.109	Likely Benign	Likely Benign	0.046	Likely Benign	0.3687	0.4380		0.51	Ambiguous	0.3	1.15	Ambiguous	0.83	Ambiguous	0.65	Ambiguous	-3.20	Deleterious	0.006	Benign	0.002	Benign	3.44	Benign	0.12	Tolerated	3.40	25	1	0	2.5	-30.03	188.5	42.5	-0.1	0.3	0.2	0.0		X						Potentially Pathogenic	The hydroxyl group of Thr672, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop itself, such as Lys566, Glu666, and Asn669. In the variant simulations, Ala672 can only form a hydrogen bond with Lys566 via its backbone carbonyl group. Consequently, it cannot maintain the Lys566-Glu666 salt bridge through hydrogen bonding, leading to a significant disruption of the intricate and stable hydrogen-bond network between the loop and the helices.
c.2014A>T	T672S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T672S is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign or likely benign. No tool predicts pathogenicity. High‑accuracy methods corroborate this: AlphaMissense‑Optimized reports benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. 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	GAP	0.116183	Structured	0.102069	Uncertain	0.586	0.362	0.000							-4.932	Likely Benign	0.097	Likely Benign	Likely Benign	0.044	Likely Benign	0.3005	0.4282		-0.13	Likely Benign	0.1	0.29	Likely Benign	0.08	Likely Benign	0.61	Ambiguous	-2.32	Neutral	0.006	Benign	0.010	Benign	3.43	Benign	0.09	Tolerated			1	1	-0.1	-14.03
c.2015C>A	T672K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T672K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from Foldetta, premPS, and Rosetta. 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 majority of tools lean toward a benign interpretation, but the high‑accuracy consensus is split, leaving the variant’s impact uncertain. Thus, the variant is most likely benign based on the bulk of predictions, and this 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	GAP	0.116183	Structured	0.102069	Uncertain	0.586	0.362	0.000	Uncertain		1				-12.192	Likely Pathogenic	0.698	Likely Pathogenic	Likely Benign	0.065	Likely Benign	0.1152	0.3250		0.20	Likely Benign	0.5	1.21	Ambiguous	0.71	Ambiguous	0.72	Ambiguous	-4.31	Deleterious	0.745	Possibly Damaging	0.051	Benign	3.40	Benign	0.07	Tolerated	3.40	25	0	-1	-3.2	27.07	195.1	7.0	0.4	0.7	0.4	0.1		X				X		Potentially Pathogenic	The hydroxyl group of Thr672, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop itself, such as Lys566, Glu666, and Asn669. In the variant simulations, Lys672 can only form a hydrogen bond with the amino group of the Lys566 side chain via its backbone carbonyl group. Consequently, it cannot maintain the Lys566-Glu666 salt bridge through hydrogen bonding. However, the amino group of Lys periodically forms a salt bridge with the carboxylate group of Glu666, which prevents a drastic disruption of the hydrogen-bond network that keeps the loop close to the helices.
c.2015C>G	T672R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T672R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Foldetta, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain results from Rosetta and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus indicates a likely pathogenic outcome. Overall, the majority of individual predictors lean toward pathogenicity, but the high‑accuracy tools provide conflicting benign signals. Therefore, the variant is most likely pathogenic based on the collective 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	GAP	0.116183	Structured	0.102069	Uncertain	0.586	0.362	0.000							-12.454	Likely Pathogenic	0.626	Likely Pathogenic	Likely Benign	0.084	Likely Benign	0.0996	0.2919		-0.48	Likely Benign	0.4	1.19	Ambiguous	0.36	Likely Benign	0.60	Ambiguous	-4.47	Deleterious	0.886	Possibly Damaging	0.377	Benign	3.43	Benign	0.02	Affected			-1	-1	-3.8	55.08
c.2015C>T	T672M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T672M is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33441274‑C‑T). Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Rosetta and Foldetta report uncertain results, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta remain unavailable. Overall, the balance of evidence favors a benign effect, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.116183	Structured	0.102069	Uncertain	0.586	0.362	0.000	Conflicting		3	6-33441274-C-T	19	1.18e-5	-9.472	Likely Pathogenic	0.174	Likely Benign	Likely Benign	0.127	Likely Benign	0.1332	0.6677		0.31	Likely Benign	0.4	1.52	Ambiguous	0.92	Ambiguous	0.41	Likely Benign	-4.34	Deleterious	0.993	Probably Damaging	0.520	Possibly Damaging	3.39	Benign	0.00	Affected	3.40	25	-1	-1	2.6	30.09	231.9	-52.9	1.1	0.1	0.5	0.0		X				X		Potentially Pathogenic	The hydroxyl group of Thr672, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop itself, such as Lys566, Glu666, and Asn669. Met672 can only form a hydrogen bond with the amino group of the Lys566 side chain via its backbone carbonyl group. Nevertheless, the Lys566-Glu666 salt bridge forms intermittently. This is possible because Asn669 keeps the carboxylate group of Glu666 in the vicinity through hydrogen bonding, and the hydrophobic side chain of Met stays mostly rotated away from the salt bridge. Consequently, no drastic disruption of the hydrogen-bond network that keeps the loop close to the helices occurs in the variant simulations.
c.2143C>A	P715T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P715T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. Two tools, Foldetta and premPS, returned uncertain results. High‑accuracy analyses further clarify the picture: AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenicity; Foldetta remains inconclusive. Overall, the majority of evidence points toward 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.	Likely Pathogenic	GAP	0.243554	Structured	0.409757	Uncertain	0.956	0.362	0.000							-10.501	Likely Pathogenic	0.744	Likely Pathogenic	Likely Benign	0.368	Likely Benign	0.1357	0.4072		2.55	Destabilizing	0.1	0.29	Likely Benign	1.42	Ambiguous	0.72	Ambiguous	-7.23	Deleterious	1.000	Probably Damaging	0.993	Probably Damaging	3.37	Benign	0.01	Affected			0	-1	0.9	3.99
c.2143C>G	P715A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P715A has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions are reported by FoldX, 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, is classified as Likely Pathogenic. High‑accuracy assessments further indicate AlphaMissense‑Optimized predicts Benign, whereas the SGM‑Consensus remains Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is Uncertain. Overall, the majority of evidence points toward a pathogenic effect, 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	GAP	0.243554	Structured	0.409757	Uncertain	0.956	0.362	0.000							-9.261	Likely Pathogenic	0.597	Likely Pathogenic	Likely Benign	0.229	Likely Benign	0.2993	0.3560		2.69	Destabilizing	0.0	0.28	Likely Benign	1.49	Ambiguous	0.77	Ambiguous	-7.13	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	3.45	Benign	0.02	Affected			1	-1	3.4	-26.04
c.2143C>T	P715S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P715S is listed in ClinVar as pathogenic (ClinVar ID 1804065.0) and is present in gnomAD (ID 6‑33441608‑C‑T). Functional prediction tools that agree on a benign effect are REVEL and FATHMM. Those that predict a pathogenic effect include FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. Predictions that are inconclusive are Rosetta, premPS, ESM1b, 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 pathogenic. Overall, the majority of evidence points to a pathogenic 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.		GAP	0.243554	Structured	0.409757	Uncertain	0.956	0.362	0.000	Likely Pathogenic		1	6-33441608-C-T	1	6.20e-7	-7.635	In-Between	0.787	Likely Pathogenic	Ambiguous	0.277	Likely Benign	0.2977	0.3755		3.54	Destabilizing	0.0	0.81	Ambiguous	2.18	Destabilizing	0.94	Ambiguous	-7.17	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	3.43	Benign	0.01	Affected	3.50	9	1	-1	0.8	-10.04	231.8	-14.0	-0.1	0.0	-0.8	0.1							X	Uncertain	Pro715, along with Gly712 and Pro713, are located in a hinge region of an α-helix making a ~90-degree turn (res. Lys705-Leu725). In the WT simulations, the pyrrolidine side chain of Pro715, lacking the backbone amide groups altogether, forces the tight helix turn to take place while also hydrophobically packing with nearby residues (e.g., Leu700, Leu708, Leu714, and Leu718). Leu715, with a normal amide backbone, could potentially affect protein folding and turn formation, although this was not observed in the variant simulations. Additionally, the hydroxyl group of the Ser715 side chain can form hydrogen bonds with the backbone carbonyl group of Gly712 and disrupt the hydrophobic packing arrangement of the leucine residues from the neighboring α-helices, impacting the GAP domain tertiary assembly.
c.2144C>A	P715H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P715H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of predictors (FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) indicate a pathogenic impact. Tools with inconclusive results (Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the consensus of the majority of evidence points to a pathogenic effect for P715H. Based on the aggregate predictions, 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	GAP	0.243554	Structured	0.409757	Uncertain	0.956	0.362	0.000							-10.523	Likely Pathogenic	0.906	Likely Pathogenic	Ambiguous	0.271	Likely Benign	0.1413	0.3684		2.80	Destabilizing	0.0	0.28	Likely Benign	1.54	Ambiguous	0.56	Ambiguous	-7.73	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	3.37	Benign	0.00	Affected			0	-2	-1.6	40.02
c.2144C>G	P715R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P715R 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 other in silico predictors (SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) classify the change as pathogenic. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts a likely pathogenic outcome, AlphaMissense‑Optimized is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Because the pathogenic predictions outnumber the benign ones and the high‑accuracy consensus supports a deleterious effect, the variant is most likely pathogenic. This assessment does not contradict 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	GAP	0.243554	Structured	0.409757	Uncertain	0.956	0.362	0.000							-12.191	Likely Pathogenic	0.940	Likely Pathogenic	Ambiguous	0.324	Likely Benign	0.1389	0.2620		2.19	Destabilizing	0.1	0.53	Ambiguous	1.36	Ambiguous	0.87	Ambiguous	-8.09	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	3.53	Benign	0.01	Affected			0	-2	-2.9	59.07
c.2144C>T	P715L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P715L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX and premPS give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Because the majority of consensus and individual predictors indicate pathogenicity, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, which contains no entry for P715L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.243554	Structured	0.409757	Uncertain	0.956	0.362	0.000							-12.207	Likely Pathogenic	0.764	Likely Pathogenic	Likely Benign	0.318	Likely Benign	0.1944	0.5105		1.43	Ambiguous	0.1	0.06	Likely Benign	0.75	Ambiguous	0.58	Ambiguous	-9.10	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	3.39	Benign	0.01	Affected			-3	-3	5.4	16.04
c.2110A>C	S704R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704R is not reported in gnomAD and has no ClinVar entry. Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. FoldX, Rosetta, and Foldetta provide uncertain stability results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the evidence 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	GAP	0.096677	Structured	0.383620	Uncertain	0.928	0.363	0.000							-9.417	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	0.178	Likely Benign	0.0714	0.3038		0.81	Ambiguous	0.1	0.92	Ambiguous	0.87	Ambiguous	0.31	Likely Benign	-2.65	Deleterious	0.997	Probably Damaging	0.822	Possibly Damaging	3.53	Benign	0.05	Affected			0	-1	-3.7	69.11
c.2110A>G	S704G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of reliable predictors indicate 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.	Likely Benign	GAP	0.096677	Structured	0.383620	Uncertain	0.928	0.363	0.000							-7.827	In-Between	0.169	Likely Benign	Likely Benign	0.091	Likely Benign	0.2224	0.3378		1.05	Ambiguous	0.1	1.33	Ambiguous	1.19	Ambiguous	0.53	Ambiguous	-2.25	Neutral	0.981	Probably Damaging	0.514	Possibly Damaging	3.42	Benign	0.07	Tolerated			1	0	0.4	-30.03
c.2110A>T	S704C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704C 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Other stability‑based tools such as FoldX, Rosetta, and premPS also return uncertain results. Overall, the majority of individual predictors lean toward pathogenicity, and the high‑accuracy consensus also supports a pathogenic classification. Thus, 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.		GAP	0.096677	Structured	0.383620	Uncertain	0.928	0.363	0.000							-10.438	Likely Pathogenic	0.423	Ambiguous	Likely Benign	0.251	Likely Benign	0.0789	0.4612		1.56	Ambiguous	0.1	0.98	Ambiguous	1.27	Ambiguous	0.52	Ambiguous	-3.52	Deleterious	0.997	Probably Damaging	0.789	Possibly Damaging	3.40	Benign	0.01	Affected			0	-1	3.3	16.06
c.2111G>A	S704N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704N is listed in ClinVar as benign (ClinVar ID 962301.0) and is present in gnomAD (ID 6‑33441370‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus all report benign or likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while premPS and AlphaMissense‑Default are 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) indicates benign stability. Overall, the predictions support a benign classification, consistent with the ClinVar status and with no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.096677	Structured	0.383620	Uncertain	0.928	0.363	0.000	Benign/Likely benign		3	6-33441370-G-A	27	1.67e-5	-5.917	Likely Benign	0.421	Ambiguous	Likely Benign	0.058	Likely Benign	0.0911	0.3754		0.48	Likely Benign	0.1	-0.12	Likely Benign	0.18	Likely Benign	0.54	Ambiguous	-0.49	Neutral	0.771	Possibly Damaging	0.275	Benign	3.39	Benign	0.08	Tolerated	3.47	10	1	1	-2.7	27.03	233.2	-29.1	-0.1	0.0	-0.1	0.1						X		Potentially Benign	Ser704 is located at the end and outer surface of an α-helix (res. Thr704-Gly712), which is connected via a tight turn or loop to another α-helix (res. Asp684-Gln702). The hydroxyl side chain of Ser704 occasionally forms a hydrogen bond with the amide group of Ala707. However, in the variant simulations, the carboxamide side chain of Asn704 achieves more lasting and numerous hydrogen-bonding interactions with the residues at the helix end, such as Glu706, Ala707, and Leu708. Consequently, the residue swap could strengthen the α-helix secondary structure integrity at the helix end, which could have either positive or negative effects on its function.
c.2111G>C	S704T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. Only polyPhen‑2 HumDiv predicts a pathogenic effect, while FoldX remains inconclusive. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Overall, the aggregate evidence indicates that S704T is most likely benign, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.096677	Structured	0.383620	Uncertain	0.928	0.363	0.000	Uncertain		1				-4.930	Likely Benign	0.265	Likely Benign	Likely Benign	0.071	Likely Benign	0.1036	0.4674		0.80	Ambiguous	0.0	0.15	Likely Benign	0.48	Likely Benign	0.29	Likely Benign	-1.72	Neutral	0.525	Possibly Damaging	0.107	Benign	3.45	Benign	0.07	Tolerated	3.47	10	1	1	0.1	14.03	201.7	-18.0	0.0	0.0	-0.2	0.7						X		Potentially Benign	Ser704 is located at the end and outer surface of an α-helix (res. Thr704-Gly712), which is connected via a tight turn or loop to another α-helix (res. Asp684-Gln702). The hydroxyl side chain of Ser704 occasionally forms a hydrogen bond with the amide group of Ala707. Similarly, in the variant simulations, the hydroxyl side chain of Thr704 forms hydrogen bonds with the amide groups of Ala707 and Leu708. Thus, the residue swap does not cause any apparent structural change.
c.2111G>T	S704I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704I lies in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) report a pathogenic or likely pathogenic outcome. FoldX, Rosetta, and Foldetta provide uncertain results. High‑accuracy methods specifically give AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall consensus, 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	GAP	0.096677	Structured	0.383620	Uncertain	0.928	0.363	0.000							-14.222	Likely Pathogenic	0.978	Likely Pathogenic	Likely Pathogenic	0.232	Likely Benign	0.0727	0.4798		1.63	Ambiguous	0.1	1.32	Ambiguous	1.48	Ambiguous	0.29	Likely Benign	-4.05	Deleterious	0.997	Probably Damaging	0.758	Possibly Damaging	3.49	Benign	0.02	Affected			-1	-2	5.3	26.08
c.2112C>A	S704R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM, while pathogenic predictions arise from 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 confirms Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result, providing no additional evidence. Overall, the preponderance of evidence from multiple independent predictors indicates that S704R 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	GAP	0.096677	Structured	0.383620	Uncertain	0.928	0.363	0.000							-9.417	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	0.200	Likely Benign	0.0714	0.3038		0.81	Ambiguous	0.1	0.92	Ambiguous	0.87	Ambiguous	0.31	Likely Benign	-2.65	Deleterious	0.997	Probably Damaging	0.822	Possibly Damaging	3.53	Benign	0.05	Affected			0	-1	-3.7	69.11
c.2112C>G	S704R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704R 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, and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). FoldX and Rosetta give uncertain results, and Foldetta (a combined FoldX‑MD/Rosetta stability assessment) 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 and the lack of benign consensus, 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	GAP	0.096677	Structured	0.383620	Uncertain	0.928	0.363	0.000							-9.417	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	0.200	Likely Benign	0.0714	0.3038		0.81	Ambiguous	0.1	0.92	Ambiguous	0.87	Ambiguous	0.31	Likely Benign	-2.65	Deleterious	0.997	Probably Damaging	0.822	Possibly Damaging	3.53	Benign	0.05	Affected			0	-1	-3.7	69.11
c.2116G>A	E706K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E706K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM all classify the change as benign. In contrast, ESM1b and AlphaMissense‑Default predict a pathogenic impact. Tools that return uncertain results—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—do not provide decisive evidence. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic versus two benign calls). High‑accuracy assessments are likewise ambiguous: AlphaMissense‑Optimized is uncertain, Foldetta is uncertain, and the SGM Consensus remains inconclusive. Overall, the preponderance 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.		GAP	0.200174	Structured	0.377033	Uncertain	0.929	0.363	0.000	Uncertain		1				-10.519	Likely Pathogenic	0.833	Likely Pathogenic	Ambiguous	0.080	Likely Benign	0.2065	0.4511		1.17	Ambiguous	0.1	0.51	Ambiguous	0.84	Ambiguous	0.08	Likely Benign	-1.51	Neutral	0.345	Benign	0.028	Benign	4.15	Benign	0.52	Tolerated	3.47	10	0	1	-0.4	-0.94	187.1	49.2	0.0	0.0	0.4	0.1						X		Uncertain	The carboxylate side chain of Glu706, located at the end and outer surface of an α-helix (res. Thr704-Gly712), forms a salt bridge with Lys710 and a hydrogen bond with its own backbone amino group at the helix end in the WT simulations. Although Lys706 is unable to make these transient interactions in the variant simulations, there is no apparent negative effect on the protein structure due to the residue swap. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations.
c.2116G>C	E706Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E706Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are AlphaMissense‑Default and ESM1b. Rosetta and Foldetta provide uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta also yields an uncertain outcome. Overall, the majority of evidence points to a benign impact. 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.		GAP	0.200174	Structured	0.377033	Uncertain	0.929	0.363	0.000							-8.171	Likely Pathogenic	0.588	Likely Pathogenic	Likely Benign	0.059	Likely Benign	0.0941	0.3831		0.44	Likely Benign	0.0	0.61	Ambiguous	0.53	Ambiguous	-0.14	Likely Benign	-1.00	Neutral	0.433	Benign	0.051	Benign	4.13	Benign	0.31	Tolerated			2	2	0.0	-0.98
c.2117A>C	E706A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E706A has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only polyPhen2_HumDiv suggests pathogenicity, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy methods reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of ClinVar classification or gnomAD observation. Thus, the variant is most likely benign, and this is consistent with the lack of ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.200174	Structured	0.377033	Uncertain	0.929	0.363	0.000							-4.604	Likely Benign	0.443	Ambiguous	Likely Benign	0.117	Likely Benign	0.3413	0.4089		0.80	Ambiguous	0.0	0.48	Likely Benign	0.64	Ambiguous	-0.12	Likely Benign	-0.81	Neutral	0.613	Possibly Damaging	0.180	Benign	4.20	Benign	0.65	Tolerated			0	-1	5.3	-58.04
c.2117A>G	E706G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E706G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar all classify the substitution as benign or tolerated. Only polyPhen2_HumDiv predicts a pathogenic effect. Tools with uncertain outcomes—AlphaMissense‑Default, FoldX, Rosetta, and Foldetta—do not provide a definitive assessment. High‑accuracy predictors reinforce the benign consensus: AlphaMissense‑Optimized reports a benign change; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the majority of evidence supports a benign impact, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Thus, 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	GAP	0.200174	Structured	0.377033	Uncertain	0.929	0.363	0.000							-5.289	Likely Benign	0.535	Ambiguous	Likely Benign	0.071	Likely Benign	0.2781	0.3614		1.22	Ambiguous	0.0	1.32	Ambiguous	1.27	Ambiguous	0.12	Likely Benign	-1.71	Neutral	0.931	Possibly Damaging	0.138	Benign	4.07	Benign	0.23	Tolerated			0	-2	3.1	-72.06
c.2117A>T	E706V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E706V 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, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Two tools, FoldX and Foldetta, give uncertain or inconclusive results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of predictions lean toward a benign impact, and this assessment 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.	Likely Pathogenic	GAP	0.200174	Structured	0.377033	Uncertain	0.929	0.363	0.000							-9.306	Likely Pathogenic	0.667	Likely Pathogenic	Likely Benign	0.099	Likely Benign	0.0528	0.4275		1.05	Ambiguous	0.0	0.30	Likely Benign	0.68	Ambiguous	0.05	Likely Benign	-2.63	Deleterious	0.555	Possibly Damaging	0.109	Benign	4.07	Benign	0.16	Tolerated			-2	-2	7.7	-29.98
c.2118A>C	E706D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E706D is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the consensus SGM score (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign effect. No tool predicts pathogenicity. High‑accuracy assessments likewise support a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. **Thus, the variant is most likely benign, and this prediction 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	GAP	0.200174	Structured	0.377033	Uncertain	0.929	0.363	0.000							-4.216	Likely Benign	0.087	Likely Benign	Likely Benign	0.182	Likely Benign	0.1681	0.2726		0.22	Likely Benign	0.0	0.02	Likely Benign	0.12	Likely Benign	-0.16	Likely Benign	-0.01	Neutral	0.000	Benign	0.000	Benign	4.17	Benign	0.41	Tolerated			3	2	0.0	-14.03
c.2118A>T	E706D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E706D is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the consensus SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts pathogenicity. High‑accuracy assessments further support a benign effect: AlphaMissense‑Optimized predicts benign, the SGM Consensus indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. With all evidence pointing to a neutral impact and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.200174	Structured	0.377033	Uncertain	0.929	0.363	0.000							-4.216	Likely Benign	0.087	Likely Benign	Likely Benign	0.182	Likely Benign	0.1681	0.2726		0.22	Likely Benign	0.0	0.02	Likely Benign	0.12	Likely Benign	-0.16	Likely Benign	-0.01	Neutral	0.000	Benign	0.000	Benign	4.17	Benign	0.41	Tolerated			3	2	0.0	-14.03
c.2113A>C	K705Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K705Q missense variant (ClinVar ID 3699560.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (variant ID 6‑33441372‑A‑C). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (benign), FATHMM (benign), and PROVEAN (benign)—also yields a benign classification; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence supports a benign impact for K705Q, and this conclusion does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.134866	Structured	0.379324	Uncertain	0.922	0.364	0.000	Uncertain		1	6-33441372-A-C	1	6.20e-7	-5.787	Likely Benign	0.436	Ambiguous	Likely Benign	0.142	Likely Benign	0.3063	0.1014		-0.10	Likely Benign	0.0	0.33	Likely Benign	0.12	Likely Benign	-0.02	Likely Benign	-0.24	Neutral	0.997	Probably Damaging	0.969	Probably Damaging	3.42	Benign	0.78	Tolerated	3.47	10	1	1	0.4	-0.04
c.2113A>G	K705E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K705E 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, SIFT, AlphaMissense‑Optimized, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta predicts a benign stability change. Overall, the majority of evidence (9 benign vs. 4 pathogenic) supports a benign 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.		GAP	0.134866	Structured	0.379324	Uncertain	0.922	0.364	0.000							-9.371	Likely Pathogenic	0.704	Likely Pathogenic	Likely Benign	0.075	Likely Benign	0.2601	0.0789		0.10	Likely Benign	0.0	-0.09	Likely Benign	0.01	Likely Benign	0.47	Likely Benign	-1.53	Neutral	0.935	Possibly Damaging	0.537	Possibly Damaging	3.33	Benign	0.14	Tolerated			0	1	0.4	0.94
c.2114A>C	K705T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K705T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain calls are made by FoldX and AlphaMissense‑Optimized. High‑accuracy assessments indicate that the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts a pathogenic effect, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign outcome. Overall, the balance of evidence leans toward a pathogenic interpretation, and this assessment does not conflict with 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	GAP	0.134866	Structured	0.379324	Uncertain	0.922	0.364	0.000							-8.617	Likely Pathogenic	0.826	Likely Pathogenic	Ambiguous	0.272	Likely Benign	0.1299	0.2612		0.60	Ambiguous	0.0	0.04	Likely Benign	0.32	Likely Benign	0.17	Likely Benign	-4.05	Deleterious	0.995	Probably Damaging	0.991	Probably Damaging	3.38	Benign	0.02	Affected			0	-1	3.2	-27.07
c.2114A>G	K705R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K705R 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a benign or likely benign outcome. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic effect. 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) predicts benign stability. Thus, the variant 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.	Likely Benign	GAP	0.134866	Structured	0.379324	Uncertain	0.922	0.364	0.000							-4.679	Likely Benign	0.126	Likely Benign	Likely Benign	0.094	Likely Benign	0.3456	0.0789		0.10	Likely Benign	0.0	0.35	Likely Benign	0.23	Likely Benign	0.18	Likely Benign	-1.66	Neutral	0.960	Probably Damaging	0.545	Possibly Damaging	3.33	Benign	0.06	Tolerated			3	2	-0.6	28.01
c.2114A>T	K705M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K705M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, FoldX, Foldetta, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by Rosetta and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM‑Consensus) aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and yields a pathogenic verdict (3/4 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of evidence points toward a pathogenic impact, 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	GAP	0.134866	Structured	0.379324	Uncertain	0.922	0.364	0.000							-9.595	Likely Pathogenic	0.939	Likely Pathogenic	Ambiguous	0.306	Likely Benign	0.0724	0.3057		-0.13	Likely Benign	0.0	0.53	Ambiguous	0.20	Likely Benign	0.17	Likely Benign	-3.65	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	3.26	Benign	0.00	Affected			0	-1	5.8	3.02
c.2115G>C	K705N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K705N is listed in ClinVar (ID 872011.0) as Pathogenic and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, Rosetta, premPS, FATHMM) and pathogenic predictions (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default). Uncertain results come from FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as Likely Pathogenic, and Foldetta also yields an uncertain stability change. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, 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.	Likely Pathogenic	GAP	0.134866	Structured	0.379324	Uncertain	0.922	0.364	0.000	Likely Pathogenic		1				-9.767	Likely Pathogenic	0.925	Likely Pathogenic	Ambiguous	0.183	Likely Benign	0.2480	0.1124		0.74	Ambiguous	0.0	0.37	Likely Benign	0.56	Ambiguous	0.44	Likely Benign	-3.12	Deleterious	0.996	Probably Damaging	0.876	Possibly Damaging	3.37	Benign	0.02	Affected	3.47	10	1	0	0.4	-14.07	221.4	-20.2	0.0	0.0	0.0	0.1						X		Uncertain	The amino side chain of Lys705, located at the end and outer surface of an α-helix (res. Thr704-Gly712), does not form any interactions in the WT simulations. In the variant simulations, the carboxamide side chain of Asn705 briefly forms a salt bridge with Glu706. However, there is no apparent difference between the systems. Due to the model ending abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations.
c.2115G>T	K705N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K705N is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Three tools (FoldX, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments further support a pathogenic interpretation: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic”; AlphaMissense‑Optimized remains uncertain, and Foldetta is also uncertain. Overall, the balance of evidence favors a pathogenic effect for K705N, 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	GAP	0.134866	Structured	0.379324	Uncertain	0.922	0.364	0.000							-9.767	Likely Pathogenic	0.925	Likely Pathogenic	Ambiguous	0.183	Likely Benign	0.2480	0.1124		0.74	Ambiguous	0.0	0.37	Likely Benign	0.56	Ambiguous	0.44	Likely Benign	-3.12	Deleterious	0.996	Probably Damaging	0.876	Possibly Damaging	3.37	Benign	0.02	Affected	3.47	10	1	0	0.4	-14.07	221.4	-20.2	0.0	0.0	0.0	0.1						X		Uncertain	The amino side chain of Lys705, located at the end and outer surface of an α-helix (res. Thr704-Gly712), does not form any interactions in the WT simulations. In the variant simulations, the carboxamide side chain of Asn705 briefly forms a salt bridge with Glu706. However, there is no apparent difference between the systems. Due to the model ending abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations.
c.2131C>A	L711M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L711M 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta reports an uncertain stability change, which is treated as unavailable evidence. Overall, the majority of individual predictors (six pathogenic vs. five benign) and the available high‑accuracy results lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic, 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.		GAP	0.308712	Structured	0.377436	Uncertain	0.950	0.364	0.000							-9.368	Likely Pathogenic	0.679	Likely Pathogenic	Likely Benign	0.216	Likely Benign	0.0755	0.2758		0.39	Likely Benign	0.0	1.11	Ambiguous	0.75	Ambiguous	1.40	Destabilizing	-1.86	Neutral	1.000	Probably Damaging	1.000	Probably Damaging	3.34	Benign	0.00	Affected			4	2	-1.9	18.03
c.2131C>G	L711V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L711V is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33441596‑C‑G). Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. The majority of other in silico predictors—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—classify the change as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the preponderance of evidence points to a pathogenic effect, which does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.308712	Structured	0.377436	Uncertain	0.950	0.364	0.000	Uncertain		1	6-33441596-C-G	1	6.20e-7	-10.045	Likely Pathogenic	0.709	Likely Pathogenic	Likely Benign	0.170	Likely Benign	0.1318	0.3010		3.48	Destabilizing	0.1	2.22	Destabilizing	2.85	Destabilizing	1.40	Destabilizing	-2.59	Deleterious	0.992	Probably Damaging	0.970	Probably Damaging	3.34	Benign	0.00	Affected	3.50	9	1	2	0.4	-14.03
c.2132T>A	L711Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L711Q 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 REVEL and FATHMM. Tools that predict a pathogenic effect include FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM Consensus, and Foldetta; Rosetta is uncertain. High‑accuracy methods give a consistent pathogenic signal: 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) predicts Pathogenic. No predictions are missing or inconclusive. Based on the preponderance of pathogenic 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	GAP	0.308712	Structured	0.377436	Uncertain	0.950	0.364	0.000							-11.792	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	0.388	Likely Benign	0.1041	0.0488		2.93	Destabilizing	0.0	1.68	Ambiguous	2.31	Destabilizing	1.63	Destabilizing	-5.67	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	3.31	Benign	0.00	Affected			-2	-2	-7.3	14.97
c.2132T>C	L711P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L711P 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 REVEL and FATHMM; all other evaluated algorithms—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. 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	GAP	0.308712	Structured	0.377436	Uncertain	0.950	0.364	0.000							-12.128	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.375	Likely Benign	0.3300	0.0986		5.70	Destabilizing	0.1	8.15	Destabilizing	6.93	Destabilizing	2.09	Destabilizing	-6.59	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	3.28	Benign	0.00	Affected			-3	-3	-5.4	-16.04
c.2132T>G	L711R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L711R lies in the GAP domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM; all other evaluated algorithms (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, and the SGM‑Consensus score is “Likely Pathogenic.” 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. No predictions or stability results are missing or inconclusive. Based on the overwhelming majority of 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	GAP	0.308712	Structured	0.377436	Uncertain	0.950	0.364	0.000							-14.009	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	0.432	Likely Benign	0.1345	0.0488		3.71	Destabilizing	0.0	3.98	Destabilizing	3.85	Destabilizing	2.13	Destabilizing	-5.71	Deleterious	0.999	Probably Damaging	0.992	Probably Damaging	3.35	Benign	0.00	Affected			-3	-2	-8.3	43.03
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	0.661	Likely Pathogenic	0.0710	0.3511		0.65	Ambiguous	0.2	0.76	Ambiguous	0.71	Ambiguous	0.87	Ambiguous	-1.79	Neutral	0.997	Probably Damaging	0.916	Probably Damaging	4.72	Benign	0.01	Affected			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	0.736	Likely Pathogenic	0.1434	0.3607		2.09	Destabilizing	0.1	1.52	Ambiguous	1.81	Ambiguous	1.13	Destabilizing	-2.60	Deleterious	0.930	Possibly Damaging	0.504	Possibly Damaging	4.71	Benign	0.01	Affected	3.41	14	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	0.921	Likely Pathogenic	0.1092	0.0758		2.82	Destabilizing	0.3	1.79	Ambiguous	2.31	Destabilizing	1.69	Destabilizing	-5.43	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	4.67	Benign	0.00	Affected			-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	0.944	Likely Pathogenic	0.3731	0.1582		6.42	Destabilizing	0.3	8.72	Destabilizing	7.57	Destabilizing	1.79	Destabilizing	-6.30	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	4.67	Benign	0.00	Affected			-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	0.925	Likely Pathogenic	0.1266	0.0600		3.94	Destabilizing	0.8	2.77	Destabilizing	3.36	Destabilizing	1.72	Destabilizing	-5.43	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	4.67	Benign	0.00	Affected			-3	-2	-8.3	43.03
c.1621G>A	A541T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A541T missense variant is not listed in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that report a benign effect include Rosetta, Foldetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools (FoldX and AlphaMissense‑Default) returned uncertain results. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized predicts benign; Foldetta predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic. Overall, the majority of tools (six benign vs. five pathogenic) suggest 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.		GAP	0.050641	Structured	0.029947	Uncertain	0.955	0.365	0.000							-8.555	Likely Pathogenic	0.541	Ambiguous	Likely Benign	0.500	Likely Pathogenic	0.1088	0.4164		0.52	Ambiguous	0.0	-0.07	Likely Benign	0.23	Likely Benign	0.45	Likely Benign	-2.02	Neutral	0.998	Probably Damaging	0.993	Probably Damaging	-1.28	Pathogenic	0.15	Tolerated			1	0	-2.5	30.03
c.1621G>C	A541P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic. 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) predicts pathogenicity. No predictions are inconclusive or missing. Overall, the collective evidence points to a pathogenic effect for A541P, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.050641	Structured	0.029947	Uncertain	0.955	0.365	0.000	Uncertain		1				-14.733	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.594	Likely Pathogenic	0.1706	0.2707		2.47	Destabilizing	0.3	7.26	Destabilizing	4.87	Destabilizing	0.86	Ambiguous	-3.16	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	-1.34	Pathogenic	0.07	Tolerated	3.37	35	1	-1	-3.4	26.04	170.4	-11.2	0.1	0.0	0.1	0.0	X							Potentially Pathogenic	Ala541 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala541 is on the surface and does not form any interactions. Proline lacks a free backbone amide group, and thus, Pro541 is unable to form a hydrogen bond with the carbonyl group of Ala537 in the variant simulations. Consequently, Pro541 disrupts the continuity of the secondary structure element, causing the α-helix to bend slightly in the variant simulations.
c.1621G>T	A541S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541S is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools overwhelmingly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all classify the change as tolerated. In contrast, only three tools—polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM—predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized reports 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. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of evidence, 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.	Likely Benign	GAP	0.050641	Structured	0.029947	Uncertain	0.955	0.365	0.000							-5.941	Likely Benign	0.187	Likely Benign	Likely Benign	0.347	Likely Benign	0.2182	0.3340		0.15	Likely Benign	0.0	0.18	Likely Benign	0.17	Likely Benign	0.35	Likely Benign	-0.45	Neutral	0.983	Probably Damaging	0.993	Probably Damaging	-1.27	Pathogenic	0.44	Tolerated			1	1	-2.6	16.00
c.1622C>A	A541D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SIFT and FoldX, whereas a larger group—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. 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. Overall, the majority of evidence points to a pathogenic impact. 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	GAP	0.050641	Structured	0.029947	Uncertain	0.955	0.365	0.000							-11.510	Likely Pathogenic	0.864	Likely Pathogenic	Ambiguous	0.571	Likely Pathogenic	0.1581	0.1902		0.36	Likely Benign	0.0	0.65	Ambiguous	0.51	Ambiguous	0.65	Ambiguous	-3.18	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	-1.15	Pathogenic	0.14	Tolerated			0	-2	-5.3	44.01
c.1622C>G	A541G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A541G is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438865‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, 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) is inconclusive, and Foldetta is also inconclusive. Overall, the balance of evidence leans toward 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.		GAP	0.050641	Structured	0.029947	Uncertain	0.955	0.365	0.000	Uncertain		1	6-33438865-C-G	2	1.24e-6	-7.233	In-Between	0.341	Ambiguous	Likely Benign	0.421	Likely Benign	0.1787	0.2428		0.67	Ambiguous	0.0	0.94	Ambiguous	0.81	Ambiguous	0.76	Ambiguous	-1.48	Neutral	0.999	Probably Damaging	0.995	Probably Damaging	-1.31	Pathogenic	0.57	Tolerated	3.37	35	1	0	-2.2	-14.03	170.1	23.6	0.0	0.0	0.0	0.0	X							Potentially Pathogenic	Ala541 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala541 is on the surface and does not form any interactions. Glycine, known as an “α-helix breaker,” weakens the integrity of the helix. Indeed, in the variant simulations, the hydrogen bond formation between Gly541 and the backbone carbonyl of Ala537 is disrupted.
c.1622C>T	A541V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541V is not reported in ClinVar and is absent from gnomAD. Benign predictions come from REVEL, Foldetta, premPS, SIFT, Rosetta, and AlphaMissense‑Optimized, whereas pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy tools give mixed results: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. FoldX is uncertain and therefore not considered. Overall, the majority of tools predict pathogenicity, and this assessment 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	GAP	0.050641	Structured	0.029947	Uncertain	0.955	0.365	0.000							-9.777	Likely Pathogenic	0.762	Likely Pathogenic	Likely Benign	0.497	Likely Benign	0.0985	0.3648		0.63	Ambiguous	0.1	0.06	Likely Benign	0.35	Likely Benign	0.43	Likely Benign	-3.09	Deleterious	0.999	Probably Damaging	0.988	Probably Damaging	-1.33	Pathogenic	0.06	Tolerated			0	0	2.4	28.05
c.2119G>A	A707T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A707T is reported in gnomAD (ID 6‑33441584‑G‑A) but has no ClinVar entry. 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 further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. The Foldetta stability prediction is inconclusive and therefore not considered evidence. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.203355	Structured	0.371229	Uncertain	0.927	0.365	0.000				6-33441584-G-A	1	6.20e-7	-0.836	Likely Benign	0.175	Likely Benign	Likely Benign	0.252	Likely Benign	0.0880	0.4330		0.50	Ambiguous	0.0	2.36	Destabilizing	1.43	Ambiguous	0.10	Likely Benign	-0.57	Neutral	0.980	Probably Damaging	0.947	Probably Damaging	3.52	Benign	0.44	Tolerated	3.50	9	0	1	-2.5	30.03
c.2119G>C	A707P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A707P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, SIFT, and FATHMM, whereas pathogenic predictions come from Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and premPS. 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) as Pathogenic. Overall, the majority of evidence points to 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	GAP	0.203355	Structured	0.371229	Uncertain	0.927	0.365	0.000							-8.082	Likely Pathogenic	0.885	Likely Pathogenic	Ambiguous	0.228	Likely Benign	0.1375	0.3095		0.28	Likely Benign	0.1	5.75	Destabilizing	3.02	Destabilizing	0.76	Ambiguous	-2.92	Deleterious	0.996	Probably Damaging	0.983	Probably Damaging	3.41	Benign	0.09	Tolerated			1	-1	-3.4	26.04
c.2119G>T	A707S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A707S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign. In contrast, polyPhen‑2 HumDiv and HumVar classify the variant as pathogenic. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence supports a benign impact, 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	GAP	0.203355	Structured	0.371229	Uncertain	0.927	0.365	0.000							-4.432	Likely Benign	0.113	Likely Benign	Likely Benign	0.150	Likely Benign	0.1825	0.2924		0.70	Ambiguous	0.1	0.63	Ambiguous	0.67	Ambiguous	0.28	Likely Benign	-1.07	Neutral	0.848	Possibly Damaging	0.945	Probably Damaging	3.43	Benign	0.08	Tolerated			1	1	-2.6	16.00
c.2120C>A	A707D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A707D is not reported in ClinVar (status: None) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are SGM‑Consensus, AlphaMissense‑Default, ESM1b, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools give uncertain results: premPS and Rosetta. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta predicts benign. Overall, the majority of evidence points to a pathogenic impact, 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	GAP	0.203355	Structured	0.371229	Uncertain	0.927	0.365	0.000							-9.160	Likely Pathogenic	0.772	Likely Pathogenic	Likely Benign	0.225	Likely Benign	0.1376	0.1741		0.29	Likely Benign	0.0	-0.61	Ambiguous	-0.16	Likely Benign	0.89	Ambiguous	-3.16	Deleterious	0.996	Probably Damaging	0.983	Probably Damaging	3.39	Benign	0.02	Affected			0	-2	-5.3	44.01
c.2120C>G	A707G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A707G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) give uncertain or inconclusive results and are treated as unavailable evidence. 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 definitive predictions lean toward a benign effect, and there is no ClinVar status 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.		GAP	0.203355	Structured	0.371229	Uncertain	0.927	0.365	0.000							-7.480	In-Between	0.224	Likely Benign	Likely Benign	0.198	Likely Benign	0.1678	0.2388		1.45	Ambiguous	0.0	1.52	Ambiguous	1.49	Ambiguous	0.62	Ambiguous	-2.60	Deleterious	0.991	Probably Damaging	0.960	Probably Damaging	3.42	Benign	0.01	Affected			1	0	-2.2	-14.03
c.2120C>T	A707V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A707V variant is not reported in ClinVar (no ClinVar ID) but is present in gnomAD (variant ID 6‑33441585‑C‑T). Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign classification. Only three tools—Rosetta, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar—predict pathogenicity, while Foldetta reports an uncertain stability change. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM‑Consensus is benign, and Foldetta remains uncertain. Overall, the majority of evidence supports a benign impact for A707V, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.203355	Structured	0.371229	Uncertain	0.927	0.365	0.000				6-33441585-C-T	1	6.20e-7	-6.479	Likely Benign	0.277	Likely Benign	Likely Benign	0.212	Likely Benign	0.0794	0.4048		0.05	Likely Benign	0.0	2.17	Destabilizing	1.11	Ambiguous	-0.30	Likely Benign	-1.62	Neutral	0.991	Probably Damaging	0.912	Probably Damaging	3.45	Benign	1.00	Tolerated	3.50	9	0	0	2.4	28.05
c.2134G>A	G712S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G712S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. Uncertain results come from premPS, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive and therefore unavailable. Overall, the majority of evidence points to a pathogenic effect for G712S. This conclusion does not contradict ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.278302	Structured	0.384858	Uncertain	0.947	0.365	0.000							-7.942	In-Between	0.422	Ambiguous	Likely Benign	0.282	Likely Benign	0.2862	0.4501		2.30	Destabilizing	0.1	4.79	Destabilizing	3.55	Destabilizing	0.62	Ambiguous	-4.84	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	3.42	Benign	0.02	Affected			1	0	-0.4	30.03
c.2134G>C	G712R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G712R 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 other in silico predictors—PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, SIFT, ESM1b, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, Rosetta, and the SGM Consensus—classify it as pathogenic. Two tools, FoldX and premPS, return uncertain results. High‑accuracy methods all support pathogenicity: AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta each predict a deleterious effect. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.278302	Structured	0.384858	Uncertain	0.947	0.365	0.000							-11.776	Likely Pathogenic	0.963	Likely Pathogenic	Likely Pathogenic	0.458	Likely Benign	0.1229	0.4482		1.75	Ambiguous	0.0	4.68	Destabilizing	3.22	Destabilizing	0.82	Ambiguous	-6.58	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	3.35	Benign	0.01	Affected			-3	-2	-4.1	99.14
c.2134G>T	G712C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G712C is catalogued in gnomAD (6‑33441599‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Two tools report uncertainty: premPS 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 (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, 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 Pathogenic	GAP	0.278302	Structured	0.384858	Uncertain	0.947	0.365	0.000				6-33441599-G-T	1	6.20e-7	-11.376	Likely Pathogenic	0.829	Likely Pathogenic	Ambiguous	0.516	Likely Pathogenic	0.1513	0.3947		2.54	Destabilizing	0.0	5.72	Destabilizing	4.13	Destabilizing	0.56	Ambiguous	-7.75	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	3.31	Benign	0.00	Affected	3.50	9	-3	-3	2.9	46.09
c.2135G>A	G712D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G712D is catalogued in gnomAD (ID 6‑33441600‑G‑A) but has no ClinVar entry. In silico predictors show mixed results: benign calls come from REVEL, SIFT, and FATHMM, while pathogenic calls are made by FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain predictions are reported by premPS and AlphaMissense‑Optimized. The high‑accuracy consensus tools give a pathogenic verdict: AlphaMissense‑Optimized is inconclusive, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Overall, the majority of reliable predictors and the consensus methods lean toward a pathogenic effect, and this assessment 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	GAP	0.278302	Structured	0.384858	Uncertain	0.947	0.365	0.000				6-33441600-G-A	1	6.20e-7	-8.211	Likely Pathogenic	0.946	Likely Pathogenic	Ambiguous	0.320	Likely Benign	0.2146	0.2533		2.87	Destabilizing	0.1	5.37	Destabilizing	4.12	Destabilizing	0.90	Ambiguous	-5.69	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	3.67	Benign	0.12	Tolerated	3.50	9	-1	1	-3.1	58.04
c.2135G>C	G712A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G712A missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. Two tools report uncertainty: premPS and AlphaMissense‑Default. High‑accuracy assessments further refine the picture. 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 (2 benign vs. 1 pathogenic vote). Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic effect. Because the majority of conventional predictors (7/11) indicate pathogenicity, the overall consensus leans toward a pathogenic impact, despite the mixed high‑accuracy results. This conclusion 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.		GAP	0.278302	Structured	0.384858	Uncertain	0.947	0.365	0.000							-6.444	Likely Benign	0.553	Ambiguous	Likely Benign	0.281	Likely Benign	0.3993	0.4105		2.89	Destabilizing	0.1	4.98	Destabilizing	3.94	Destabilizing	0.70	Ambiguous	-4.99	Deleterious	0.999	Probably Damaging	0.991	Probably Damaging	3.44	Benign	0.02	Affected			1	0	2.2	14.03
c.2135G>T	G712V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G712V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, while the majority of tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. Two tools report uncertainty: 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 pathogenic. 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	GAP	0.278302	Structured	0.384858	Uncertain	0.947	0.365	0.000							-10.466	Likely Pathogenic	0.877	Likely Pathogenic	Ambiguous	0.410	Likely Benign	0.1395	0.3712		3.79	Destabilizing	0.0	6.18	Destabilizing	4.99	Destabilizing	0.79	Ambiguous	-7.55	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	3.32	Benign	0.00	Affected			-1	-3	4.6	42.08
c.2128A>C	K710Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K710Q missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The high‑accuracy AlphaMissense‑Optimized score classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (pathogenic), FATHMM (benign), and PROVEAN (pathogenic)—indicates pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign effect. Overall, the majority of evidence points to a benign impact, 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.		GAP	0.321458	Structured	0.370438	Uncertain	0.949	0.368	0.000							-8.920	Likely Pathogenic	0.372	Ambiguous	Likely Benign	0.183	Likely Benign	0.3043	0.1214		0.12	Likely Benign	0.0	0.02	Likely Benign	0.07	Likely Benign	0.49	Likely Benign	-3.58	Deleterious	0.999	Probably Damaging	0.999	Probably Damaging	3.39	Benign	0.01	Affected			1	1	0.4	-0.04
c.2128A>G	K710E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K710E missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect. 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.	Likely Pathogenic	GAP	0.321458	Structured	0.370438	Uncertain	0.949	0.368	0.000							-11.405	Likely Pathogenic	0.885	Likely Pathogenic	Ambiguous	0.178	Likely Benign	0.2655	0.0789		0.56	Ambiguous	0.0	0.94	Ambiguous	0.75	Ambiguous	0.39	Likely Benign	-3.53	Deleterious	0.998	Probably Damaging	0.991	Probably Damaging	3.45	Benign	0.08	Tolerated			0	1	0.4	0.94
c.2129A>C	K710T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K710T 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. 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 (no definitive stability change). Other stability predictions (FoldX, Rosetta) are also uncertain and thus unavailable for interpretation. Overall, the majority of evidence points to a pathogenic impact. 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	GAP	0.321458	Structured	0.370438	Uncertain	0.949	0.368	0.000							-10.454	Likely Pathogenic	0.759	Likely Pathogenic	Likely Benign	0.305	Likely Benign	0.1487	0.3000		1.02	Ambiguous	0.0	1.57	Ambiguous	1.30	Ambiguous	0.21	Likely Benign	-5.45	Deleterious	0.999	Probably Damaging	1.000	Probably Damaging	3.41	Benign	0.06	Tolerated			0	-1	3.2	-27.07
c.2129A>G	K710R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K710R 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, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments—all of which are available—show benign predictions: 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 collective evidence, the variant 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	GAP	0.321458	Structured	0.370438	Uncertain	0.949	0.368	0.000							-6.295	Likely Benign	0.141	Likely Benign	Likely Benign	0.209	Likely Benign	0.3351	0.0789		0.04	Likely Benign	0.0	-0.14	Likely Benign	-0.05	Likely Benign	0.29	Likely Benign	-2.78	Deleterious	0.983	Probably Damaging	0.962	Probably Damaging	3.44	Benign	0.02	Affected			3	2	-0.6	28.01
c.2129A>T	K710M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K710M 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, FoldX, Rosetta, Foldetta, premPS, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM Consensus as Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of individual predictors (seven pathogenic vs. six benign) and the SGM Consensus lean toward a pathogenic interpretation, while the high‑accuracy Foldetta result is contradictory. Based on the collective evidence, 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	GAP	0.321458	Structured	0.370438	Uncertain	0.949	0.368	0.000							-13.081	Likely Pathogenic	0.822	Likely Pathogenic	Ambiguous	0.298	Likely Benign	0.0835	0.3444		-0.13	Likely Benign	0.0	0.28	Likely Benign	0.08	Likely Benign	0.20	Likely Benign	-5.61	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	3.38	Benign	0.00	Affected			0	-1	5.8	3.02
c.2130G>C	K710N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K710N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain or unavailable results are reported for FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic impact for K710N, 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	GAP	0.321458	Structured	0.370438	Uncertain	0.949	0.368	0.000							-9.330	Likely Pathogenic	0.943	Likely Pathogenic	Ambiguous	0.201	Likely Benign	0.2485	0.1124		0.85	Ambiguous	0.0	0.50	Ambiguous	0.68	Ambiguous	0.33	Likely Benign	-4.39	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	3.42	Benign	0.04	Affected			1	0	0.4	-14.07
c.2130G>T	K710N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K710N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM. In contrast, a majority of algorithms predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, 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 uncertain. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not conflict with 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	GAP	0.321458	Structured	0.370438	Uncertain	0.949	0.368	0.000							-9.330	Likely Pathogenic	0.943	Likely Pathogenic	Ambiguous	0.201	Likely Benign	0.2485	0.1124		0.85	Ambiguous	0.0	0.50	Ambiguous	0.68	Ambiguous	0.33	Likely Benign	-4.39	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	3.42	Benign	0.04	Affected			1	0	0.4	-14.07
c.2017C>A	L673I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L673I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The remaining tools (FoldX, Rosetta, Foldetta, ESM1b) return uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of reliable predictors indicate a benign effect, and there is no conflict with ClinVar status (which has no entry). Therefore, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.060549	Structured	0.104692	Uncertain	0.545	0.369	0.000							-7.823	In-Between	0.099	Likely Benign	Likely Benign	0.036	Likely Benign	0.0910	0.3689		1.51	Ambiguous	0.2	1.89	Ambiguous	1.70	Ambiguous	-0.02	Likely Benign	-0.14	Neutral	0.535	Possibly Damaging	0.112	Benign	3.37	Benign	0.47	Tolerated			2	2	0.7	0.00
c.2017C>G	L673V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L673V 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, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Benign, and Foldetta as pathogenic, yielding one pathogenic versus two benign predictions. 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	GAP	0.060549	Structured	0.104692	Uncertain	0.545	0.369	0.000							-8.132	Likely Pathogenic	0.099	Likely Benign	Likely Benign	0.017	Likely Benign	0.1448	0.3777		2.18	Destabilizing	0.3	2.10	Destabilizing	2.14	Destabilizing	0.10	Likely Benign	-0.58	Neutral	0.016	Benign	0.003	Benign	3.36	Benign	0.28	Tolerated			2	1	0.4	-14.03
c.2018T>A	L673Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L673Q 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, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. FoldX and Foldetta, as well as AlphaMissense‑Default, are inconclusive and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta remains uncertain. Overall, the majority of available predictions (seven pathogenic vs. three benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.060549	Structured	0.104692	Uncertain	0.545	0.369	0.000							-11.963	Likely Pathogenic	0.445	Ambiguous	Likely Benign	0.190	Likely Benign	0.1045	0.1172		1.56	Ambiguous	0.2	2.32	Destabilizing	1.94	Ambiguous	1.02	Destabilizing	-3.40	Deleterious	1.000	Probably Damaging	0.968	Probably Damaging	3.32	Benign	0.03	Affected			-2	-2	-7.3	14.97
c.2018T>C	L673P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L673P 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, FATHMM, and AlphaMissense‑Optimized. All other evaluated tools—SGM‑Consensus, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized indicates benign, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts Pathogenic. Taken together, the overwhelming majority of predictions, including the high‑accuracy tools, classify the variant as 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	GAP	0.060549	Structured	0.104692	Uncertain	0.545	0.369	0.000							-12.160	Likely Pathogenic	0.622	Likely Pathogenic	Likely Benign	0.207	Likely Benign	0.3552	0.1474		2.41	Destabilizing	0.3	1.63	Ambiguous	2.02	Destabilizing	1.17	Destabilizing	-4.10	Deleterious	1.000	Probably Damaging	0.978	Probably Damaging	3.37	Benign	0.02	Affected			-3	-3	-5.4	-16.04
c.2018T>G	L673R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L673R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized; pathogenic calls come from Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote). FoldX and Foldetta are inconclusive. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM Consensus, and an uncertain outcome from Foldetta. Overall, the majority of evidence points toward pathogenicity, and this conclusion does not conflict with 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	GAP	0.060549	Structured	0.104692	Uncertain	0.545	0.369	0.000							-14.474	Likely Pathogenic	0.714	Likely Pathogenic	Likely Benign	0.178	Likely Benign	0.1348	0.1015		1.10	Ambiguous	0.2	2.04	Destabilizing	1.57	Ambiguous	1.23	Destabilizing	-3.81	Deleterious	0.991	Probably Damaging	0.433	Benign	3.36	Benign	0.03	Affected			-3	-2	-8.3	43.03
c.2140C>A	L714M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L714M is not reported in ClinVar (no entry) and is absent from gnomAD. Benign predictions are provided by REVEL, FoldX, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (likely benign). Pathogenic predictions come from Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy tools give mixed results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign; Foldetta (combining FoldX‑MD and Rosetta) predicts pathogenic. Overall, the majority of 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 Benign	GAP	0.314870	Structured	0.402311	Uncertain	0.961	0.369	0.000							-0.989	Likely Benign	0.827	Likely Pathogenic	Ambiguous	0.249	Likely Benign	0.0687	0.2626		0.45	Likely Benign	0.0	4.49	Destabilizing	2.47	Destabilizing	1.00	Destabilizing	-1.86	Neutral	1.000	Probably Damaging	1.000	Probably Damaging	3.09	Benign	0.00	Affected			4	2	-1.9	18.03
c.2140C>G	L714V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L714V has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. 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 (2 pathogenic vs. 2 benign). Overall, the majority of predictions (10 pathogenic vs. 4 benign) indicate a likely pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no record for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.314870	Structured	0.402311	Uncertain	0.961	0.369	0.000							-4.966	Likely Benign	0.781	Likely Pathogenic	Likely Benign	0.259	Likely Benign	0.1421	0.2689		3.91	Destabilizing	0.1	6.19	Destabilizing	5.05	Destabilizing	1.21	Destabilizing	-2.76	Deleterious	0.995	Probably Damaging	0.970	Probably Damaging	3.16	Benign	0.00	Affected			2	1	0.4	-14.03
c.2141T>A	L714Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L714Q is not reported in ClinVar (ClinVar: not reported) and is absent from gnomAD (gnomAD: not found). Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated tools—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), 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 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. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.314870	Structured	0.402311	Uncertain	0.961	0.369	0.000							-12.145	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.378	Likely Benign	0.1096	0.0558		2.91	Destabilizing	0.0	5.23	Destabilizing	4.07	Destabilizing	2.13	Destabilizing	-5.56	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	3.11	Benign	0.00	Affected			-2	-2	-7.3	14.97
c.2141T>C	L714P 2D AIThe SynGAP1 missense variant L714P 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 REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the preponderance of evidence from these tools, 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	GAP	0.314870	Structured	0.402311	Uncertain	0.961	0.369	0.000							-12.562	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.441	Likely Benign	0.3572	0.1253		7.48	Destabilizing	1.9	13.54	Destabilizing	10.51	Destabilizing	2.26	Destabilizing	-6.44	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	3.08	Benign	0.00	Affected			-3	-3	-5.4	-16.04
c.2141T>G	L714R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L714R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. 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, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of 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	GAP	0.314870	Structured	0.402311	Uncertain	0.961	0.369	0.000							-12.763	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.402	Likely Benign	0.1186	0.0558		4.38	Destabilizing	0.2	7.54	Destabilizing	5.96	Destabilizing	2.09	Destabilizing	-5.62	Deleterious	0.999	Probably Damaging	0.992	Probably Damaging	3.09	Benign	0.00	Affected			-3	-2	-8.3	43.03
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	0.270	Likely Benign	0.0637	0.3010		0.11	Likely Benign	0.1	1.82	Ambiguous	0.97	Ambiguous	0.93	Ambiguous	-1.02	Neutral	0.997	Probably Damaging	0.939	Probably Damaging	0.64	Pathogenic	0.03	Affected			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	0.227	Likely Benign	0.1277	0.2656		2.18	Destabilizing	0.3	2.22	Destabilizing	2.20	Destabilizing	0.17	Likely Benign	0.19	Neutral	0.898	Possibly Damaging	0.472	Possibly Damaging	0.80	Pathogenic	0.80	Tolerated			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	0.728	Likely Pathogenic	0.0915	0.0758		3.19	Destabilizing	0.2	3.28	Destabilizing	3.24	Destabilizing	1.85	Destabilizing	-4.54	Deleterious	0.999	Probably Damaging	0.977	Probably Damaging	0.59	Pathogenic	0.00	Affected			-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	0.762	Likely Pathogenic	0.3678	0.1221		3.39	Destabilizing	0.6	8.46	Destabilizing	5.93	Destabilizing	2.20	Destabilizing	-4.80	Deleterious	0.999	Probably Damaging	0.977	Probably Damaging	0.59	Pathogenic	0.01	Affected	4.29	398	-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	0.692	Likely Pathogenic	0.1066	0.0600		3.75	Destabilizing	0.4	4.47	Destabilizing	4.11	Destabilizing	2.15	Destabilizing	-4.70	Deleterious	0.999	Probably Damaging	0.969	Probably Damaging	0.59	Pathogenic	0.01	Affected	3.39	22	-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.2002T>A	S668T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668T 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, premPS, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from FoldX or Rosetta alone is conclusive. Overall, the balance of predictions leans toward pathogenicity, 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	GAP	0.247041	Structured	0.084935	Uncertain	0.922	0.370	0.000							-11.860	Likely Pathogenic	0.703	Likely Pathogenic	Likely Benign	0.238	Likely Benign	0.1212	0.5918		1.73	Ambiguous	0.7	0.89	Ambiguous	1.31	Ambiguous	0.27	Likely Benign	-2.99	Deleterious	0.844	Possibly Damaging	0.198	Benign	3.24	Benign	0.02	Affected			1	1	0.1	14.03
c.2002T>C	S668P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668P has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the only benign predictor, while the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify it as pathogenic or likely pathogenic. The premPS score is uncertain and therefore not used as evidence. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports 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 any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.247041	Structured	0.084935	Uncertain	0.922	0.370	0.000							-13.452	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.612	Likely Pathogenic	0.1979	0.5137		6.40	Destabilizing	1.1	10.90	Destabilizing	8.65	Destabilizing	0.61	Ambiguous	-4.82	Deleterious	0.998	Probably Damaging	0.790	Possibly Damaging	3.16	Benign	0.02	Affected			1	-1	-0.8	10.04
c.2002T>G	S668A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S668A 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, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools—AlphaMissense‑Default and FoldX—return uncertain results. 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. Taking all evidence together, the majority of predictions (seven benign versus four pathogenic) and the two high‑accuracy benign calls suggest that the variant is most likely benign. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.247041	Structured	0.084935	Uncertain	0.922	0.370	0.000							-12.011	Likely Pathogenic	0.506	Ambiguous	Likely Benign	0.399	Likely Benign	0.4866	0.3967		0.73	Ambiguous	0.3	-0.44	Likely Benign	0.15	Likely Benign	0.48	Likely Benign	-2.99	Deleterious	0.887	Possibly Damaging	0.738	Possibly Damaging	3.28	Benign	0.19	Tolerated			1	1	2.6	-16.00
c.2003C>A	S668Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and FATHMM, whereas the remaining 12 tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict it to be pathogenic or likely pathogenic. High‑accuracy methods give consistent results: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions are missing or inconclusive. Based on the overwhelming majority of pathogenic 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	GAP	0.247041	Structured	0.084935	Uncertain	0.922	0.370	0.000							-14.833	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.641	Likely Pathogenic	0.0647	0.5693		18.34	Destabilizing	6.2	12.69	Destabilizing	15.52	Destabilizing	0.06	Likely Benign	-5.95	Deleterious	0.999	Probably Damaging	0.935	Probably Damaging	3.18	Benign	0.00	Affected			-3	-2	-0.5	76.10
c.2003C>G	S668C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S668C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are returned by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) supports a pathogenic outcome; Foldetta remains inconclusive. Overall, the majority of evidence points toward a pathogenic 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.	Likely Pathogenic	GAP	0.247041	Structured	0.084935	Uncertain	0.922	0.370	0.000							-12.815	Likely Pathogenic	0.758	Likely Pathogenic	Likely Benign	0.503	Likely Pathogenic	0.0962	0.5528		1.31	Ambiguous	0.6	1.36	Ambiguous	1.34	Ambiguous	0.18	Likely Benign	-4.99	Deleterious	0.999	Probably Damaging	0.944	Probably Damaging	3.27	Benign	0.02	Affected			0	-1	3.3	16.06
c.2003C>T	S668F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668F is reported in ClinVar as Pathogenic (ClinVar ID 1309930.0) and is not found in gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, while the remaining 12 tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also Pathogenic. No predictions are inconclusive. Overall, the computational evidence strongly supports a pathogenic effect, consistent with the ClinVar classification. Therefore, the variant is most likely pathogenic based on the consensus of prediction tools, and this assessment aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.247041	Structured	0.084935	Uncertain	0.922	0.370	0.000	Likely Pathogenic		1				-15.047	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.643	Likely Pathogenic	0.0656	0.5849		16.72	Destabilizing	5.0	11.07	Destabilizing	13.90	Destabilizing	0.00	Likely Benign	-5.98	Deleterious	0.999	Probably Damaging	0.935	Probably Damaging	3.18	Benign	0.00	Affected	3.38	28	-3	-2	3.6	60.10	250.9	-59.6	-0.1	0.1	0.0	0.1		X	X				X	Potentially Pathogenic	In the WT simulations, the hydroxyl side chain of Ser668, located on an α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), forms hydrogen bonds with the backbone carbonyl groups of Leu664, Tyr665, and Glu666, as well as the guanidinium group of Arg573 on a nearby α-helix (res. Arg563-Glu578). In the variant simulations, the side chain of Phe668 cannot maintain the same hydrogen-bond network. Due to its larger size, it moves away to avoid steric hindrance. In the WT simulations, a network of hydrogen bonds between several residues (e.g., Asn669, Lys566, and Glu666) keeps both α-helices and the proceeding loop (res. Asn669-Asp684) tightly connected, but this setup is not present in the variant simulations. Additionally, in the variant simulations, the side chain of Arg573 shifts to form a more stable salt bridge with the carboxylate group of Glu582 instead of hydrogen bonding with Ser668 as in the WT simulations.
c.2011G>A	D671N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D671N is reported in gnomAD (6‑33441270‑G‑A) but has no ClinVar entry. Functional prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus remains pathogenic. Overall, the predictions are split, with a slight bias toward benign outcomes from the majority of tools, but the consensus pathogenic signal from SGM and several high‑confidence predictors suggests uncertainty. The variant is most likely benign based on the preponderance of benign predictions, and this 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	GAP	0.194234	Structured	0.096749	Uncertain	0.677	0.370	0.000				6-33441270-G-A			-10.347	Likely Pathogenic	0.685	Likely Pathogenic	Likely Benign	0.184	Likely Benign	0.1298	0.6463		0.18	Likely Benign	0.1	0.39	Likely Benign	0.29	Likely Benign	0.19	Likely Benign	-3.19	Deleterious	0.887	Possibly Damaging	0.592	Possibly Damaging	3.36	Benign	0.02	Affected	3.39	27	1	2	0.0	-0.98
c.2011G>C	D671H 2D 3DClick to see structure in 3D Viewer AISynGAP1 D671H is not reported in ClinVar and is absent from gnomAD. Benign predictions are provided by REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy tools give mixed results: AlphaMissense‑Optimized is uncertain, SGM Consensus predicts pathogenic, and Foldetta predicts benign. Overall, the balance of evidence leans toward pathogenicity, and this 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	GAP	0.194234	Structured	0.096749	Uncertain	0.677	0.370	0.000							-11.501	Likely Pathogenic	0.940	Likely Pathogenic	Ambiguous	0.300	Likely Benign	0.1627	0.6509		0.49	Likely Benign	0.0	0.29	Likely Benign	0.39	Likely Benign	0.09	Likely Benign	-4.35	Deleterious	0.999	Probably Damaging	0.939	Probably Damaging	3.30	Benign	0.01	Affected			1	-1	0.3	22.05
c.2011G>T	D671Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D671Y missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split consensus: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized and the SGM‑Consensus both indicate pathogenicity, while Foldetta predicts a benign effect on protein stability. Because the majority of standard predictors lean toward pathogenicity and the two high‑confidence tools also favor a deleterious outcome, the variant is most likely pathogenic. This assessment does not contradict 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	GAP	0.194234	Structured	0.096749	Uncertain	0.677	0.370	0.000							-13.107	Likely Pathogenic	0.964	Likely Pathogenic	Likely Pathogenic	0.385	Likely Benign	0.0564	0.6376		0.31	Likely Benign	0.1	0.05	Likely Benign	0.18	Likely Benign	0.11	Likely Benign	-6.05	Deleterious	1.000	Probably Damaging	0.961	Probably Damaging	3.29	Benign	0.00	Affected			-4	-3	2.2	48.09
c.2012A>C	D671A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D671A missense variant is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the 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 uncertain. Overall, the balance of evidence favors a pathogenic interpretation, with seven tools supporting pathogenicity versus four supporting benignity. This conclusion does not conflict with ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.194234	Structured	0.096749	Uncertain	0.677	0.370	0.000							-11.709	Likely Pathogenic	0.911	Likely Pathogenic	Ambiguous	0.245	Likely Benign	0.4056	0.5895		0.25	Likely Benign	0.1	0.79	Ambiguous	0.52	Ambiguous	0.10	Likely Benign	-5.08	Deleterious	0.980	Probably Damaging	0.804	Possibly Damaging	3.34	Benign	0.03	Affected			0	-2	5.3	-44.01
c.2012A>G	D671G 2D AIThe SynGAP1 D671G 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, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. 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 evidence from these tools contradicts the pathogenic prediction. Overall, the balance of evidence favors a pathogenic classification for D671G, 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	GAP	0.194234	Structured	0.096749	Uncertain	0.677	0.370	0.000							-10.346	Likely Pathogenic	0.857	Likely Pathogenic	Ambiguous	0.279	Likely Benign	0.4032	0.5823		0.50	Ambiguous	0.5	1.53	Ambiguous	1.02	Ambiguous	0.00	Likely Benign	-4.78	Deleterious	0.995	Probably Damaging	0.946	Probably Damaging	3.45	Benign	0.01	Affected			1	-1	3.1	-58.04
c.2012A>T	D671V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D671V missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods give a pathogenic signal: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the majority of predictions (seven pathogenic vs. three benign) support a pathogenic classification. There is no ClinVar entry to contradict this assessment, so the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.194234	Structured	0.096749	Uncertain	0.677	0.370	0.000							-12.376	Likely Pathogenic	0.963	Likely Pathogenic	Likely Pathogenic	0.379	Likely Benign	0.0820	0.6651		0.63	Ambiguous	0.1	0.51	Ambiguous	0.57	Ambiguous	0.14	Likely Benign	-6.08	Deleterious	0.975	Probably Damaging	0.885	Possibly Damaging	3.31	Benign	0.01	Affected			-2	-3	7.7	-15.96
c.2013C>A	D671E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D671E is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the substitution as benign. The only inconclusive result is AlphaMissense‑Default, which is listed as uncertain; all other high‑accuracy predictors support a benign outcome. In particular, AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports 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 annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.194234	Structured	0.096749	Uncertain	0.677	0.370	0.000							-3.657	Likely Benign	0.371	Ambiguous	Likely Benign	0.066	Likely Benign	0.1520	0.6388		-0.17	Likely Benign	0.1	0.22	Likely Benign	0.03	Likely Benign	0.03	Likely Benign	-0.83	Neutral	0.013	Benign	0.009	Benign	3.47	Benign	0.53	Tolerated			3	2	0.0	14.03
c.2013C>G	D671E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D671E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. 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, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized indicates 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 Benign. With all available evidence pointing to a benign effect and no ClinVar record to contradict this, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.194234	Structured	0.096749	Uncertain	0.677	0.370	0.000							-3.657	Likely Benign	0.371	Ambiguous	Likely Benign	0.066	Likely Benign	0.1520	0.6388		-0.17	Likely Benign	0.1	0.22	Likely Benign	0.03	Likely Benign	0.03	Likely Benign	-0.83	Neutral	0.013	Benign	0.009	Benign	3.47	Benign	0.53	Tolerated			3	2	0.0	14.03
c.1048G>A	V350M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350M 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, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The remaining tools (FoldX, premPS, ESM1b) give 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, and Foldetta as benign. Taken together, the majority of evidence supports a benign classification. There is no ClinVar entry 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.		C2	0.179055	Structured	0.353227	Uncertain	0.931	0.371	0.000							-7.493	In-Between	0.273	Likely Benign	Likely Benign	0.075	Likely Benign	0.1005	0.4359		-0.65	Ambiguous	0.1	0.40	Likely Benign	-0.13	Likely Benign	0.69	Ambiguous	-1.95	Neutral	0.868	Possibly Damaging	0.383	Benign	1.63	Pathogenic	0.06	Tolerated			2	1	-2.3	32.06
c.1048G>C	V350L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350L 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, Rosetta, 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, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign status. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support, 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	0.179055	Structured	0.353227	Uncertain	0.931	0.371	0.000							-5.941	Likely Benign	0.238	Likely Benign	Likely Benign	0.042	Likely Benign	0.1173	0.4958		-1.31	Ambiguous	0.1	-0.34	Likely Benign	-0.83	Ambiguous	0.36	Likely Benign	-1.63	Neutral	0.068	Benign	0.022	Benign	2.37	Pathogenic	0.27	Tolerated			2	1	-0.4	14.03
c.1048G>T	V350L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350L 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, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No other tools provide conflicting evidence. Based on the preponderance of predictions, V350L is most likely benign, 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 Benign	C2	0.179055	Structured	0.353227	Uncertain	0.931	0.371	0.000							-5.941	Likely Benign	0.238	Likely Benign	Likely Benign	0.042	Likely Benign	0.1173	0.4958		-1.31	Ambiguous	0.1	-0.34	Likely Benign	-0.83	Ambiguous	0.36	Likely Benign	-1.63	Neutral	0.068	Benign	0.022	Benign	2.37	Pathogenic	0.27	Tolerated			2	1	-0.4	14.03
c.1049T>A	V350E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign effect include REVEL and SIFT, whereas a majority of tools predict pathogenicity: premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, Foldetta, and Rosetta. Two tools give inconclusive results: FoldX (Uncertain) and AlphaMissense‑Optimized (Uncertain). 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 Pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for V350E. 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	0.179055	Structured	0.353227	Uncertain	0.931	0.371	0.000							-15.975	Likely Pathogenic	0.941	Likely Pathogenic	Ambiguous	0.304	Likely Benign	0.1078	0.1568		1.73	Ambiguous	0.2	2.61	Destabilizing	2.17	Destabilizing	1.93	Destabilizing	-4.67	Deleterious	0.976	Probably Damaging	0.559	Possibly Damaging	1.61	Pathogenic	0.08	Tolerated			-2	-2	-7.7	29.98
c.1049T>C	V350A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant V350A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), premPS, PROVEAN, ESM1b, and FATHMM. Stability‑based methods FoldX, Rosetta, and Foldetta give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as unavailable. Overall, the predictions are split, with a slight edge toward pathogenicity from the consensus and high‑accuracy tools. Therefore, the variant is most likely pathogenic based on the 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.	Likely Pathogenic	C2	0.179055	Structured	0.353227	Uncertain	0.931	0.371	0.000							-8.323	Likely Pathogenic	0.280	Likely Benign	Likely Benign	0.096	Likely Benign	0.3207	0.2967		1.42	Ambiguous	0.0	1.97	Ambiguous	1.70	Ambiguous	2.07	Destabilizing	-2.73	Deleterious	0.435	Benign	0.115	Benign	1.64	Pathogenic	0.55	Tolerated			0	0	-2.4	-28.05
c.1049T>G	V350G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350G lies in the C2 domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, polyPhen‑2 HumDiv, and AlphaMissense‑Optimized. The remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—predict it to be pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All predictions are available and consistent. Based on the preponderance of pathogenic calls, 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.		C2	0.179055	Structured	0.353227	Uncertain	0.931	0.371	0.000							-12.267	Likely Pathogenic	0.597	Likely Pathogenic	Likely Benign	0.330	Likely Benign	0.2316	0.2522		2.57	Destabilizing	0.0	4.25	Destabilizing	3.41	Destabilizing	1.93	Destabilizing	-5.46	Deleterious	0.435	Benign	0.920	Probably Damaging	1.61	Pathogenic	0.02	Affected			-1	-3	-4.6	-42.08
c.1618C>A	Q540K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q540K 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 FoldX, Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, 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 (10 pathogenic vs. 5 benign) indicate a likely pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.085092	Structured	0.029522	Uncertain	0.958	0.371	0.000							-11.418	Likely Pathogenic	0.638	Likely Pathogenic	Likely Benign	0.808	Likely Pathogenic	0.1508	0.2472		-0.37	Likely Benign	0.0	-0.03	Likely Benign	-0.20	Likely Benign	0.76	Ambiguous	-3.98	Deleterious	0.985	Probably Damaging	0.965	Probably Damaging	-1.31	Pathogenic	0.06	Tolerated			1	1	-0.4	0.04
c.1618C>G	Q540E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q540E 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 AlphaMissense‑Optimized. All other evaluated tools—REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus majority vote—predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX and Rosetta individually also returned uncertain results. Based on the overall consensus of the majority of prediction algorithms, the variant is most likely pathogenic. 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.	Likely Pathogenic	GAP	0.085092	Structured	0.029522	Uncertain	0.958	0.371	0.000							-14.417	Likely Pathogenic	0.622	Likely Pathogenic	Likely Benign	0.747	Likely Pathogenic	0.1171	0.1337		0.69	Ambiguous	0.1	0.85	Ambiguous	0.77	Ambiguous	0.80	Ambiguous	-2.98	Deleterious	0.999	Probably Damaging	0.991	Probably Damaging	-1.32	Pathogenic	0.04	Affected			2	2	0.0	0.98
c.1619A>C	Q540P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q540P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic, while premPS is uncertain. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a pathogenic effect. No tool predicts a benign outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.085092	Structured	0.029522	Uncertain	0.958	0.371	0.000							-16.096	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.922	Likely Pathogenic	0.1882	0.3654		3.95	Destabilizing	0.3	10.06	Destabilizing	7.01	Destabilizing	0.73	Ambiguous	-5.96	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-1.32	Pathogenic	0.01	Affected			0	-1	1.9	-31.01
c.1619A>G	Q540R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q540R has no ClinVar entry and is present in gnomAD (ID 6‑33438862‑A‑G). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools report uncertainty: premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from 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 benign impact, with only a minority of tools indicating pathogenicity. This conclusion does not contradict 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	GAP	0.085092	Structured	0.029522	Uncertain	0.958	0.371	0.000				6-33438862-A-G	1	6.19e-7	-13.312	Likely Pathogenic	0.540	Ambiguous	Likely Benign	0.795	Likely Pathogenic	0.1328	0.1886		-0.06	Likely Benign	0.0	-0.07	Likely Benign	-0.07	Likely Benign	0.88	Ambiguous	-3.98	Deleterious	0.991	Probably Damaging	0.985	Probably Damaging	-1.28	Pathogenic	0.08	Tolerated	3.37	35	1	1	-1.0	28.06
c.1619A>T	Q540L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q540L has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from Rosetta, Foldetta, premPS, and SIFT, while pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX is uncertain and therefore not considered. 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, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of evidence points to a pathogenic impact for Q540L, 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	GAP	0.085092	Structured	0.029522	Uncertain	0.958	0.371	0.000							-14.266	Likely Pathogenic	0.965	Likely Pathogenic	Likely Pathogenic	0.756	Likely Pathogenic	0.0654	0.3601		-0.71	Ambiguous	0.1	0.44	Likely Benign	-0.14	Likely Benign	0.50	Likely Benign	-6.96	Deleterious	0.994	Probably Damaging	0.977	Probably Damaging	-1.06	Pathogenic	0.08	Tolerated			-2	-2	7.3	-14.97
c.1620G>C	Q540H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q540H 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 predicts a benign effect. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. 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 (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the evidence strongly favors a pathogenic impact for Q540H, 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	GAP	0.085092	Structured	0.029522	Uncertain	0.958	0.371	0.000							-12.730	Likely Pathogenic	0.980	Likely Pathogenic	Likely Pathogenic	0.832	Likely Pathogenic	0.1179	0.2072		1.79	Ambiguous	0.6	1.46	Ambiguous	1.63	Ambiguous	0.72	Ambiguous	-4.97	Deleterious	0.998	Probably Damaging	0.993	Probably Damaging	-1.30	Pathogenic	0.03	Affected			3	0	0.3	9.01
c.1620G>T	Q540H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q540H 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 predicts a benign effect. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. 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 (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the evidence strongly favors a pathogenic impact for Q540H, 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	GAP	0.085092	Structured	0.029522	Uncertain	0.958	0.371	0.000							-12.730	Likely Pathogenic	0.980	Likely Pathogenic	Likely Pathogenic	0.832	Likely Pathogenic	0.1179	0.2072		1.79	Ambiguous	0.6	1.46	Ambiguous	1.63	Ambiguous	0.72	Ambiguous	-4.97	Deleterious	0.998	Probably Damaging	0.993	Probably Damaging	-1.30	Pathogenic	0.03	Affected			3	0	0.3	9.01
c.2137C>A	P713T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P713T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further clarify the picture: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic, whereas AlphaMissense‑Optimized and Foldetta provide inconclusive results and are treated as unavailable. Taken together, the preponderance of evidence points to a pathogenic effect for P713T, 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	GAP	0.271506	Structured	0.393235	Uncertain	0.961	0.371	0.000							-9.915	Likely Pathogenic	0.819	Likely Pathogenic	Ambiguous	0.225	Likely Benign	0.1417	0.3818		1.15	Ambiguous	0.0	0.46	Likely Benign	0.81	Ambiguous	0.65	Ambiguous	-6.72	Deleterious	1.000	Probably Damaging	0.993	Probably Damaging	3.34	Benign	0.00	Affected			0	-1	0.9	3.99
c.2137C>G	P713A 2D 3DClick to see structure in 3D Viewer AISynGAP1 P713A is not reported in ClinVar and is absent from gnomAD. Benign predictions are provided by REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; the SGM‑Consensus score is labeled Likely Pathogenic. FoldX, Foldetta, and premPS give uncertain results. High‑accuracy tools: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; Foldetta remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, 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	GAP	0.271506	Structured	0.393235	Uncertain	0.961	0.371	0.000							-8.535	Likely Pathogenic	0.689	Likely Pathogenic	Likely Benign	0.235	Likely Benign	0.3159	0.3475		1.04	Ambiguous	0.1	0.15	Likely Benign	0.60	Ambiguous	0.75	Ambiguous	-6.80	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	3.34	Benign	0.00	Affected			1	-1	3.4	-26.04
c.2137C>T	P713S 2D AIThe SynGAP1 missense variant P713S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, Rosetta, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are provided by FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight this ambiguity: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus indicates a likely pathogenic effect, and Foldetta likewise yields an uncertain stability change. Overall, the majority of tools lean toward a pathogenic interpretation, and this aligns 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	GAP	0.271506	Structured	0.393235	Uncertain	0.961	0.371	0.000							-8.496	Likely Pathogenic	0.846	Likely Pathogenic	Ambiguous	0.261	Likely Benign	0.3234	0.3674		0.91	Ambiguous	0.7	0.19	Likely Benign	0.55	Ambiguous	0.62	Ambiguous	-6.60	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	3.29	Benign	0.00	Affected			1	-1	0.8	-10.04
c.2138C>A	P713Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P713Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, FoldX, Foldetta, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain calls are made by Rosetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight this discordance: 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 a benign effect. Overall, the majority of evidence leans toward a benign interpretation, 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	GAP	0.271506	Structured	0.393235	Uncertain	0.961	0.371	0.000							-10.253	Likely Pathogenic	0.875	Likely Pathogenic	Ambiguous	0.364	Likely Benign	0.1225	0.3388		0.26	Likely Benign	0.0	-0.77	Ambiguous	-0.26	Likely Benign	0.95	Ambiguous	-6.38	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	3.37	Benign	0.00	Affected			0	-1	-1.9	31.01
c.2138C>G	P713R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P713R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The remaining tools, premPS and AlphaMissense‑Optimized, are inconclusive. 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 majority of predictions lean toward pathogenicity, while the most accurate methods give conflicting results. Thus, the variant is most likely pathogenic based on the current evidence, and this assessment does not contradict ClinVar status, which has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.271506	Structured	0.393235	Uncertain	0.961	0.371	0.000							-12.101	Likely Pathogenic	0.930	Likely Pathogenic	Ambiguous	0.331	Likely Benign	0.1366	0.2335		0.29	Likely Benign	0.0	0.21	Likely Benign	0.25	Likely Benign	0.86	Ambiguous	-7.42	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	3.29	Benign	0.00	Affected			0	-2	-2.9	59.07
c.2138C>T	P713L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P713L 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 REVEL, FoldX, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized and premPS are uncertain. 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 absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.271506	Structured	0.393235	Uncertain	0.961	0.371	0.000							-11.323	Likely Pathogenic	0.850	Likely Pathogenic	Ambiguous	0.324	Likely Benign	0.1993	0.5261		0.18	Likely Benign	0.1	-0.03	Likely Benign	0.08	Likely Benign	0.55	Ambiguous	-8.60	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	3.34	Benign	0.00	Affected			-3	-3	5.4	16.04
c.1207A>C	K403Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K403Q 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, and FATHMM. In contrast, a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. The premPS assessment is uncertain and does not influence the overall consensus. High‑accuracy analyses show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.275179	Structured	0.424920	Uncertain	0.960	0.372	0.000							-12.479	Likely Pathogenic	0.971	Likely Pathogenic	Likely Pathogenic	0.376	Likely Benign	0.4405	0.1954		0.36	Likely Benign	0.0	0.27	Likely Benign	0.32	Likely Benign	0.70	Ambiguous	-3.59	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	3.76	Benign	0.01	Affected			1	1	0.4	-0.04
c.1207A>G	K403E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K403E 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 FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for K403E, 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	0.275179	Structured	0.424920	Uncertain	0.960	0.372	0.000							-15.279	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.445	Likely Benign	0.3650	0.1715		1.01	Ambiguous	0.1	0.79	Ambiguous	0.90	Ambiguous	0.70	Ambiguous	-3.62	Deleterious	0.998	Probably Damaging	0.981	Probably Damaging	3.79	Benign	0.04	Affected			0	1	0.4	0.94
c.1208A>C	K403T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K403T 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, which scores the variant as benign. In contrast, 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 all classify the variant as pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; SGM‑Consensus predicts likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Other stability predictors (FoldX, Rosetta, premPS) are also uncertain. Overall, the consensus of the majority of tools indicates a pathogenic effect. This conclusion is not contradicted by 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	0.275179	Structured	0.424920	Uncertain	0.960	0.372	0.000							-13.135	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.522	Likely Pathogenic	0.1861	0.4230		1.41	Ambiguous	0.1	0.59	Ambiguous	1.00	Ambiguous	0.67	Ambiguous	-5.43	Deleterious	0.999	Probably Damaging	1.000	Probably Damaging	3.73	Benign	0.01	Affected			0	-1	3.2	-27.07
c.1208A>G	K403R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K403R 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, Foldetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The remaining tools—FoldX, ESM1b, 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) is inconclusive due to a tie, and Foldetta also predicts benign. Overall, the majority of evidence 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.		C2	0.275179	Structured	0.424920	Uncertain	0.960	0.372	0.000							-7.362	In-Between	0.355	Ambiguous	Likely Benign	0.335	Likely Benign	0.4834	0.1861		-0.78	Ambiguous	0.1	0.23	Likely Benign	-0.28	Likely Benign	0.41	Likely Benign	-2.56	Deleterious	0.983	Probably Damaging	0.926	Probably Damaging	3.91	Benign	0.15	Tolerated			3	2	-0.6	28.01
c.1208A>T	K403I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K403I 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, and FATHMM, while the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. 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 majority of predictions (nine pathogenic vs. five benign) and the high‑accuracy tools lean toward a pathogenic effect. Thus, 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	C2	0.275179	Structured	0.424920	Uncertain	0.960	0.372	0.000							-15.239	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.519	Likely Pathogenic	0.1223	0.4141		0.17	Likely Benign	0.1	-0.46	Likely Benign	-0.15	Likely Benign	0.36	Likely Benign	-7.27	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	3.70	Benign	0.00	Affected			-2	-3	8.4	-15.01
c.1209A>C	K403N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K403N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict a pathogenic impact. Predictions from FoldX, Foldetta, and premPS are uncertain or inconclusive and are treated as unavailable. 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 outputs) 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	0.275179	Structured	0.424920	Uncertain	0.960	0.372	0.000							-10.913	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.201	Likely Benign	0.3374	0.2492		1.87	Ambiguous	0.1	0.41	Likely Benign	1.14	Ambiguous	0.74	Ambiguous	-4.51	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	3.73	Benign	0.05	Affected			1	0	0.4	-14.07
c.1209A>T	K403N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K403N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict a pathogenic impact. Predictions from FoldX, Foldetta, and premPS are uncertain or inconclusive and are treated as unavailable. 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 outputs) 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	0.275179	Structured	0.424920	Uncertain	0.960	0.372	0.000							-10.913	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.201	Likely Benign	0.3374	0.2492		1.87	Ambiguous	0.1	0.41	Likely Benign	1.14	Ambiguous	0.74	Ambiguous	-4.51	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	3.73	Benign	0.05	Affected			1	0	0.4	-14.07
c.1066C>A	R356S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R356S is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL and SIFT, whereas the remaining tools—premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized—predict it to be pathogenic. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is inconclusive. Taken together, the preponderance of evidence points to a pathogenic effect for R356S, 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	0.219301	Structured	0.395028	Uncertain	0.802	0.373	0.250							-13.059	Likely Pathogenic	0.965	Likely Pathogenic	Likely Pathogenic	0.292	Likely Benign	0.2891	0.4491		1.00	Ambiguous	0.1	0.79	Ambiguous	0.90	Ambiguous	1.04	Destabilizing	-5.28	Deleterious	0.993	Probably Damaging	0.982	Probably Damaging	1.84	Pathogenic	0.07	Tolerated			0	-1	3.7	-69.11
c.1066C>G	R356G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R356G 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 REVEL and SIFT, while the majority of tools predict a pathogenic outcome: SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are uncertain and therefore treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Overall, the preponderance of pathogenic predictions indicates that the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which contains no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.219301	Structured	0.395028	Uncertain	0.802	0.373	0.250							-12.305	Likely Pathogenic	0.883	Likely Pathogenic	Ambiguous	0.271	Likely Benign	0.3505	0.3793		1.02	Ambiguous	0.0	1.80	Ambiguous	1.41	Ambiguous	1.06	Destabilizing	-6.20	Deleterious	0.993	Probably Damaging	0.982	Probably Damaging	1.95	Pathogenic	0.08	Tolerated			-3	-2	4.1	-99.14
c.1066C>T	R356C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R356C is listed in ClinVar as Benign (ClinVar ID 469145.0) and is present in gnomAD (ID 6‑33437971‑C‑T). Functional prediction tools cluster into two groups: benign predictions from REVEL and AlphaMissense‑Optimized, and pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. Uncertain results are reported 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 majority of evidence points to a pathogenic effect, contradicting the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.219301	Structured	0.395028	Uncertain	0.802	0.373	0.250	Likely Benign		1	6-33437971-C-T	5	3.10e-6	-11.827	Likely Pathogenic	0.774	Likely Pathogenic	Likely Benign	0.312	Likely Benign	0.3238	0.3618		0.76	Ambiguous	0.0	1.19	Ambiguous	0.98	Ambiguous	0.84	Ambiguous	-7.12	Deleterious	1.000	Probably Damaging	0.990	Probably Damaging	1.67	Pathogenic	0.00	Affected	3.39	22	-4	-3	7.0	-53.05	212.3	91.0	-0.1	0.3	-0.3	0.1		X						Potentially Pathogenic	Arg356 is located in a loop that includes a short helical section and connects two anti-parallel β sheet strands (res. Gly341-Pro349, res. Thr359-Pro364). In the WT simulations, the guanidinium group of Arg356 alternately forms salt bridges with the carboxylate groups of the GAP domain residues, Glu446 and Glu698. Arg356 also forms hydrogen bonds with the hydroxyl group of the GAP domain residue Thr691 and interacts with Met409 at the C2-GAP interface.In the variant simulations, the Cys356 mutation fails to maintain any of the Arg356 interactions and only occasionally forms weak hydrogen bonds with nearby C2 domain residues (e.g., Gln407). Although no negative structural effects are observed during the simulations, Arg356 is located at the C2 and GAP domain interface, making the residue swap potentially detrimental to the tertiary structure assembly.
c.1067G>A	R356H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R356H is recorded in ClinVar as benign (ClinVar ID 2984966.0) and is present in the gnomAD database (6‑33437972‑G‑A). Prediction tools that indicate a benign effect include REVEL, Rosetta, Foldetta, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default, with the SGM‑Consensus also labeling it likely pathogenic. 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 predictions support a pathogenic impact, which contradicts the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.219301	Structured	0.395028	Uncertain	0.802	0.373	0.250	Likely Benign		1	6-33437972-G-A	9	5.66e-6	-11.453	Likely Pathogenic	0.614	Likely Pathogenic	Likely Benign	0.314	Likely Benign	0.3493	0.2206		0.59	Ambiguous	0.1	-0.27	Likely Benign	0.16	Likely Benign	1.17	Destabilizing	-4.43	Deleterious	0.999	Probably Damaging	0.987	Probably Damaging	1.70	Pathogenic	0.01	Affected	3.39	22	0	2	1.3	-19.05
c.1067G>C	R356P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R356P missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FoldX, whereas a majority of tools (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive are AlphaMissense‑Optimized, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, 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 preponderance of evidence points to a pathogenic effect for R356P, 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	0.219301	Structured	0.395028	Uncertain	0.802	0.373	0.250							-12.956	Likely Pathogenic	0.919	Likely Pathogenic	Ambiguous	0.451	Likely Benign	0.2213	0.5033		0.48	Likely Benign	0.1	0.72	Ambiguous	0.60	Ambiguous	1.05	Destabilizing	-6.23	Deleterious	0.998	Probably Damaging	0.992	Probably Damaging	1.72	Pathogenic	0.02	Affected			0	-2	2.9	-59.07
c.1067G>T	R356L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R356L is not reported in ClinVar and is present in gnomAD (ID 6‑33437972‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, FoldX, and Foldetta, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are AlphaMissense‑Optimized, Rosetta, and premPS. 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 benign. Overall, the preponderance of evidence points to a pathogenic effect for R356L, and this conclusion 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	C2	0.219301	Structured	0.395028	Uncertain	0.802	0.373	0.250				6-33437972-G-T			-13.957	Likely Pathogenic	0.911	Likely Pathogenic	Ambiguous	0.412	Likely Benign	0.2110	0.5242		-0.04	Likely Benign	0.1	-0.57	Ambiguous	-0.31	Likely Benign	0.68	Ambiguous	-6.20	Deleterious	0.993	Probably Damaging	0.982	Probably Damaging	1.69	Pathogenic	0.02	Affected	3.39	22	-2	-3	8.3	-43.03
c.1564G>A	E522K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E522K has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from Rosetta, Foldetta, premPS, and SIFT, while pathogenic calls are made by REVEL, PROVEAN, both polyPhen‑2 versions, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further indicate AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus also predicts Likely Pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts Benign. No prediction is available from FoldX (Uncertain). Overall, the majority of high‑confidence tools lean toward pathogenicity, 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	GAP	0.092881	Structured	0.046216	Uncertain	0.823	0.376	0.000							-12.637	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.631	Likely Pathogenic	0.2019	0.4291		-0.69	Ambiguous	0.1	0.14	Likely Benign	-0.28	Likely Benign	-0.13	Likely Benign	-3.81	Deleterious	0.994	Probably Damaging	0.994	Probably Damaging	-1.09	Pathogenic	0.23	Tolerated			0	1	-0.4	-0.94
c.1564G>C	E522Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E522Q is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools show a split: benign predictions come from FoldX, Rosetta, Foldetta, premPS, and SIFT, whereas pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods reinforce this pattern: AlphaMissense‑Optimized classifies the change as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also labels it likely pathogenic, while Foldetta predicts a benign effect on protein stability. Overall, the majority of evidence points to a pathogenic impact. This assessment does not conflict with ClinVar, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.092881	Structured	0.046216	Uncertain	0.823	0.376	0.000							-10.861	Likely Pathogenic	0.987	Likely Pathogenic	Likely Pathogenic	0.560	Likely Pathogenic	0.0944	0.4130		-0.13	Likely Benign	0.1	-0.06	Likely Benign	-0.10	Likely Benign	0.03	Likely Benign	-2.85	Deleterious	0.992	Probably Damaging	0.993	Probably Damaging	-1.33	Pathogenic	0.07	Tolerated			2	2	0.0	-0.98
c.1565A>C	E522A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E522A 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, Rosetta, Foldetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the preponderance of evidence (10 pathogenic vs. 4 benign predictions) indicates that E522A is most likely pathogenic, 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	GAP	0.092881	Structured	0.046216	Uncertain	0.823	0.376	0.000							-10.509	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	0.739	Likely Pathogenic	0.3137	0.4128		0.18	Likely Benign	0.1	0.01	Likely Benign	0.10	Likely Benign	0.40	Likely Benign	-5.67	Deleterious	0.998	Probably Damaging	0.999	Probably Damaging	-1.34	Pathogenic	0.02	Affected			0	-1	5.3	-58.04
c.1565A>G	E522G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E522G missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as deleterious. No tool reports a benign outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a damaging effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, while Foldetta’s stability analysis is inconclusive. FoldX, Rosetta, and premPS are uncertain and are treated as unavailable evidence. Overall, the computational evidence overwhelmingly points to a pathogenic impact, 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	GAP	0.092881	Structured	0.046216	Uncertain	0.823	0.376	0.000							-10.053	Likely Pathogenic	0.986	Likely Pathogenic	Likely Pathogenic	0.823	Likely Pathogenic	0.2672	0.3654		0.72	Ambiguous	0.0	1.62	Ambiguous	1.17	Ambiguous	0.58	Ambiguous	-6.59	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	-1.34	Pathogenic	0.01	Affected			0	-2	3.1	-72.06
c.1565A>T	E522V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E522V 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 FoldX, Rosetta, Foldetta, and premPS, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—consistently predict a pathogenic or likely 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) also indicates likely pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of evidence points to a pathogenic effect, 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	GAP	0.092881	Structured	0.046216	Uncertain	0.823	0.376	0.000							-11.985	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	0.751	Likely Pathogenic	0.0537	0.4514		0.09	Likely Benign	0.2	0.00	Likely Benign	0.05	Likely Benign	0.18	Likely Benign	-6.59	Deleterious	0.995	Probably Damaging	0.996	Probably Damaging	-1.31	Pathogenic	0.01	Affected			-2	-2	7.7	-29.98
c.1566A>C	E522D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E522D missense variant is not reported in ClinVar and has no gnomAD entry. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and ESM1b, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, indicates a benign effect. Overall, the balance of evidence points to a likely pathogenic impact for E522D, 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	GAP	0.092881	Structured	0.046216	Uncertain	0.823	0.376	0.000							-5.385	Likely Benign	0.984	Likely Pathogenic	Likely Pathogenic	0.494	Likely Benign	0.1499	0.2765		0.04	Likely Benign	0.1	-0.02	Likely Benign	0.01	Likely Benign	0.32	Likely Benign	-2.65	Deleterious	0.986	Probably Damaging	0.989	Probably Damaging	-1.33	Pathogenic	0.10	Tolerated			3	2	0.0	-14.03
c.1566A>T	E522D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E522D missense variant is not reported in ClinVar and has no gnomAD entry. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and ESM1b, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, indicates a benign effect. Overall, the balance of evidence points to a likely pathogenic impact for E522D, 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	GAP	0.092881	Structured	0.046216	Uncertain	0.823	0.376	0.000							-5.385	Likely Benign	0.984	Likely Pathogenic	Likely Pathogenic	0.494	Likely Benign	0.1499	0.2765		0.04	Likely Benign	0.1	-0.02	Likely Benign	0.01	Likely Benign	0.32	Likely Benign	-2.65	Deleterious	0.986	Probably Damaging	0.989	Probably Damaging	-1.33	Pathogenic	0.10	Tolerated			3	2	0.0	-14.03
c.2122C>A	L708I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708I is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the substitution as benign: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and FATHMM. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Consequently, the variant is most likely benign based on current predictions, 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 Benign	GAP	0.250310	Structured	0.365875	Uncertain	0.931	0.378	0.000							-4.406	Likely Benign	0.116	Likely Benign	Likely Benign	0.108	Likely Benign	0.0749	0.2729		0.42	Likely Benign	0.0	-0.21	Likely Benign	0.11	Likely Benign	-0.05	Likely Benign	0.02	Neutral	0.022	Benign	0.021	Benign	3.34	Benign	0.20	Tolerated			2	2	0.7	0.00
c.2122C>G	L708V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708V is not reported in ClinVar and is absent from gnomAD. 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 are from FoldX (uncertain) and Foldetta (uncertain). 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 remains uncertain. Overall, the evidence strongly indicates that 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	GAP	0.250310	Structured	0.365875	Uncertain	0.931	0.378	0.000							-4.361	Likely Benign	0.097	Likely Benign	Likely Benign	0.122	Likely Benign	0.1094	0.2460		1.59	Ambiguous	0.0	0.12	Likely Benign	0.86	Ambiguous	-0.02	Likely Benign	-0.23	Neutral	0.158	Benign	0.035	Benign	3.35	Benign	0.94	Tolerated			2	1	0.4	-14.03
c.2122C>T	L708F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L708F is not reported in ClinVar and is present in gnomAD (ID 6‑33441587‑C‑T). Functional prediction tools that reach consensus classify the change as benign: REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Pathogenic predictions are limited to polyPhen‑2 HumDiv and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) return uncertain or no result. High‑accuracy assessments give AlphaMissense‑Optimized a benign score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta indicates no significant destabilization (uncertain). Overall, the preponderance of evidence supports a benign effect for L708F, 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.		GAP	0.250310	Structured	0.365875	Uncertain	0.931	0.378	0.000				6-33441587-C-T	2	1.24e-6	-9.154	Likely Pathogenic	0.436	Ambiguous	Likely Benign	0.110	Likely Benign	0.0497	0.2366		1.48	Ambiguous	0.3	0.93	Ambiguous	1.21	Ambiguous	0.37	Likely Benign	-2.46	Neutral	0.931	Possibly Damaging	0.326	Benign	3.29	Benign	0.07	Tolerated	3.50	9	0	2	-1.0	34.02
c.2123T>A	L708H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708H is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default; the SGM Consensus score is also labeled Likely Pathogenic. Stability‑based methods FoldX and Rosetta return uncertain results, and Foldetta likewise is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, whereas a few high‑accuracy tools suggest benign or are inconclusive. Thus, the variant is most likely pathogenic based on the prevailing predictions, 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	GAP	0.250310	Structured	0.365875	Uncertain	0.931	0.378	0.000							-8.059	Likely Pathogenic	0.677	Likely Pathogenic	Likely Benign	0.243	Likely Benign	0.0824	0.0288		1.84	Ambiguous	0.1	1.55	Ambiguous	1.70	Ambiguous	1.44	Destabilizing	-4.68	Deleterious	1.000	Probably Damaging	0.981	Probably Damaging	3.25	Benign	0.02	Affected			-2	-3	-7.0	23.98
c.2123T>C	L708P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708P is not reported in ClinVar and is absent from gnomAD. Consensus among most in‑silico predictors is strongly pathogenic: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a deleterious effect. Only REVEL and FATHMM predict a benign outcome, while AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, SGM Consensus reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic change. Taken together, the preponderance of evidence points to a pathogenic impact for L708P, 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	GAP	0.250310	Structured	0.365875	Uncertain	0.931	0.378	0.000							-10.268	Likely Pathogenic	0.932	Likely Pathogenic	Ambiguous	0.298	Likely Benign	0.2800	0.0825		4.29	Destabilizing	0.1	6.43	Destabilizing	5.36	Destabilizing	1.62	Destabilizing	-4.47	Deleterious	1.000	Probably Damaging	0.989	Probably Damaging	3.39	Benign	0.04	Affected			-3	-3	-5.4	-16.04
c.2123T>G	L708R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as Likely Pathogenic. FoldX, 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 tools (six pathogenic vs. four benign) and the SGM Consensus support a pathogenic classification, whereas AlphaMissense‑Optimized suggests benign. The variant is most likely pathogenic based on the collective predictions, 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	GAP	0.250310	Structured	0.365875	Uncertain	0.931	0.378	0.000							-9.154	Likely Pathogenic	0.638	Likely Pathogenic	Likely Benign	0.249	Likely Benign	0.1091	0.0488		0.87	Ambiguous	0.0	0.90	Ambiguous	0.89	Ambiguous	1.24	Destabilizing	-4.18	Deleterious	0.988	Probably Damaging	0.598	Possibly Damaging	3.27	Benign	0.19	Tolerated			-3	-2	-8.3	43.03
c.1999A>C	I667L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I667L 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, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Default—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 consistent with the lack of ClinVar annotation and gnomAD presence, indicating no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.142424	Structured	0.083597	Uncertain	0.927	0.379	0.000							-10.452	Likely Pathogenic	0.459	Ambiguous	Likely Benign	0.300	Likely Benign	0.0980	0.3145		0.93	Ambiguous	0.2	0.72	Ambiguous	0.83	Ambiguous	0.75	Ambiguous	-1.97	Neutral	0.457	Possibly Damaging	0.392	Benign	3.36	Benign	0.13	Tolerated			2	2	-0.7	0.00
c.1999A>G	I667V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I667V 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, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Only ESM1b predicts a pathogenic outcome; all other tools (FoldX, Rosetta, premPS, AlphaMissense‑Default, Foldetta) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority vote. Foldetta’s stability prediction is uncertain. Overall, the preponderance of evidence points to a benign 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.		GAP	0.142424	Structured	0.083597	Uncertain	0.927	0.379	0.000							-8.482	Likely Pathogenic	0.406	Ambiguous	Likely Benign	0.234	Likely Benign	0.1178	0.3059		1.32	Ambiguous	0.0	1.06	Ambiguous	1.19	Ambiguous	0.85	Ambiguous	-0.86	Neutral	0.341	Benign	0.052	Benign	3.35	Benign	0.15	Tolerated			4	3	-0.3	-14.03
c.1999A>T	I667F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I667F missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign calls are limited to FATHMM, while the remaining 11 predictors—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—classify the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a pathogenic effect. No prediction is inconclusive. 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	GAP	0.142424	Structured	0.083597	Uncertain	0.927	0.379	0.000							-14.389	Likely Pathogenic	0.963	Likely Pathogenic	Likely Pathogenic	0.569	Likely Pathogenic	0.0668	0.2648		7.55	Destabilizing	0.3	1.80	Ambiguous	4.68	Destabilizing	0.86	Ambiguous	-3.98	Deleterious	0.998	Probably Damaging	0.790	Possibly Damaging	2.96	Benign	0.00	Affected			1	0	-1.7	34.02
c.2000T>A	I667N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I667N 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 all other evaluated algorithms—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 assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No prediction or folding 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 the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.142424	Structured	0.083597	Uncertain	0.927	0.379	0.000							-15.730	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.572	Likely Pathogenic	0.0841	0.0470		2.89	Destabilizing	0.2	2.84	Destabilizing	2.87	Destabilizing	2.56	Destabilizing	-6.73	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	2.95	Benign	0.00	Affected			-2	-3	-8.0	0.94
c.2000T>C	I667T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I667T 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 all other evaluated algorithms—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 scores the variant as pathogenic; 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 calculations, also predicts pathogenicity. Based on the collective evidence, 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	GAP	0.142424	Structured	0.083597	Uncertain	0.927	0.379	0.000							-11.917	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	0.676	Likely Pathogenic	0.0967	0.0608		3.29	Destabilizing	0.1	2.44	Destabilizing	2.87	Destabilizing	2.23	Destabilizing	-4.81	Deleterious	1.000	Probably Damaging	0.985	Probably Damaging	2.98	Benign	0.00	Affected			0	-1	-5.2	-12.05
c.2000T>G	I667S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I667S 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 all other evaluated algorithms—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 further support a deleterious impact: 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) 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 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	GAP	0.142424	Structured	0.083597	Uncertain	0.927	0.379	0.000							-14.328	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.690	Likely Pathogenic	0.2462	0.0858		3.69	Destabilizing	0.1	3.97	Destabilizing	3.83	Destabilizing	2.48	Destabilizing	-5.90	Deleterious	1.000	Probably Damaging	0.995	Probably Damaging	2.96	Benign	0.00	Affected			-1	-2	-5.3	-26.08
c.2001C>G	I667M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I667M 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, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy methods give AlphaMissense‑Optimized a benign prediction, SGM‑Consensus a pathogenic prediction (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta an uncertain result. Overall, the majority of evidence—including the high‑accuracy consensus—points to a pathogenic impact. 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	GAP	0.142424	Structured	0.083597	Uncertain	0.927	0.379	0.000							-10.679	Likely Pathogenic	0.579	Likely Pathogenic	Likely Benign	0.360	Likely Benign	0.0746	0.2612		1.29	Ambiguous	0.3	1.68	Ambiguous	1.49	Ambiguous	0.92	Ambiguous	-2.90	Deleterious	1.000	Probably Damaging	0.993	Probably Damaging	2.98	Benign	0.00	Affected			2	1	-2.6	18.03
c.2125C>A	L709M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. 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) also predicts benign. No predictions are 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 is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.243554	Structured	0.365830	Uncertain	0.934	0.379	0.000							-5.242	Likely Benign	0.108	Likely Benign	Likely Benign	0.065	Likely Benign	0.0629	0.2409		0.18	Likely Benign	0.0	0.40	Likely Benign	0.29	Likely Benign	-0.10	Likely Benign	0.03	Neutral	0.688	Possibly Damaging	0.235	Benign	3.41	Benign	0.17	Tolerated			4	2	-1.9	18.03
c.2125C>G	L709V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709V is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool that produced a definitive call classifies the variant as benign: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. The only inconclusive results are FoldX (uncertain) and Foldetta (uncertain), which are treated as unavailable evidence. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also benign; Foldetta remains uncertain. Consequently, the variant is most likely benign, 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 Benign	GAP	0.243554	Structured	0.365830	Uncertain	0.934	0.379	0.000							-4.406	Likely Benign	0.101	Likely Benign	Likely Benign	0.063	Likely Benign	0.1162	0.2460		0.75	Ambiguous	0.0	0.42	Likely Benign	0.59	Ambiguous	0.03	Likely Benign	-0.36	Neutral	0.062	Benign	0.016	Benign	3.42	Benign	0.45	Tolerated			2	1	0.4	-14.03
c.2126T>A	L709Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709Q 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, 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) predicts benign stability. Thus, the variant is most likely benign, 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	GAP	0.243554	Structured	0.365830	Uncertain	0.934	0.379	0.000							-5.758	Likely Benign	0.179	Likely Benign	Likely Benign	0.033	Likely Benign	0.0838	0.0488		0.13	Likely Benign	0.0	0.40	Likely Benign	0.27	Likely Benign	0.18	Likely Benign	-0.78	Neutral	0.998	Probably Damaging	0.923	Probably Damaging	3.52	Benign	0.48	Tolerated			-2	-2	-7.3	14.97
c.2126T>C	L709P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709P is not reported in ClinVar and is absent from gnomAD. Benign predictions come from REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from FoldX, Rosetta, Foldetta, polyPhen2_HumDiv, polyPhen2_HumVar, and AlphaMissense‑Default. High‑accuracy tools give mixed results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, FATHMM, PROVEAN) also predicts benign; Foldetta predicts pathogenic. Because the majority of standard predictors and the SGM Consensus favor benign, the variant is most likely benign, and this is consistent with the lack of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.243554	Structured	0.365830	Uncertain	0.934	0.379	0.000							-7.517	In-Between	0.767	Likely Pathogenic	Likely Benign	0.167	Likely Benign	0.3004	0.0825		2.81	Destabilizing	0.0	5.65	Destabilizing	4.23	Destabilizing	0.31	Likely Benign	-1.93	Neutral	1.000	Probably Damaging	0.975	Probably Damaging	3.47	Benign	0.37	Tolerated			-3	-3	-5.4	-16.04
c.2126T>G	L709R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709R 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, SIFT, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. Tools with uncertain or inconclusive results are Rosetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Overall, the majority of evidence indicates a benign impact for the variant, 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.		GAP	0.243554	Structured	0.365830	Uncertain	0.934	0.379	0.000							-8.636	Likely Pathogenic	0.482	Ambiguous	Likely Benign	0.061	Likely Benign	0.1127	0.0488		0.22	Likely Benign	0.0	0.68	Ambiguous	0.45	Likely Benign	0.62	Ambiguous	-1.56	Neutral	0.906	Possibly Damaging	0.314	Benign	3.50	Benign	0.44	Tolerated			-3	-2	-8.3	43.03
c.2146C>G	R716G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R716G 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, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified 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. Other stability predictors (FoldX, Rosetta, premPS) are also Uncertain. Overall, the balance of evidence from the majority of tools and the SGM‑Consensus indicates a pathogenic effect, 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	GAP	0.247041	Structured	0.419135	Uncertain	0.962	0.379	0.000							-9.927	Likely Pathogenic	0.728	Likely Pathogenic	Likely Benign	0.359	Likely Benign	0.3437	0.2466		1.32	Ambiguous	0.1	1.63	Ambiguous	1.48	Ambiguous	0.72	Ambiguous	-5.70	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	3.36	Benign	0.01	Affected			-3	-2	4.1	-99.14
c.2146C>T	R716W 2D 3DClick to see structure in 3D Viewer AIClinVar has no entry for this SynGAP1 R716W variant, and it is present in the gnomAD database (ID 6‑33441611‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Optimized, premPS, and Foldetta, while those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic. With two high‑accuracy tools supporting benign and one supporting pathogenic, the overall prediction leans toward a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.247041	Structured	0.419135	Uncertain	0.962	0.379	0.000				6-33441611-C-T	5	3.10e-6	-11.543	Likely Pathogenic	0.766	Likely Pathogenic	Likely Benign	0.339	Likely Benign	0.1303	0.3252		-0.11	Likely Benign	0.0	0.87	Ambiguous	0.38	Likely Benign	0.31	Likely Benign	-6.72	Deleterious	1.000	Probably Damaging	0.995	Probably Damaging	3.32	Benign	0.00	Affected	3.50	9	-3	2	3.6	30.03
c.2147G>A	R716Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R716Q is listed in ClinVar with an uncertain significance (ClinVar ID 411585.0) and is present in gnomAD (ID 6‑33441612‑G‑A). Functional prediction tools that report a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b, while premPS is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the balance of evidence leans toward 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.		GAP	0.247041	Structured	0.419135	Uncertain	0.962	0.379	0.000	Conflicting		2	6-33441612-G-A	4	2.48e-6	-8.338	Likely Pathogenic	0.308	Likely Benign	Likely Benign	0.210	Likely Benign	0.2834	0.2180		-0.01	Likely Benign	0.0	0.47	Likely Benign	0.23	Likely Benign	0.58	Ambiguous	-3.14	Deleterious	1.000	Probably Damaging	0.990	Probably Damaging	3.35	Benign	0.02	Affected	3.50	9	1	1	1.0	-28.06	250.0	48.9	0.0	0.0	-0.5	0.0						X		Uncertain	The guanidinium group of Arg716, located on the outer surface of an α-helix (res. Leu714-Arg726), forms a salt bridge with the carboxylate group of Asp720. In the variant simulations, the carboxamide group of Gln716 also forms a hydrogen bond with the carboxylate group of Asp720, although this bond is weaker than the Arg716 salt bridge in the WT. Overall, no adverse effects on the protein structure are observed in the simulations. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations.
c.2147G>C	R716P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R716P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, and FATHMM; pathogenic predictions come from AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, Rosetta, Foldetta, and the SGM‑Consensus score. 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, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or stability result is missing or inconclusive. 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	GAP	0.247041	Structured	0.419135	Uncertain	0.962	0.379	0.000							-10.744	Likely Pathogenic	0.956	Likely Pathogenic	Likely Pathogenic	0.320	Likely Benign	0.2140	0.3576		0.18	Likely Benign	0.1	5.67	Destabilizing	2.93	Destabilizing	0.49	Likely Benign	-5.75	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	3.33	Benign	0.01	Affected			0	-2	2.9	-59.07
c.2147G>T	R716L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R716L 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, FATHMM, premPS, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions (7/13) lean toward pathogenicity, with a near‑even split and a slight edge for pathogenic. The variant is therefore most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for R716L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.247041	Structured	0.419135	Uncertain	0.962	0.379	0.000							-10.690	Likely Pathogenic	0.713	Likely Pathogenic	Likely Benign	0.289	Likely Benign	0.1701	0.3775		0.31	Likely Benign	0.0	0.51	Ambiguous	0.41	Likely Benign	0.37	Likely Benign	-5.70	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	3.46	Benign	0.01	Affected			-3	-2	8.3	-43.03
c.2005A>C	N669H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669H has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) are uncertain 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, the majority of evidence points toward a pathogenic impact, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.142424	Structured	0.086615	Uncertain	0.872	0.380	0.000							-10.364	Likely Pathogenic	0.421	Ambiguous	Likely Benign	0.432	Likely Benign	0.1732	0.4839		1.26	Ambiguous	0.2	1.69	Ambiguous	1.48	Ambiguous	0.80	Ambiguous	-4.49	Deleterious	0.999	Probably Damaging	0.993	Probably Damaging	3.35	Benign	0.01	Affected			2	1	0.3	23.04
c.2005A>G	N669D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N669D has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, leans toward pathogenicity (3/4 votes). High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote) predicts pathogenic, and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. Overall, the majority of high‑confidence tools (AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus majority) suggest a pathogenic effect, but the presence of several benign predictions introduces uncertainty. Based on the current computational evidence, the variant is most likely pathogenic, which 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	GAP	0.142424	Structured	0.086615	Uncertain	0.872	0.380	0.000							-10.384	Likely Pathogenic	0.674	Likely Pathogenic	Likely Benign	0.336	Likely Benign	0.2182	0.2827		0.53	Ambiguous	0.2	0.00	Likely Benign	0.27	Likely Benign	1.00	Destabilizing	-4.45	Deleterious	0.999	Probably Damaging	0.990	Probably Damaging	3.50	Benign	0.07	Tolerated			2	1	0.0	0.98
c.2005A>T	N669Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669Y is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include FoldX, FATHMM, and premPS. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, 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 uncertain. With eight pathogenic predictions versus three benign, the overall evidence points to a pathogenic impact. This conclusion is not contradicted by 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	GAP	0.142424	Structured	0.086615	Uncertain	0.872	0.380	0.000							-13.548	Likely Pathogenic	0.802	Likely Pathogenic	Ambiguous	0.546	Likely Pathogenic	0.0666	0.4151		0.45	Likely Benign	0.4	1.29	Ambiguous	0.87	Ambiguous	0.21	Likely Benign	-7.01	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	3.34	Benign	0.00	Affected			-2	-2	2.2	49.07
c.2006A>C	N669T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy methods give a split verdict: AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts it to be pathogenic; Foldetta remains inconclusive. Overall, the majority of tools favor a pathogenic interpretation, and this assessment 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	GAP	0.142424	Structured	0.086615	Uncertain	0.872	0.380	0.000							-9.875	Likely Pathogenic	0.565	Likely Pathogenic	Likely Benign	0.292	Likely Benign	0.1504	0.4803		0.74	Ambiguous	0.1	0.68	Ambiguous	0.71	Ambiguous	0.49	Likely Benign	-5.25	Deleterious	0.991	Probably Damaging	0.962	Probably Damaging	3.50	Benign	0.17	Tolerated			0	0	2.8	-13.00
c.2006A>G	N669S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669S is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33441265‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. 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 (combining FoldX‑MD and Rosetta) is also inconclusive. No folding‑stability metrics (FoldX, Rosetta, Foldetta) provide definitive evidence. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.142424	Structured	0.086615	Uncertain	0.872	0.380	0.000				6-33441265-A-G	3	1.86e-6	-8.369	Likely Pathogenic	0.187	Likely Benign	Likely Benign	0.210	Likely Benign	0.3521	0.4480		0.55	Ambiguous	0.1	1.88	Ambiguous	1.22	Ambiguous	0.35	Likely Benign	-4.02	Deleterious	0.999	Probably Damaging	0.960	Probably Damaging	3.52	Benign	0.14	Tolerated	3.39	27	1	1	2.7	-27.03
c.2006A>T	N669I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N669I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include premPS and FATHMM, whereas the remaining ten tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the majority‑vote SGM‑Consensus—predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain (treated as unavailable), SGM‑Consensus as likely pathogenic, and Foldetta as uncertain (also treated as unavailable). The overall consensus of the available predictions leans strongly toward pathogenicity, and this conclusion does not conflict with 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	GAP	0.142424	Structured	0.086615	Uncertain	0.872	0.380	0.000							-13.324	Likely Pathogenic	0.862	Likely Pathogenic	Ambiguous	0.517	Likely Pathogenic	0.0749	0.4697		0.84	Ambiguous	0.0	1.09	Ambiguous	0.97	Ambiguous	0.31	Likely Benign	-8.18	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	3.34	Benign	0.00	Affected			-2	-3	8.0	-0.94
c.2007T>A	N669K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 outputs, yields an uncertain result. Overall, the majority of evidence points toward 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	GAP	0.142424	Structured	0.086615	Uncertain	0.872	0.380	0.000							-10.797	Likely Pathogenic	0.957	Likely Pathogenic	Likely Pathogenic	0.243	Likely Benign	0.2647	0.3312		0.39	Likely Benign	0.3	1.50	Ambiguous	0.95	Ambiguous	0.94	Ambiguous	-5.35	Deleterious	0.999	Probably Damaging	0.989	Probably Damaging	3.41	Benign	0.03	Affected			1	0	-0.4	14.07
c.2007T>G	N669K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, 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 pathogenicity, SGM‑Consensus concurs, and the Foldetta stability analysis is inconclusive and therefore not used as evidence. No other tools provide definitive support for benignity. Consequently, the preponderance of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.142424	Structured	0.086615	Uncertain	0.872	0.380	0.000							-10.797	Likely Pathogenic	0.957	Likely Pathogenic	Likely Pathogenic	0.243	Likely Benign	0.2647	0.3312		0.39	Likely Benign	0.3	1.50	Ambiguous	0.95	Ambiguous	0.94	Ambiguous	-5.35	Deleterious	0.999	Probably Damaging	0.989	Probably Damaging	3.41	Benign	0.03	Affected			1	0	-0.4	14.07
c.1573G>A	E525K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E525K is reported in gnomAD (ID 6‑33438816‑G‑A) but has no ClinVar entry. Functional prediction tools show a split assessment: benign predictions come from FoldX, Rosetta, Foldetta, 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 (majority vote). The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as pathogenic, the SGM‑Consensus also indicates likely pathogenic, while the Foldetta stability analysis predicts a benign effect. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence points toward a pathogenic effect, 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	GAP	0.206376	Structured	0.023618	Uncertain	0.937	0.382	0.125				6-33438816-G-A	1	6.20e-7	-15.628	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	0.629	Likely Pathogenic	0.2349	0.4293		-0.13	Likely Benign	0.5	0.34	Likely Benign	0.11	Likely Benign	0.96	Ambiguous	-3.98	Deleterious	0.999	Probably Damaging	0.988	Probably Damaging	2.71	Benign	0.00	Affected	3.37	35	1	0	-0.4	-0.94
c.1573G>C	E525Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E525Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely disagree: benign predictions come from Rosetta, Foldetta, and FATHMM, while pathogenic predictions are returned by 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 (integrating FoldX‑MD and Rosetta) as benign. Overall, the majority of evidence points toward a pathogenic 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.	Likely Pathogenic	GAP	0.206376	Structured	0.023618	Uncertain	0.937	0.382	0.125							-13.722	Likely Pathogenic	0.961	Likely Pathogenic	Likely Pathogenic	0.516	Likely Pathogenic	0.1173	0.3962		1.05	Ambiguous	0.7	-0.11	Likely Benign	0.47	Likely Benign	0.84	Ambiguous	-2.98	Deleterious	0.998	Probably Damaging	0.992	Probably Damaging	2.68	Benign	0.00	Affected			2	2	0.0	-0.98
c.1574A>C	E525A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E525A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Foldetta, premPS, and FATHMM, whereas the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic effect. 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) is labeled Likely Pathogenic, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the preponderance of evidence from both general and high‑accuracy tools points to a pathogenic classification for E525A, 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.	Likely Pathogenic	GAP	0.206376	Structured	0.023618	Uncertain	0.937	0.382	0.125							-12.627	Likely Pathogenic	0.977	Likely Pathogenic	Likely Pathogenic	0.680	Likely Pathogenic	0.3554	0.3960		1.23	Ambiguous	0.6	-0.62	Ambiguous	0.31	Likely Benign	0.09	Likely Benign	-5.97	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	2.68	Benign	0.00	Affected			0	-1	5.3	-58.04
c.1574A>G	E525G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E525G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized returns a pathogenic score, the SGM‑Consensus also indicates pathogenicity, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. Taken together, the overwhelming majority of evidence points to a pathogenic impact for E525G. This conclusion is consistent with the absence of ClinVar annotation and gnomAD data, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.206376	Structured	0.023618	Uncertain	0.937	0.382	0.125							-13.181	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	0.691	Likely Pathogenic	0.2947	0.3886		1.71	Ambiguous	0.6	0.90	Ambiguous	1.31	Ambiguous	0.78	Ambiguous	-6.96	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	2.68	Benign	0.00	Affected			0	-2	3.1	-72.06
c.1574A>T	E525V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E525V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Foldetta, 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 outcome; FoldX and Rosetta 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 (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic effect for E525V, 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	GAP	0.206376	Structured	0.023618	Uncertain	0.937	0.382	0.125							-13.622	Likely Pathogenic	0.989	Likely Pathogenic	Likely Pathogenic	0.683	Likely Pathogenic	0.0721	0.4946		1.10	Ambiguous	0.7	-0.69	Ambiguous	0.21	Likely Benign	0.00	Likely Benign	-6.96	Deleterious	0.996	Probably Damaging	0.991	Probably Damaging	2.66	Benign	0.00	Affected			-2	-2	7.7	-29.98
c.1575G>C	E525D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E525D 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, FATHMM, and Foldetta, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta provide uncertain results and are therefore not used to weigh the overall assessment. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic, while Foldetta predicts benign. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic effect for E525D. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.206376	Structured	0.023618	Uncertain	0.937	0.382	0.125							-11.207	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	0.362	Likely Benign	0.1876	0.2197		0.78	Ambiguous	0.6	-0.55	Ambiguous	0.12	Likely Benign	1.00	Destabilizing	-2.98	Deleterious	0.989	Probably Damaging	0.979	Probably Damaging	2.90	Benign	0.00	Affected			3	2	0.0	-14.03
c.1575G>T	E525D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E525D 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, FATHMM, and Foldetta, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta provide uncertain results and are not counted 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 benign. Overall, the balance of evidence (nine pathogenic versus three benign predictions) indicates that the variant 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	GAP	0.206376	Structured	0.023618	Uncertain	0.937	0.382	0.125							-11.207	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	0.362	Likely Benign	0.1876	0.2197		0.78	Ambiguous	0.6	-0.55	Ambiguous	0.12	Likely Benign	1.00	Destabilizing	-2.98	Deleterious	0.989	Probably Damaging	0.979	Probably Damaging	2.90	Benign	0.00	Affected			3	2	0.0	-14.03
c.1204C>A	L402M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402M is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. 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 (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.243554	Structured	0.431978	Uncertain	0.961	0.383	0.000							-6.991	Likely Benign	0.305	Likely Benign	Likely Benign	0.071	Likely Benign	0.1064	0.4095		0.12	Likely Benign	0.0	1.33	Ambiguous	0.73	Ambiguous	0.80	Ambiguous	-0.99	Neutral	0.994	Probably Damaging	0.938	Probably Damaging	3.73	Benign	0.02	Affected			4	2	-1.9	18.03
c.1204C>G	L402V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a benign outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result and is therefore not considered evidence for pathogenicity. In summary, all available predictions support a benign classification for the L402V variant, 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	0.243554	Structured	0.431978	Uncertain	0.961	0.383	0.000							-3.467	Likely Benign	0.105	Likely Benign	Likely Benign	0.203	Likely Benign	0.1807	0.3657		1.91	Ambiguous	0.1	0.78	Ambiguous	1.35	Ambiguous	-0.11	Likely Benign	0.18	Neutral	0.004	Benign	0.004	Benign	4.01	Benign	0.29	Tolerated			2	1	0.4	-14.03
c.1205T>A	L402Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402Q 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 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 reinforce 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 pathogenicity. 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	0.243554	Structured	0.431978	Uncertain	0.961	0.383	0.000							-13.403	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.523	Likely Pathogenic	0.1384	0.1173		2.93	Destabilizing	0.0	2.55	Destabilizing	2.74	Destabilizing	2.09	Destabilizing	-4.52	Deleterious	0.999	Probably Damaging	0.957	Probably Damaging	3.69	Benign	0.00	Affected			-2	-2	-7.3	14.97
c.1205T>C	L402P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L402P is not reported in ClinVar and is absent from gnomAD. Consensus among in‑silico predictors is overwhelmingly pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect, whereas only FATHMM predicts a benign outcome. High‑accuracy tools reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Taken together, the evidence strongly supports a pathogenic classification, 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	0.243554	Structured	0.431978	Uncertain	0.961	0.383	0.000							-12.030	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.616	Likely Pathogenic	0.3628	0.1874		7.40	Destabilizing	0.1	5.82	Destabilizing	6.61	Destabilizing	2.22	Destabilizing	-4.80	Deleterious	1.000	Probably Damaging	0.980	Probably Damaging	3.68	Benign	0.01	Affected			-3	-3	-5.4	-16.04
c.1205T>G	L402R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402R is listed in ClinVar as Pathogenic (ClinVar ID 559657.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy methods give the following 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 outputs) predicts Pathogenic. Based on the overwhelming agreement among pathogenic predictions and the concordance with ClinVar, 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	0.243554	Structured	0.431978	Uncertain	0.961	0.383	0.000	Likely Pathogenic		1				-13.800	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.522	Likely Pathogenic	0.1467	0.1173		4.10	Destabilizing	0.2	3.82	Destabilizing	3.96	Destabilizing	2.24	Destabilizing	-4.69	Deleterious	0.967	Probably Damaging	0.459	Possibly Damaging	3.69	Benign	0.00	Affected	3.38	28	-3	-2	-8.3	43.03	259.5	-55.4	0.0	0.0	1.4	0.0	X		X				X	Potentially Pathogenic	The iso-butyl side chain of Leu402, located in an anti-parallel β sheet strand (res. Ala399-Ile411), packs with residues inside the hydrophobic core of the C2 domain (e.g., Ile268, Ala404, Leu266, Val400). In the variant simulations, the positively charged guanidinium group of the Arg402 side chain is not suitable for the hydrophobic niche. Consequently, the side chain moves outward from the hydrophobic C2 domain core and stacks with the phenol ring of Tyr363 or forms H-bonds with the carboxamide group of the Gln361 side chain in the β sheet strand (res. Thr359-Tyr364). This movement induces extensive negative effects on the C2 domain structure.
c.1567A>C	N523H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523H is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect are Rosetta and Foldetta, while the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Uncertain results come from FoldX, premPS, and AlphaMissense‑Optimized. 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 as Benign. Overall, the preponderance of evidence points to a pathogenic effect for this variant, 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	GAP	0.069024	Structured	0.033426	Uncertain	0.883	0.383	0.125							-9.755	Likely Pathogenic	0.815	Likely Pathogenic	Ambiguous	0.694	Likely Pathogenic	0.1132	0.3461		0.56	Ambiguous	0.2	0.09	Likely Benign	0.33	Likely Benign	0.64	Ambiguous	-4.52	Deleterious	0.996	Probably Damaging	0.941	Probably Damaging	-1.40	Pathogenic	0.02	Affected			2	1	0.3	23.04
c.1567A>G	N523D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 N523D missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the 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 predictions are mixed, but the majority of high‑confidence tools lean toward pathogenicity. Thus, 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	GAP	0.069024	Structured	0.033426	Uncertain	0.883	0.383	0.125							-8.955	Likely Pathogenic	0.641	Likely Pathogenic	Likely Benign	0.272	Likely Benign	0.1553	0.1866		0.14	Likely Benign	0.2	1.10	Ambiguous	0.62	Ambiguous	0.56	Ambiguous	-3.57	Deleterious	0.112	Benign	0.079	Benign	-1.25	Pathogenic	0.22	Tolerated			2	1	0.0	0.98
c.1567A>T	N523Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523Y is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX, premPS, and SIFT. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. 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. With eight tools supporting pathogenicity versus three supporting benign, the overall evidence points to a likely pathogenic impact. This conclusion is consistent with the absence of a ClinVar classification, as no contradictory status exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.069024	Structured	0.033426	Uncertain	0.883	0.383	0.125							-11.701	Likely Pathogenic	0.836	Likely Pathogenic	Ambiguous	0.624	Likely Pathogenic	0.0586	0.3388		0.13	Likely Benign	0.3	-1.36	Ambiguous	-0.62	Ambiguous	-0.01	Likely Benign	-7.34	Deleterious	0.999	Probably Damaging	0.972	Probably Damaging	-1.39	Pathogenic	0.10	Tolerated			-2	-2	2.2	49.07
c.1568A>C	N523T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523T is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. Tools that predict pathogenicity are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The premPS score is uncertain and does not contribute to the consensus. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding result is missing or inconclusive. Overall, the majority of tools (10/14) predict pathogenicity, whereas four predict benign. Therefore, the variant is most likely pathogenic based on current predictions, 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	GAP	0.069024	Structured	0.033426	Uncertain	0.883	0.383	0.125							-10.056	Likely Pathogenic	0.704	Likely Pathogenic	Likely Benign	0.646	Likely Pathogenic	0.0920	0.3780		0.47	Likely Benign	0.2	-0.22	Likely Benign	0.13	Likely Benign	0.65	Ambiguous	-5.33	Deleterious	0.898	Possibly Damaging	0.592	Possibly Damaging	-1.40	Pathogenic	0.02	Affected			0	0	2.8	-13.00
c.1568A>G	N523S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523S 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, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and FATHMM. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) returned uncertain or inconclusive results. For high‑accuracy assessment, AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports an uncertain folding‑stability change. Taken together, the majority of evidence (five benign versus three pathogenic predictions) points to a benign effect, and this conclusion does not contradict any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.069024	Structured	0.033426	Uncertain	0.883	0.383	0.125							-6.188	Likely Benign	0.552	Ambiguous	Likely Benign	0.492	Likely Benign	0.2213	0.4178		0.64	Ambiguous	0.2	0.66	Ambiguous	0.65	Ambiguous	0.17	Likely Benign	-4.31	Deleterious	0.976	Probably Damaging	0.410	Benign	-1.27	Pathogenic	0.27	Tolerated			1	1	2.7	-27.03
c.1568A>T	N523I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N523I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools report uncertain results: Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—indicates pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains inconclusive. Overall, the preponderance of evidence (eight pathogenic versus three benign predictions) suggests 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	GAP	0.069024	Structured	0.033426	Uncertain	0.883	0.383	0.125							-12.862	Likely Pathogenic	0.761	Likely Pathogenic	Likely Benign	0.726	Likely Pathogenic	0.0627	0.3714		0.26	Likely Benign	0.2	-1.53	Ambiguous	-0.64	Ambiguous	0.33	Likely Benign	-8.18	Deleterious	0.989	Probably Damaging	0.946	Probably Damaging	-1.42	Pathogenic	0.00	Affected			-2	-3	8.0	-0.94
c.1569C>A	N523K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523K is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX and Foldetta, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome. Uncertain results are reported only by Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Taken together, the preponderance of evidence supports a pathogenic classification for this variant, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.069024	Structured	0.033426	Uncertain	0.883	0.383	0.125							-12.276	Likely Pathogenic	0.983	Likely Pathogenic	Likely Pathogenic	0.607	Likely Pathogenic	0.1837	0.2866		-0.17	Likely Benign	0.2	-0.58	Ambiguous	-0.38	Likely Benign	0.73	Ambiguous	-5.35	Deleterious	0.972	Probably Damaging	0.728	Possibly Damaging	-1.30	Pathogenic	0.04	Affected			1	0	-0.4	14.07
c.1569C>G	N523K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523K is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX and Foldetta, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome. Uncertain results are reported only by Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Taken together, the preponderance of evidence supports a pathogenic classification for this variant, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.069024	Structured	0.033426	Uncertain	0.883	0.383	0.125							-12.276	Likely Pathogenic	0.983	Likely Pathogenic	Likely Pathogenic	0.607	Likely Pathogenic	0.1837	0.2866		-0.17	Likely Benign	0.2	-0.58	Ambiguous	-0.38	Likely Benign	0.73	Ambiguous	-5.35	Deleterious	0.972	Probably Damaging	0.728	Possibly Damaging	-1.30	Pathogenic	0.04	Affected			1	0	-0.4	14.07
c.1570T>A	C524S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524S is listed in gnomAD (variant ID 6‑33438813‑T‑A) but has no ClinVar entry. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome, while FoldX, Rosetta, and Foldetta are uncertain and therefore not counted as evidence. Grouping by agreement yields a benign‑prediction set that is empty and a pathogenic‑prediction set that contains the eleven tools above. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta remains uncertain. Consequently, 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	GAP	0.134866	Structured	0.024729	Uncertain	0.916	0.385	0.125				6-33438813-T-A	1	6.20e-7	-11.174	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.915	Likely Pathogenic	0.5362	0.1848	Weaken	0.80	Ambiguous	0.1	1.55	Ambiguous	1.18	Ambiguous	1.58	Destabilizing	-9.94	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-1.38	Pathogenic	0.00	Affected	3.37	35	-1	0	-3.3	-16.06
c.1570T>C	C524R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524R is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Across the evaluated in‑silico tools, all pathogenic‑predicating algorithms—REVEL, SGM‑Consensus, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—return a pathogenic or likely pathogenic verdict. The only tool with an inconclusive result is FoldX, which is treated as unavailable. High‑accuracy predictors reinforce this assessment: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.134866	Structured	0.024729	Uncertain	0.916	0.385	0.125							-14.337	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.917	Likely Pathogenic	0.2031	0.1463		-0.53	Ambiguous	0.5	9.04	Destabilizing	4.26	Destabilizing	1.62	Destabilizing	-11.93	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	-1.40	Pathogenic	0.00	Affected			-4	-3	-7.0	53.05
c.1570T>G	C524G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change at residue 524 (C524G) is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while FoldX and Foldetta are uncertain. No tool predicts a benign effect. 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”; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, remains uncertain. Overall, the evidence strongly favors a pathogenic impact for C524G, 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	GAP	0.134866	Structured	0.024729	Uncertain	0.916	0.385	0.125							-13.597	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	0.924	Likely Pathogenic	0.3579	0.2745		1.07	Ambiguous	0.2	2.00	Destabilizing	1.54	Ambiguous	1.66	Destabilizing	-11.93	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-1.40	Pathogenic	0.00	Affected			-3	-3	-2.9	-46.09
c.1571G>A	C524Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). 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 classify it as pathogenic, while premPS is the sole tool predicting 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) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. With the overwhelming majority of evidence pointing to a damaging effect 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	GAP	0.134866	Structured	0.024729	Uncertain	0.916	0.385	0.125							-11.032	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.863	Likely Pathogenic	0.1496	0.3911		3.20	Destabilizing	1.4	6.24	Destabilizing	4.72	Destabilizing	0.18	Likely Benign	-10.94	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	-1.36	Pathogenic	0.00	Affected			0	-2	-3.8	60.04
c.1571G>C	C524S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 C524S variant has no ClinVar entry and is not present in gnomAD. Prediction tools that agree on a benign effect are none; those that predict pathogenicity include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta returned inconclusive results and are treated as unavailable 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 inconclusive. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by 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	GAP	0.134866	Structured	0.024729	Uncertain	0.916	0.385	0.125							-11.174	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.904	Likely Pathogenic	0.5362	0.1848	Weaken	0.80	Ambiguous	0.1	1.55	Ambiguous	1.18	Ambiguous	1.58	Destabilizing	-9.94	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-1.38	Pathogenic	0.00	Affected	3.37	35	-1	0	-3.3	-16.06
c.1571G>T	C524F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524F is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). 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 classify it as pathogenic, while only premPS predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized reports pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, 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	GAP	0.134866	Structured	0.024729	Uncertain	0.916	0.385	0.125							-12.145	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.831	Likely Pathogenic	0.1678	0.4259		2.18	Destabilizing	1.4	5.20	Destabilizing	3.69	Destabilizing	-0.04	Likely Benign	-10.94	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	-1.22	Pathogenic	0.05	Affected			-4	-2	0.3	44.04
c.1572C>G	C524W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524W is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: benign predictions are absent, while pathogenic predictions are made by REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. 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 the consensus of all available predictions, 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	GAP	0.134866	Structured	0.024729	Uncertain	0.916	0.385	0.125							-12.351	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.675	Likely Pathogenic	0.1953	0.3920		3.03	Destabilizing	1.2	9.88	Destabilizing	6.46	Destabilizing	0.93	Ambiguous	-10.94	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	-1.41	Pathogenic	0.00	Affected			-8	-2	-3.4	83.07
c.1594A>C	T532P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532P is listed in ClinVar as Benign (ClinVar ID 1598909.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM Consensus, and Foldetta (combining FoldX‑MD and Rosetta outputs)—all indicate a benign impact. No prediction or folding‑stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.275179	Structured	0.021478	Uncertain	0.889	0.385	0.000	Benign		1				-2.143	Likely Benign	0.061	Likely Benign	Likely Benign	0.201	Likely Benign	0.1850	0.3811		-0.30	Likely Benign	0.2	0.06	Likely Benign	-0.12	Likely Benign	0.08	Likely Benign	-0.90	Neutral	0.005	Benign	0.008	Benign	-1.28	Pathogenic	0.18	Tolerated	3.37	35	0	-1	-0.9	-3.99	174.2	35.1	0.4	0.0	0.1	0.0						X		Potentially Benign	Thr532 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560) facing the membrane. In the WT simulations, the hydroxyl group of Thr532 occasionally forms hydrogen bonds with the backbone atoms of other loop residues without any specific interaction. In the variant simulations, the Pro532 residue swap does not cause structural changes. Although hydrophilic residues seem more favorable in the loop, the pyrrolidine side chain of proline is well suited for unstructured protein regions such as loops. However, due to its location at the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations.
c.1594A>G	T532A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532A 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 change 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 predicts 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 (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.275179	Structured	0.021478	Uncertain	0.889	0.385	0.000							-2.907	Likely Benign	0.088	Likely Benign	Likely Benign	0.165	Likely Benign	0.3573	0.3114		0.16	Likely Benign	0.0	0.13	Likely Benign	0.15	Likely Benign	0.11	Likely Benign	-0.80	Neutral	0.032	Benign	0.023	Benign	-1.15	Pathogenic	0.14	Tolerated			1	0	2.5	-30.03
c.1594A>T	T532S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532S 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. When high‑accuracy methods are considered separately, AlphaMissense‑Optimized remains 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 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 assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.275179	Structured	0.021478	Uncertain	0.889	0.385	0.000							0.616	Likely Benign	0.062	Likely Benign	Likely Benign	0.160	Likely Benign	0.2988	0.2866		0.15	Likely Benign	0.1	-0.23	Likely Benign	-0.04	Likely Benign	-0.10	Likely Benign	0.53	Neutral	0.005	Benign	0.013	Benign	-1.22	Pathogenic	1.00	Tolerated			1	1	-0.1	-14.03
c.1595C>A	T532K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T532K missense variant is not reported in ClinVar and has no entries in gnomAD. Prediction tools that classify the change as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With ten benign versus four pathogenic predictions and two of the three high‑accuracy tools supporting a benign outcome, the variant is most likely benign. This assessment does not contradict the ClinVar status, which currently has no classification for T532K. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.275179	Structured	0.021478	Uncertain	0.889	0.385	0.000							-8.460	Likely Pathogenic	0.644	Likely Pathogenic	Likely Benign	0.376	Likely Benign	0.0943	0.1992		-0.44	Likely Benign	0.2	0.24	Likely Benign	-0.10	Likely Benign	0.34	Likely Benign	-1.97	Neutral	0.259	Benign	0.033	Benign	-1.21	Pathogenic	0.29	Tolerated			0	-1	-3.2	27.07
c.1595C>G	T532R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T532R missense variant is not listed in ClinVar and has no reported allele in gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, FATHMM, and AlphaMissense‑Default. FoldX and Rosetta provide uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling it likely pathogenic, and Foldetta predicting a benign effect. Overall, the balance of evidence (seven benign versus five pathogenic predictions) indicates that the variant is most likely benign, 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	GAP	0.275179	Structured	0.021478	Uncertain	0.889	0.385	0.000							-6.564	Likely Benign	0.608	Likely Pathogenic	Likely Benign	0.495	Likely Benign	0.0841	0.1755		-0.57	Ambiguous	0.2	0.68	Ambiguous	0.06	Likely Benign	0.48	Likely Benign	-2.62	Deleterious	0.694	Possibly Damaging	0.230	Benign	-1.20	Pathogenic	0.06	Tolerated			-1	-1	-3.8	55.08
c.1595C>T	T532I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized classifies the variant as benign, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) reports a benign effect. Overall, the balance of evidence leans toward pathogenicity, 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	GAP	0.275179	Structured	0.021478	Uncertain	0.889	0.385	0.000							-9.031	Likely Pathogenic	0.591	Likely Pathogenic	Likely Benign	0.428	Likely Benign	0.0713	0.4983		-0.11	Likely Benign	0.2	0.87	Ambiguous	0.38	Likely Benign	0.22	Likely Benign	-3.31	Deleterious	0.633	Possibly Damaging	0.202	Benign	-1.31	Pathogenic	0.03	Affected			0	-1	5.2	12.05
c.2008C>A	L670M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L670M occurs in the GAP domain. ClinVar contains no entry for this variant, but it is present in gnomAD (ID 6‑33441267‑C‑A). Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, Foldetta, and the SGM‑Consensus score (Likely Benign). Tools that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; Rosetta gives an uncertain result. 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. 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.	Likely Benign	GAP	0.161087	Structured	0.090855	Uncertain	0.812	0.385	0.000				6-33441267-C-A	2	1.24e-6	-9.438	Likely Pathogenic	0.125	Likely Benign	Likely Benign	0.038	Likely Benign	0.0826	0.3849		-0.11	Likely Benign	0.0	0.70	Ambiguous	0.30	Likely Benign	0.06	Likely Benign	-0.16	Neutral	0.970	Probably Damaging	0.777	Possibly Damaging	3.40	Benign	0.25	Tolerated	3.39	27	2	4	-1.9	18.03
c.2008C>G	L670V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L670V 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score all indicate benign. Only ESM1b predicts pathogenicity, while FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta remains uncertain. Taken together, the overwhelming majority of evidence supports a benign interpretation, 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 Benign	GAP	0.161087	Structured	0.090855	Uncertain	0.812	0.385	0.000							-9.829	Likely Pathogenic	0.113	Likely Benign	Likely Benign	0.025	Likely Benign	0.1558	0.4108		1.45	Ambiguous	0.1	1.05	Ambiguous	1.25	Ambiguous	0.15	Likely Benign	-0.60	Neutral	0.127	Benign	0.023	Benign	3.67	Benign	0.74	Tolerated			2	1	0.4	-14.03
c.2009T>A	L670Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L670Q is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, 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 ESM1b. Predictions that are inconclusive (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also as Likely Benign, while Foldetta remains uncertain. Overall, the majority of available evidence points to a benign 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 Benign	GAP	0.161087	Structured	0.090855	Uncertain	0.812	0.385	0.000							-8.217	Likely Pathogenic	0.306	Likely Benign	Likely Benign	0.152	Likely Benign	0.1088	0.1303		1.02	Ambiguous	0.1	1.21	Ambiguous	1.12	Ambiguous	0.96	Ambiguous	-1.12	Neutral	1.000	Probably Damaging	0.988	Probably Damaging	3.40	Benign	0.36	Tolerated			-2	-2	-7.3	14.97
c.2009T>C	L670P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L670P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. Stability‑based methods are inconclusive: FoldX, Rosetta, and the combined Foldetta output are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar assertion; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.161087	Structured	0.090855	Uncertain	0.812	0.385	0.000							-4.916	Likely Benign	0.237	Likely Benign	Likely Benign	0.211	Likely Benign	0.3590	0.1474		0.56	Ambiguous	0.3	1.83	Ambiguous	1.20	Ambiguous	-0.25	Likely Benign	2.42	Neutral	1.000	Probably Damaging	0.996	Probably Damaging	3.41	Benign	0.26	Tolerated			-3	-3	-5.4	-16.04
c.2009T>G	L670R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L670R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Default—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 predictions indicate a benign effect. There is no ClinVar annotation to contradict this assessment, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.161087	Structured	0.090855	Uncertain	0.812	0.385	0.000							-9.801	Likely Pathogenic	0.552	Ambiguous	Likely Benign	0.193	Likely Benign	0.1327	0.1145		0.64	Ambiguous	0.1	1.42	Ambiguous	1.03	Ambiguous	0.67	Ambiguous	-1.74	Neutral	0.993	Probably Damaging	0.755	Possibly Damaging	3.43	Benign	0.41	Tolerated			-3	-2	-8.3	43.03
c.2152C>A	L718I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L718I is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus (Likely Pathogenic), FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Three tools (Foldetta, premPS, Rosetta) give uncertain results and are not considered evidence. High‑accuracy methods specifically show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Because the majority of reliable predictors (eight out of eleven) indicate pathogenicity, the variant is most likely pathogenic. This assessment does not contradict ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.298791	Structured	0.438417	Uncertain	0.966	0.385	0.000							-10.560	Likely Pathogenic	0.615	Likely Pathogenic	Likely Benign	0.296	Likely Benign	0.0876	0.3206		2.21	Destabilizing	0.2	1.37	Ambiguous	1.79	Ambiguous	0.89	Ambiguous	-1.90	Neutral	0.999	Probably Damaging	0.997	Probably Damaging	1.37	Pathogenic	0.00	Affected			2	2	0.7	0.00
c.2152C>G	L718V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L718V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and AlphaMissense‑Optimized, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized reports benign, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy 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	GAP	0.298791	Structured	0.438417	Uncertain	0.966	0.385	0.000							-11.585	Likely Pathogenic	0.693	Likely Pathogenic	Likely Benign	0.237	Likely Benign	0.1485	0.2656		3.15	Destabilizing	0.1	2.11	Destabilizing	2.63	Destabilizing	1.14	Destabilizing	-2.83	Deleterious	0.998	Probably Damaging	0.992	Probably Damaging	1.36	Pathogenic	0.00	Affected			2	1	0.4	-14.03
c.2152C>T	L718F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L718F lies in the GAP domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools cluster into two groups: benign predictions are made only by REVEL, whereas the remaining tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity; premPS is uncertain and is not counted as evidence. High‑accuracy assessments further support a deleterious effect: 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 predicts pathogenic. Based on the overwhelming consensus of these 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	GAP	0.298791	Structured	0.438417	Uncertain	0.966	0.385	0.000							-11.302	Likely Pathogenic	0.982	Likely Pathogenic	Likely Pathogenic	0.347	Likely Benign	0.0590	0.2979		3.87	Destabilizing	0.2	2.64	Destabilizing	3.26	Destabilizing	0.78	Ambiguous	-3.73	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	1.32	Pathogenic	0.00	Affected			2	0	-1.0	34.02
c.2153T>A	L718H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L718H is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools cluster into two groups: the single benign predictor REVEL, and a consensus of pathogenic predictions from 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) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are inconclusive or missing. Based on the overwhelming agreement among these tools, 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	GAP	0.298791	Structured	0.438417	Uncertain	0.966	0.385	0.000							-14.923	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.460	Likely Benign	0.1020	0.0526		3.84	Destabilizing	0.1	2.68	Destabilizing	3.26	Destabilizing	2.69	Destabilizing	-6.64	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.28	Pathogenic	0.00	Affected			-2	-3	-7.0	23.98
c.2153T>C	L718P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L718P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign effect, so the benign‑prediction group is empty. 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) also predicts pathogenic. Consequently, the variant is most likely pathogenic based on the available 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.	Likely Pathogenic	GAP	0.298791	Structured	0.438417	Uncertain	0.966	0.385	0.000							-15.643	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.660	Likely Pathogenic	0.3854	0.1221		6.56	Destabilizing	0.1	9.69	Destabilizing	8.13	Destabilizing	2.35	Destabilizing	-6.64	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.28	Pathogenic	0.00	Affected			-3	-3	-5.4	-16.04
c.2153T>G	L718R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L718R 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—FoldX, Rosetta, Foldetta, premPS, 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) indicates “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. 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	GAP	0.298791	Structured	0.438417	Uncertain	0.966	0.385	0.000							-16.119	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.484	Likely Benign	0.1254	0.0600		5.90	Destabilizing	0.2	5.05	Destabilizing	5.48	Destabilizing	2.57	Destabilizing	-5.69	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.28	Pathogenic	0.00	Affected			-3	-2	-8.3	43.03
c.2155A>C	N719H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719H 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only two tools—polyPhen‑2 HumDiv and polyPhen‑2 HumVar—predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports Benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates 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	GAP	0.384043	Structured	0.445381	Uncertain	0.961	0.386	0.000							-6.310	Likely Benign	0.130	Likely Benign	Likely Benign	0.095	Likely Benign	0.0782	0.4209		-0.04	Likely Benign	0.0	-0.36	Likely Benign	-0.20	Likely Benign	0.12	Likely Benign	-2.22	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	2.71	Benign	0.19	Tolerated			2	1	0.3	23.04
c.2155A>G	N719D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719D 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, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. 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 individual predictors (seven benign vs. four pathogenic) support a benign effect, and this conclusion does not contradict the lack of ClinVar annotation. Thus, based on the available predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.384043	Structured	0.445381	Uncertain	0.961	0.386	0.000							-9.016	Likely Pathogenic	0.416	Ambiguous	Likely Benign	0.106	Likely Benign	0.1581	0.2345		-0.03	Likely Benign	0.0	0.64	Ambiguous	0.31	Likely Benign	0.46	Likely Benign	-2.56	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	2.75	Benign	0.84	Tolerated			2	1	0.0	0.98
c.2155A>T	N719Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719Y 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Rosetta and Foldetta provide 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) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is also uncertain. Overall, the majority of evaluated tools (7 benign vs 4 pathogenic) support a benign classification. Thus, the variant is most likely benign, 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.		GAP	0.384043	Structured	0.445381	Uncertain	0.961	0.386	0.000							-11.005	Likely Pathogenic	0.302	Likely Benign	Likely Benign	0.187	Likely Benign	0.0412	0.3951		-0.38	Likely Benign	0.0	-0.62	Ambiguous	-0.50	Ambiguous	0.33	Likely Benign	-4.15	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.70	Benign	0.09	Tolerated			-2	-2	2.2	49.07
c.2156A>C	N719T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all predict a neutral impact. In contrast, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar predict a pathogenic effect, while Rosetta 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 points to a benign 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 Benign	GAP	0.384043	Structured	0.445381	Uncertain	0.961	0.386	0.000							-6.251	Likely Benign	0.103	Likely Benign	Likely Benign	0.078	Likely Benign	0.0851	0.4620		0.39	Likely Benign	0.0	-0.59	Ambiguous	-0.10	Likely Benign	0.44	Likely Benign	-2.60	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	2.76	Benign	0.38	Tolerated			0	0	2.8	-13.00
c.2156A>G	N719S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719S is reported in gnomAD (variant ID 6‑33441621‑A‑G) but has no ClinVar entry. 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. 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 status: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus itself is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts Benign. Overall, the preponderance of evidence indicates that the variant is most likely benign, 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	GAP	0.384043	Structured	0.445381	Uncertain	0.961	0.386	0.000				6-33441621-A-G	2	1.24e-6	-5.190	Likely Benign	0.072	Likely Benign	Likely Benign	0.087	Likely Benign	0.2611	0.4653		-0.06	Likely Benign	0.0	-0.29	Likely Benign	-0.18	Likely Benign	0.46	Likely Benign	-1.83	Neutral	0.999	Probably Damaging	0.992	Probably Damaging	2.85	Benign	0.40	Tolerated	3.50	9	1	1	2.7	-27.03
c.2156A>T	N719I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719I 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, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools report uncertainty: 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 predictions lean toward a benign impact, with no conflict with ClinVar status. Thus, the variant is most likely benign based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.384043	Structured	0.445381	Uncertain	0.961	0.386	0.000							-10.794	Likely Pathogenic	0.399	Ambiguous	Likely Benign	0.146	Likely Benign	0.0408	0.4493		-0.19	Likely Benign	0.0	-0.74	Ambiguous	-0.47	Likely Benign	0.40	Likely Benign	-4.88	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.71	Benign	0.10	Tolerated			-2	-3	8.0	-0.94
c.2157C>A	N719K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, ESM1b, and Foldetta) give 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 predictions indicate a benign impact, and this conclusion 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.		GAP	0.384043	Structured	0.445381	Uncertain	0.961	0.386	0.000							-7.454	In-Between	0.651	Likely Pathogenic	Likely Benign	0.250	Likely Benign	0.1424	0.3112		-0.64	Ambiguous	0.0	-0.62	Ambiguous	-0.63	Ambiguous	0.42	Likely Benign	-1.84	Neutral	1.000	Probably Damaging	0.998	Probably Damaging	2.80	Benign	0.55	Tolerated			1	0	-0.4	14.07
c.2157C>G	N719K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719K is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors shows a predominance of benign calls: REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized all predict a neutral effect, whereas polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict pathogenicity. FoldX, Rosetta, ESM1b, and Foldetta are inconclusive. High‑accuracy assessment further supports a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign outcome; Foldetta remains uncertain. Consequently, 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.		GAP	0.384043	Structured	0.445381	Uncertain	0.961	0.386	0.000							-7.454	In-Between	0.651	Likely Pathogenic	Likely Benign	0.244	Likely Benign	0.1424	0.3112		-0.64	Ambiguous	0.0	-0.62	Ambiguous	-0.63	Ambiguous	0.42	Likely Benign	-1.84	Neutral	1.000	Probably Damaging	0.998	Probably Damaging	2.80	Benign	0.55	Tolerated			1	0	-0.4	14.07
c.1996G>A	E666K 2D AIThe SynGAP1 missense variant E666K 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, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of predictions lean toward pathogenicity, 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	GAP	0.155435	Structured	0.086870	Uncertain	0.925	0.387	0.000							-11.367	Likely Pathogenic	0.946	Likely Pathogenic	Ambiguous	0.401	Likely Benign	0.2953	0.5300		0.20	Likely Benign	0.6	0.30	Likely Benign	0.25	Likely Benign	0.43	Likely Benign	-3.26	Deleterious	0.992	Probably Damaging	0.717	Possibly Damaging	3.46	Benign	0.05	Affected			0	1	-0.4	-0.94
c.1996G>C	E666Q 2D AIThe SynGAP1 E666Q missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; FoldX is uncertain and therefore not counted. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split and is treated as unavailable. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of reliable predictions indicate 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.		GAP	0.155435	Structured	0.086870	Uncertain	0.925	0.387	0.000							-10.963	Likely Pathogenic	0.737	Likely Pathogenic	Likely Benign	0.268	Likely Benign	0.1437	0.4788		0.54	Ambiguous	0.5	0.20	Likely Benign	0.37	Likely Benign	0.46	Likely Benign	-2.29	Neutral	0.997	Probably Damaging	0.696	Possibly Damaging	3.46	Benign	0.13	Tolerated			2	2	0.0	-0.98
c.1997A>C	E666A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E666A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give inconclusive results: FoldX (Uncertain) and AlphaMissense‑Optimized (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain; 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, is inconclusive because FoldX is Uncertain while Rosetta is Benign. Overall, the majority of available predictions (six pathogenic vs. five benign) lean toward a pathogenic impact. Thus, 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.	Likely Pathogenic	GAP	0.155435	Structured	0.086870	Uncertain	0.925	0.387	0.000							-11.122	Likely Pathogenic	0.921	Likely Pathogenic	Ambiguous	0.407	Likely Benign	0.3950	0.4878		0.57	Ambiguous	0.1	0.18	Likely Benign	0.38	Likely Benign	0.50	Likely Benign	-5.15	Deleterious	0.992	Probably Damaging	0.863	Possibly Damaging	3.45	Benign	0.07	Tolerated			0	-1	5.3	-58.04
c.1997A>G	E666G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E666G is listed in ClinVar as Benign (ClinVar ID 1115026.0) and is present in gnomAD (ID 6‑33441256‑A‑G). Functional prediction tools that agree on pathogenicity include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. Only FATHMM predicts a benign effect. Predictions marked Uncertain (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as Uncertain. 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.	Likely Pathogenic	GAP	0.155435	Structured	0.086870	Uncertain	0.925	0.387	0.000	Likely Benign		1	6-33441256-A-G	10	6.20e-6	-12.261	Likely Pathogenic	0.911	Likely Pathogenic	Ambiguous	0.522	Likely Pathogenic	0.3051	0.4015		1.57	Ambiguous	0.1	1.46	Ambiguous	1.52	Ambiguous	0.93	Ambiguous	-6.25	Deleterious	1.000	Probably Damaging	0.970	Probably Damaging	3.37	Benign	0.02	Affected	3.38	28	0	-2	3.1	-72.06	173.9	98.5	0.0	0.0	-0.7	0.0		X						Potentially Pathogenic	In the WT simulations, the carboxylate group of Glu666, located on the α-helix (res. Ser641-Glu666), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), such as Lys566, Thr672, and Asn669. In the variant simulations, the carbonyl group of Gly666 occasionally forms hydrogen bonds with Lys566 and Asn669. However, Gly666 lacks a side chain and thus cannot maintain as well-coordinated a hydrogen-bond network as Glu666 in the WT, which may affect the tertiary structure assembly.
c.1997A>T	E666V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E666V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools show mixed results: benign calls come from REVEL, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. FoldX alone is uncertain. Overall, the majority of tools and the high‑accuracy consensus favor a pathogenic interpretation, with no conflict from ClinVar status because no classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.155435	Structured	0.086870	Uncertain	0.925	0.387	0.000							-10.870	Likely Pathogenic	0.981	Likely Pathogenic	Likely Pathogenic	0.476	Likely Benign	0.0818	0.5613		0.61	Ambiguous	0.1	0.08	Likely Benign	0.35	Likely Benign	0.31	Likely Benign	-5.95	Deleterious	0.575	Possibly Damaging	0.214	Benign	3.44	Benign	0.03	Affected			-2	-2	7.7	-29.98
c.1998G>C	E666D 2D 3DClick to see structure in 3D Viewer AISynGAP1 E666D is listed in ClinVar with an uncertain significance (ID 587483.0) and is not reported in gnomAD. Functional prediction tools show a mixed signal: benign calls come from REVEL, SIFT, FATHMM, AlphaMissense‑Optimized, and Rosetta; pathogenic calls come from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as likely pathogenic. High‑accuracy assessments give AlphaMissense‑Optimized a benign prediction, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the balance of evidence slightly favors a pathogenic interpretation, but the predictions are not unequivocal. Thus, the variant is most likely pathogenic according to the current computational data, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.155435	Structured	0.086870	Uncertain	0.925	0.387	0.000	Uncertain		1				-8.820	Likely Pathogenic	0.704	Likely Pathogenic	Likely Benign	0.197	Likely Benign	0.1926	0.3092		0.88	Ambiguous	0.0	0.37	Likely Benign	0.63	Ambiguous	1.05	Destabilizing	-2.69	Deleterious	0.992	Probably Damaging	0.603	Possibly Damaging	3.43	Benign	0.06	Tolerated	3.38	28	3	2	0.0	-14.03	237.2	16.5	0.0	0.0	-0.3	0.1		X						Potentially Pathogenic	The carboxylate group of Glu666, located on the α-helix (res. Ser641-Glu666), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), such as Lys566, Thr672, and Asn669, in the WT simulations. In the variant simulations, the shorter side chain of Asp666 cannot maintain these interactions as efficiently as Glu666 in the WT, resulting in a less coordinated hydrogen-bond network.
c.1998G>T	E666D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E666D 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, SIFT, FATHMM, Rosetta, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX alone is also uncertain, so these results are treated as unavailable. Overall, the balance of evidence leans toward a pathogenic impact for E666D, 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	GAP	0.155435	Structured	0.086870	Uncertain	0.925	0.387	0.000							-8.820	Likely Pathogenic	0.704	Likely Pathogenic	Likely Benign	0.197	Likely Benign	0.1926	0.3092		0.88	Ambiguous	0.0	0.37	Likely Benign	0.63	Ambiguous	1.05	Destabilizing	-2.69	Deleterious	0.992	Probably Damaging	0.603	Possibly Damaging	3.43	Benign	0.06	Tolerated	3.38	28	3	2	0.0	-14.03	237.2	16.5	0.0	0.0	-0.3	0.1		X						Potentially Pathogenic	The carboxylate group of Glu666, located on the α-helix (res. Ser641-Glu666), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), such as Lys566, Thr672, and Asn669, in the WT simulations. In the variant simulations, the shorter side chain of Asp666 cannot maintain these interactions as efficiently as Glu666 in the WT, resulting in a less coordinated hydrogen-bond network.
c.616A>C	I206L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I206L 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, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and Foldetta. Those that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. Uncertain or inconclusive results come from premPS, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta predicts a benign outcome. Overall, the majority of tools (seven benign vs two pathogenic) support a benign classification. Thus, 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.		PH	0.298791	Structured	0.405123	Uncertain	0.863	0.391	0.125							-9.488	Likely Pathogenic	0.790	Likely Pathogenic	Ambiguous	0.080	Likely Benign	0.0632	0.3608		0.05	Likely Benign	0.1	0.75	Ambiguous	0.40	Likely Benign	0.78	Ambiguous	-1.72	Neutral	0.004	Benign	0.012	Benign	3.78	Benign	0.08	Tolerated			2	2	-0.7	0.00
c.616A>G	I206V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I206V 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, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive results are from FoldX (uncertain) and Foldetta (uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta remains uncertain. Based on the collective predictions, the variant is most likely benign, 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 Benign	PH	0.298791	Structured	0.405123	Uncertain	0.863	0.391	0.125							-5.709	Likely Benign	0.165	Likely Benign	Likely Benign	0.051	Likely Benign	0.0833	0.2920		1.22	Ambiguous	0.1	0.24	Likely Benign	0.73	Ambiguous	0.40	Likely Benign	-0.51	Neutral	0.001	Benign	0.007	Benign	4.27	Benign	0.53	Tolerated			4	3	-0.3	-14.03
c.616A>T	I206F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I206F 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, FATHMM, and polyPhen‑2 HumVar. Those that predict a pathogenic effect comprise SGM‑Consensus, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. Predictions that are uncertain or inconclusive are FoldX and premPS. High‑accuracy methods all support a deleterious outcome: 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) predicts pathogenic. Based on the collective evidence, 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	PH	0.298791	Structured	0.405123	Uncertain	0.863	0.391	0.125							-12.669	Likely Pathogenic	0.961	Likely Pathogenic	Likely Pathogenic	0.133	Likely Benign	0.0428	0.2721		1.82	Ambiguous	0.4	3.39	Destabilizing	2.61	Destabilizing	0.70	Ambiguous	-3.40	Deleterious	0.838	Possibly Damaging	0.368	Benign	3.64	Benign	0.01	Affected			1	0	-1.7	34.02
c.617T>A	I206N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I206N 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 and FATHMM, while the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is pathogenic. No prediction or folding result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, 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	PH	0.298791	Structured	0.405123	Uncertain	0.863	0.391	0.125							-15.211	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.334	Likely Benign	0.0689	0.0340		2.98	Destabilizing	0.2	2.57	Destabilizing	2.78	Destabilizing	2.04	Destabilizing	-5.55	Deleterious	0.940	Possibly Damaging	0.641	Possibly Damaging	3.62	Benign	0.00	Affected			-2	-3	-8.0	0.94
c.617T>C	I206T 2D AIThe SynGAP1 I206T 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give consistent results: 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 or stability results are missing or inconclusive. Based on the overall evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not currently listed. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.298791	Structured	0.405123	Uncertain	0.863	0.391	0.125							-10.812	Likely Pathogenic	0.973	Likely Pathogenic	Likely Pathogenic	0.252	Likely Benign	0.0830	0.0669		2.43	Destabilizing	0.5	2.68	Destabilizing	2.56	Destabilizing	1.94	Destabilizing	-3.78	Deleterious	0.421	Benign	0.156	Benign	3.65	Benign	0.00	Affected			0	-1	-5.2	-12.05
c.617T>G	I206S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I206S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and polyPhen‑2 HumVar. All other evaluated algorithms (SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious outcome: 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 predictions, is pathogenic. Based on the preponderance of evidence from these tools, 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	0.298791	Structured	0.405123	Uncertain	0.863	0.391	0.125							-13.711	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.251	Likely Benign	0.2189	0.0728		3.73	Destabilizing	0.3	3.89	Destabilizing	3.81	Destabilizing	1.74	Destabilizing	-4.86	Deleterious	0.838	Possibly Damaging	0.368	Benign	3.63	Benign	0.00	Affected			-1	-2	-5.3	-26.08
c.618C>G	I206M 2D AIThe SynGAP1 I206M 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 FATHMM, whereas tools that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With six pathogenic predictions versus four benign and three uncertain, the overall evidence leans toward pathogenicity. 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.		PH	0.298791	Structured	0.405123	Uncertain	0.863	0.391	0.125							-10.008	Likely Pathogenic	0.878	Likely Pathogenic	Ambiguous	0.085	Likely Benign	0.0576	0.2716		0.42	Likely Benign	0.6	1.21	Ambiguous	0.82	Ambiguous	1.08	Destabilizing	-2.42	Neutral	0.838	Possibly Damaging	0.467	Possibly Damaging	3.64	Benign	0.01	Affected			2	1	-2.6	18.03
c.1597G>A	A533T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533T is catalogued in gnomAD (6-33438840‑G‑A) but has no ClinVar entry. In silico predictors overwhelmingly favor a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes, whereas only FATHMM predicts pathogenicity. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, the SGM Consensus is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) predicts a benign stability change. Overall, the 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.	Likely Benign	GAP	0.179055	Structured	0.026324	Uncertain	0.843	0.393	0.000				6-33438840-G-A	2	1.24e-6	-5.396	Likely Benign	0.084	Likely Benign	Likely Benign	0.147	Likely Benign	0.1413	0.6541		0.30	Likely Benign	0.1	0.31	Likely Benign	0.31	Likely Benign	0.19	Likely Benign	-0.48	Neutral	0.002	Benign	0.001	Benign	-1.26	Pathogenic	0.11	Tolerated	3.37	35	0	1	-2.5	30.03
c.1597G>C	A533P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533P 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 predict benign. Only FATHMM predicts pathogenic. Stability‑based methods are inconclusive: FoldX, Rosetta, and the combined Foldetta output are listed as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as unavailable. Overall, the consensus of the majority of tools indicates a benign impact. This prediction 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 Benign	GAP	0.179055	Structured	0.026324	Uncertain	0.843	0.393	0.000							-3.951	Likely Benign	0.081	Likely Benign	Likely Benign	0.187	Likely Benign	0.1925	0.5299		-0.93	Ambiguous	0.3	-0.92	Ambiguous	-0.93	Ambiguous	-0.18	Likely Benign	-0.48	Neutral	0.000	Benign	0.001	Benign	-1.26	Pathogenic	0.09	Tolerated			1	-1	-3.4	26.04
c.1597G>T	A533S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533S 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. When predictions are grouped by consensus, the benign group contains all tools except FATHMM, which stands alone in the pathogenic group. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates a benign effect. 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	GAP	0.179055	Structured	0.026324	Uncertain	0.843	0.393	0.000							-3.740	Likely Benign	0.075	Likely Benign	Likely Benign	0.193	Likely Benign	0.2612	0.5334		0.24	Likely Benign	0.0	-0.05	Likely Benign	0.10	Likely Benign	-0.14	Likely Benign	0.33	Neutral	0.009	Benign	0.039	Benign	-1.14	Pathogenic	0.45	Tolerated			1	1	-2.6	16.00
c.1598C>A	A533E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533E 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, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM, while AlphaMissense‑Default remains uncertain. 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 benign. Overall, the majority of evidence points to a benign impact. 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.		GAP	0.179055	Structured	0.026324	Uncertain	0.843	0.393	0.000							-10.810	Likely Pathogenic	0.553	Ambiguous	Likely Benign	0.314	Likely Benign	0.1147	0.1498		-0.13	Likely Benign	0.0	-0.26	Likely Benign	-0.20	Likely Benign	0.43	Likely Benign	-1.89	Neutral	0.259	Benign	0.107	Benign	-1.18	Pathogenic	0.18	Tolerated			0	-1	-5.3	58.04
c.1598C>G	A533G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533G resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome; Rosetta is uncertain and therefore not counted as evidence. High‑accuracy assessments—all of which are available—show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Benign, reinforcing the benign consensus. Based on the collective predictions, 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	GAP	0.179055	Structured	0.026324	Uncertain	0.843	0.393	0.000							-3.412	Likely Benign	0.122	Likely Benign	Likely Benign	0.185	Likely Benign	0.2348	0.4737		0.32	Likely Benign	0.1	0.64	Ambiguous	0.48	Likely Benign	0.33	Likely Benign	-1.94	Neutral	0.258	Benign	0.099	Benign	-1.23	Pathogenic	0.23	Tolerated			1	0	-2.2	-14.03
c.1598C>T	A533V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are SIFT and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as benign, all supporting a non‑pathogenic interpretation. No prediction or folding‑stability result is missing or inconclusive. Based on the overall consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar evidence exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.179055	Structured	0.026324	Uncertain	0.843	0.393	0.000							-6.948	Likely Benign	0.148	Likely Benign	Likely Benign	0.170	Likely Benign	0.1243	0.6205		0.23	Likely Benign	0.0	0.51	Ambiguous	0.37	Likely Benign	0.25	Likely Benign	-2.41	Neutral	0.149	Benign	0.024	Benign	-1.28	Pathogenic	0.05	Affected			0	0	2.4	28.05
c.1045C>A	P349T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P349T is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and the SGM‑Consensus score (which is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools with inconclusive results are AlphaMissense‑Default, FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.167087	Structured	0.348607	Uncertain	0.947	0.396	0.000							-9.736	Likely Pathogenic	0.420	Ambiguous	Likely Benign	0.246	Likely Benign	0.1615	0.6238		1.37	Ambiguous	0.1	2.56	Destabilizing	1.97	Ambiguous	0.76	Ambiguous	-6.12	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	1.57	Pathogenic	0.07	Tolerated			0	-1	0.9	3.99
c.1045C>G	P349A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P349A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM, with the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely 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 pathogenicity scores are available. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation 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	0.167087	Structured	0.348607	Uncertain	0.947	0.396	0.000							-8.663	Likely Pathogenic	0.202	Likely Benign	Likely Benign	0.257	Likely Benign	0.3789	0.5505		1.37	Ambiguous	0.0	1.68	Ambiguous	1.53	Ambiguous	0.76	Ambiguous	-6.01	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	1.54	Pathogenic	0.01	Affected			1	-1	3.4	-26.04
c.1045C>T	P349S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P349S missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are FoldX, ESM1b, and premPS. 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 pathogenic. Overall, the majority of tools, including the high‑accuracy methods, predict a pathogenic effect. Thus, 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.		C2	0.167087	Structured	0.348607	Uncertain	0.947	0.396	0.000	Uncertain		1				-7.654	In-Between	0.217	Likely Benign	Likely Benign	0.277	Likely Benign	0.3771	0.5756		1.92	Ambiguous	0.1	2.28	Destabilizing	2.10	Destabilizing	0.87	Ambiguous	-6.13	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	1.66	Pathogenic	0.06	Tolerated	3.37	25	1	-1	0.8	-10.04	194.9	-18.1	-0.1	0.0	0.2	0.1	X						X	Potentially Pathogenic	The cyclic pyrrolidine side chain of Pro349, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), allows the strand to end and make a tight turn before a short α helical section within a loop connecting to another β strand (res. Thr359-Pro364). In the variant simulations, the hydroxyl group of Ser349 forms a hydrogen bond with the backbone amide group of Ala351 in the short helical section. Conversely, the backbone amide group of Ser349 (absent in proline) does not form any intra-protein hydrogen bonds. However, the β strand end connects to the α helical section in a more stable and consistent manner compared to the WT. Although the residue swap does not cause major adverse effects on the protein structure in the simulations, it is possible that the tight turn at the β strand end could not be created during folding without the presence of proline.
c.1046C>A	P349Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 P349Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools (FoldX, Rosetta, premPS, AlphaMissense‑Default, Foldetta) give uncertain or inconclusive results. High‑accuracy assessments further clarify the variant’s likely effect: AlphaMissense‑Optimized predicts a benign outcome; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion 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	0.167087	Structured	0.348607	Uncertain	0.947	0.396	0.000							-10.545	Likely Pathogenic	0.508	Ambiguous	Likely Benign	0.345	Likely Benign	0.1480	0.4766		0.98	Ambiguous	0.1	1.87	Ambiguous	1.43	Ambiguous	0.91	Ambiguous	-6.40	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	1.54	Pathogenic	0.06	Tolerated			0	-1	-1.9	31.01
c.1046C>G	P349R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P349R 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 majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Rosetta. Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for P349R. This conclusion is not contradicted by ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.167087	Structured	0.348607	Uncertain	0.947	0.396	0.000							-14.001	Likely Pathogenic	0.791	Likely Pathogenic	Ambiguous	0.335	Likely Benign	0.1395	0.3009		0.99	Ambiguous	0.1	2.15	Destabilizing	1.57	Ambiguous	0.93	Ambiguous	-7.22	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	1.55	Pathogenic	0.01	Affected			0	-2	-2.9	59.07
c.1046C>T	P349L 2D AIThe SynGAP1 missense variant P349L 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 REVEL and AlphaMissense‑Optimized, whereas the majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy methods give conflicting results: AlphaMissense‑Optimized reports a benign outcome, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Other stability‑based predictors (FoldX, Rosetta, premPS) are also inconclusive. Overall, the preponderance of evidence from the consensus of multiple in‑silico tools points to a pathogenic effect for P349L. 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	0.167087	Structured	0.348607	Uncertain	0.947	0.396	0.000							-11.734	Likely Pathogenic	0.650	Likely Pathogenic	Likely Benign	0.326	Likely Benign	0.2222	0.6867		0.70	Ambiguous	0.6	1.17	Ambiguous	0.94	Ambiguous	0.57	Ambiguous	-8.04	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	1.51	Pathogenic	0.00	Affected			-3	-3	5.4	16.04
c.2149C>A	L717I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L717I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only two tools—polyPhen‑2 HumDiv and HumVar—predict a pathogenic outcome, while premPS is inconclusive. High‑accuracy assessments further support a benign classification: 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. 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	GAP	0.239899	Structured	0.429342	Uncertain	0.969	0.397	0.000							-4.836	Likely Benign	0.168	Likely Benign	Likely Benign	0.182	Likely Benign	0.0712	0.2570		0.27	Likely Benign	0.0	0.33	Likely Benign	0.30	Likely Benign	-0.73	Ambiguous	0.60	Neutral	0.997	Probably Damaging	0.989	Probably Damaging	3.43	Benign	1.00	Tolerated			2	2	0.7	0.00
c.2149C>G	L717V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L717V 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, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Two tools predict a damaging effect: polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Stability‑based methods (FoldX, Rosetta, Foldetta) return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as inconclusive. Taken together, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar assertion, 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	GAP	0.239899	Structured	0.429342	Uncertain	0.969	0.397	0.000							-6.164	Likely Benign	0.308	Likely Benign	Likely Benign	0.119	Likely Benign	0.1226	0.2489		1.53	Ambiguous	0.0	1.25	Ambiguous	1.39	Ambiguous	0.09	Likely Benign	-0.25	Neutral	0.995	Probably Damaging	0.970	Probably Damaging	3.38	Benign	0.51	Tolerated			2	1	0.4	-14.03
c.2149C>T	L717F 2D AIThe SynGAP1 missense variant L717F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. No folding‑stability metrics (FoldX, Rosetta, premPS) provide decisive evidence. Overall, the majority of predictions lean toward pathogenicity, and this 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	GAP	0.239899	Structured	0.429342	Uncertain	0.969	0.397	0.000							-10.917	Likely Pathogenic	0.903	Likely Pathogenic	Ambiguous	0.157	Likely Benign	0.0444	0.2207		0.74	Ambiguous	0.6	0.59	Ambiguous	0.67	Ambiguous	0.63	Ambiguous	-2.56	Deleterious	0.999	Probably Damaging	0.988	Probably Damaging	3.36	Benign	0.02	Affected			2	0	-1.0	34.02
c.2150T>A	L717H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L717H occurs in the GAP domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM; all other evaluated algorithms (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, and the SGM‑Consensus score is “Likely Pathogenic.” 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. No predictions or stability results are missing or inconclusive. Based on the overwhelming majority of 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	GAP	0.239899	Structured	0.429342	Uncertain	0.969	0.397	0.000							-11.107	Likely Pathogenic	0.977	Likely Pathogenic	Likely Pathogenic	0.317	Likely Benign	0.0918	0.0558		2.27	Destabilizing	0.1	2.04	Destabilizing	2.16	Destabilizing	1.05	Destabilizing	-5.23	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	3.29	Benign	0.00	Affected			-2	-3	-7.0	23.98
c.2150T>C	L717P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L717P 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 FATHMM, while the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) all classify the variant as pathogenic. High‑accuracy assessments reinforce this view: 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 stability outputs, also predicts a pathogenic effect. No predictions are missing or inconclusive. Based on the preponderance of 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	GAP	0.239899	Structured	0.429342	Uncertain	0.969	0.397	0.000							-10.214	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.447	Likely Benign	0.3065	0.1053		3.96	Destabilizing	0.2	6.56	Destabilizing	5.26	Destabilizing	1.66	Destabilizing	-5.32	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	3.28	Benign	0.00	Affected			-3	-3	-5.4	-16.04
c.2150T>G	L717R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L717R is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while the remaining 13 tools (SGM‑Consensus, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the majority‑vote SGM Consensus) predict pathogenicity; FoldX is uncertain. High‑accuracy methods reinforce a pathogenic verdict: AlphaMissense‑Optimized scores it as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta also predicts pathogenic. No prediction is missing or inconclusive. Consequently, 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	GAP	0.239899	Structured	0.429342	Uncertain	0.969	0.397	0.000							-11.352	Likely Pathogenic	0.973	Likely Pathogenic	Likely Pathogenic	0.353	Likely Benign	0.1169	0.0558		1.66	Ambiguous	0.1	3.78	Destabilizing	2.72	Destabilizing	1.57	Destabilizing	-4.98	Deleterious	0.999	Probably Damaging	0.992	Probably Damaging	3.28	Benign	0.00	Affected			-3	-2	-8.3	43.03
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	0.496	Likely Benign	0.3546	0.4135		2.99	Destabilizing	0.1	3.18	Destabilizing	3.09	Destabilizing	1.27	Destabilizing	-2.64	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.84	Pathogenic	0.39	Tolerated			-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	0.481	Likely Benign	0.1517	0.4361		1.49	Ambiguous	0.3	0.56	Ambiguous	1.03	Ambiguous	0.66	Ambiguous	-3.12	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.82	Pathogenic	0.16	Tolerated	3.39	22	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	0.307	Likely Benign	0.3804	0.3214		0.56	Ambiguous	0.1	0.63	Ambiguous	0.60	Ambiguous	1.02	Destabilizing	-1.17	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	1.92	Pathogenic	0.41	Tolerated	3.39	22	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	0.486	Likely Benign	0.2291	0.5556		4.61	Destabilizing	0.5	2.19	Destabilizing	3.40	Destabilizing	1.03	Destabilizing	-2.15	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.83	Pathogenic	0.29	Tolerated			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	0.489	Likely Benign	0.2310	0.5607		-0.28	Likely Benign	0.0	-0.08	Likely Benign	-0.18	Likely Benign	0.29	Likely Benign	-2.20	Neutral	0.999	Probably Damaging	0.997	Probably Damaging	1.86	Pathogenic	0.63	Tolerated	3.39	22	-2	-3	8.3	-43.03
c.1591T>A	C531S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531S is not reported in ClinVar and has no entries in gnomAD. Prediction tools that assess pathogenicity largely agree on a deleterious effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict pathogenic. In contrast, only three tools predict a benign outcome: FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy methods provide a mixed picture: AlphaMissense‑Optimized reports a benign effect, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta also predicts benign stability. Overall, the preponderance of evidence points to a pathogenic impact for C531S. 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	GAP	0.281712	Structured	0.017941	Uncertain	0.878	0.401	0.000							-8.213	Likely Pathogenic	0.575	Likely Pathogenic	Likely Benign	0.519	Likely Pathogenic	0.3716	0.1782		-0.02	Likely Benign	0.0	0.77	Ambiguous	0.38	Likely Benign	1.23	Destabilizing	-8.00	Deleterious	0.958	Probably Damaging	0.533	Possibly Damaging	-1.18	Pathogenic	0.01	Affected			0	-1	-3.3	-16.06
c.1591T>C	C531R 2D AIThe SynGAP1 missense variant C531R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and polyPhen‑2 HumVar, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, 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 evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar classification because the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.281712	Structured	0.017941	Uncertain	0.878	0.401	0.000							-12.600	Likely Pathogenic	0.966	Likely Pathogenic	Likely Pathogenic	0.619	Likely Pathogenic	0.1322	0.1566		0.31	Likely Benign	2.0	-0.27	Likely Benign	0.02	Likely Benign	1.40	Destabilizing	-9.85	Deleterious	0.929	Possibly Damaging	0.385	Benign	-1.24	Pathogenic	0.00	Affected			-4	-3	-7.0	53.05
c.1591T>G	C531G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX and AlphaMissense‑Optimized, while the majority of other in silico predictors (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) indicate a pathogenic impact. Uncertain results come from Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the balance of evidence leans toward pathogenicity, with no ClinVar entry to contradict this assessment. 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	GAP	0.281712	Structured	0.017941	Uncertain	0.878	0.401	0.000							-10.037	Likely Pathogenic	0.577	Likely Pathogenic	Likely Benign	0.545	Likely Pathogenic	0.2653	0.2297		0.47	Likely Benign	0.3	1.49	Ambiguous	0.98	Ambiguous	1.42	Destabilizing	-9.76	Deleterious	0.985	Probably Damaging	0.832	Possibly Damaging	-1.24	Pathogenic	0.00	Affected			-3	-3	-2.9	-46.09
c.1592G>A	C531Y 2D AIThe SynGAP1 missense variant C531Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only Rosetta, whereas the remaining tools—REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus—consistently predict a pathogenic impact. Uncertain or inconclusive results come from AlphaMissense‑Optimized, Foldetta, and premPS. 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 evidence points to a pathogenic effect for C531Y. This prediction 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	GAP	0.281712	Structured	0.017941	Uncertain	0.878	0.401	0.000							-11.667	Likely Pathogenic	0.914	Likely Pathogenic	Ambiguous	0.551	Likely Pathogenic	0.0843	0.3266		3.09	Destabilizing	4.6	0.15	Likely Benign	1.62	Ambiguous	0.65	Ambiguous	-8.95	Deleterious	0.976	Probably Damaging	0.480	Possibly Damaging	-1.24	Pathogenic	0.00	Affected			0	-2	-3.8	60.04
c.1592G>C	C531S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Foldetta, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; Rosetta remains uncertain. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized indicates benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic, and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. Overall, the preponderance of evidence points to a pathogenic effect for C531S, 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	GAP	0.281712	Structured	0.017941	Uncertain	0.878	0.401	0.000							-8.213	Likely Pathogenic	0.575	Likely Pathogenic	Likely Benign	0.508	Likely Pathogenic	0.3716	0.1782		-0.02	Likely Benign	0.0	0.77	Ambiguous	0.38	Likely Benign	1.23	Destabilizing	-8.00	Deleterious	0.958	Probably Damaging	0.533	Possibly Damaging	-1.18	Pathogenic	0.01	Affected			0	-1	-3.3	-16.06
c.1592G>T	C531F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531F 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 Rosetta and polyPhen‑2 HumVar, while the majority of tools (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Tools with inconclusive or uncertain results are AlphaMissense‑Optimized, Foldetta, and premPS. High‑accuracy assessments show SGM‑Consensus as “Likely Pathogenic”; AlphaMissense‑Optimized is uncertain; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also uncertain. Taken together, the preponderance of evidence from multiple pathogenic‑predicting algorithms and the SGM‑Consensus score indicates that the variant is most likely pathogenic. 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	GAP	0.281712	Structured	0.017941	Uncertain	0.878	0.401	0.000							-10.428	Likely Pathogenic	0.842	Likely Pathogenic	Ambiguous	0.519	Likely Pathogenic	0.1103	0.3784		2.47	Destabilizing	1.6	0.26	Likely Benign	1.37	Ambiguous	0.59	Ambiguous	-8.89	Deleterious	0.866	Possibly Damaging	0.244	Benign	-1.23	Pathogenic	0.01	Affected			-4	-2	0.3	44.04
c.1593C>G	C531W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531W 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, and AlphaMissense‑Optimized, all of which classify the change as pathogenic. Tools with uncertain or mixed outputs are Rosetta (uncertain) and premPS (uncertain). High‑accuracy assessments further support a damaging impact: 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 predictions, also reports pathogenic. Based on the overwhelming agreement among pathogenic predictions and the corroborating high‑accuracy tools, 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	GAP	0.281712	Structured	0.017941	Uncertain	0.878	0.401	0.000							-14.107	Likely Pathogenic	0.970	Likely Pathogenic	Likely Pathogenic	0.510	Likely Pathogenic	0.1234	0.3074		5.27	Destabilizing	3.4	0.63	Ambiguous	2.95	Destabilizing	0.70	Ambiguous	-9.12	Deleterious	0.998	Probably Damaging	0.871	Possibly Damaging	-1.25	Pathogenic	0.00	Affected			-8	-2	-3.4	83.07
c.1576G>A	V526I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V526I variant is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33438819‑G‑A). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM; AlphaMissense‑Default remains 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 tools (seven benign vs. five pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current predictions, and this assessment does not contradict the ClinVar status, which has no entry for V526I. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		GAP	0.139895	Structured	0.023118	Uncertain	0.943	0.403	0.000				6-33438819-G-A			-9.962	Likely Pathogenic	0.526	Ambiguous	Likely Benign	0.540	Likely Pathogenic	0.0630	0.3307		0.07	Likely Benign	0.3	0.41	Likely Benign	0.24	Likely Benign	0.02	Likely Benign	-0.99	Neutral	0.929	Possibly Damaging	0.917	Probably Damaging	-1.34	Pathogenic	0.15	Tolerated	3.37	35	3	4	0.3	14.03
c.1576G>C	V526L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V526L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and SIFT, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for V526L, 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	GAP	0.139895	Structured	0.023118	Uncertain	0.943	0.403	0.000							-9.289	Likely Pathogenic	0.982	Likely Pathogenic	Likely Pathogenic	0.643	Likely Pathogenic	0.0754	0.3894		1.31	Ambiguous	0.5	1.74	Ambiguous	1.53	Ambiguous	0.38	Likely Benign	-2.97	Deleterious	0.929	Possibly Damaging	0.917	Probably Damaging	-1.16	Pathogenic	0.17	Tolerated			2	1	-0.4	14.03
c.1576G>T	V526L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V526L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and SIFT, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for V526L, 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	GAP	0.139895	Structured	0.023118	Uncertain	0.943	0.403	0.000							-9.289	Likely Pathogenic	0.982	Likely Pathogenic	Likely Pathogenic	0.643	Likely Pathogenic	0.0754	0.3894		1.31	Ambiguous	0.5	1.74	Ambiguous	1.53	Ambiguous	0.38	Likely Benign	-2.97	Deleterious	0.929	Possibly Damaging	0.917	Probably Damaging	-1.16	Pathogenic	0.17	Tolerated			2	1	-0.4	14.03
c.1577T>A	V526E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V526E is not listed in ClinVar and has no reported allele in gnomAD. In silico prediction tools 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 change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Because all available evidence points to a damaging effect and there is no conflicting ClinVar annotation or population frequency data, the variant is most likely pathogenic. This conclusion aligns with the absence of ClinVar status and gnomAD entries, indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.139895	Structured	0.023118	Uncertain	0.943	0.403	0.000							-16.080	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.962	Likely Pathogenic	0.0766	0.1326		5.19	Destabilizing	0.3	5.12	Destabilizing	5.16	Destabilizing	2.32	Destabilizing	-5.94	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-1.46	Pathogenic	0.00	Affected			-2	-2	-7.7	29.98
c.1577T>C	V526A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V526A is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all agree that the variant is deleterious: REVEL, 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) all classify it as pathogenic or likely pathogenic. No tool predicts a benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized is uncertain, SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Based on the overwhelming consensus 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	GAP	0.139895	Structured	0.023118	Uncertain	0.943	0.403	0.000							-12.055	Likely Pathogenic	0.852	Likely Pathogenic	Ambiguous	0.908	Likely Pathogenic	0.2224	0.1922		2.30	Destabilizing	0.1	2.49	Destabilizing	2.40	Destabilizing	2.05	Destabilizing	-3.93	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	-1.44	Pathogenic	0.00	Affected			0	0	-2.4	-28.05
c.1577T>G	V526G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V526G missense variant 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, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; no tool predicts it benign. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. All available evidence points to a deleterious effect. Consequently, the variant is most likely pathogenic, and this assessment 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.		GAP	0.139895	Structured	0.023118	Uncertain	0.943	0.403	0.000							-15.811	Likely Pathogenic	0.926	Likely Pathogenic	Ambiguous	0.935	Likely Pathogenic	0.1636	0.1837		3.21	Destabilizing	0.3	4.79	Destabilizing	4.00	Destabilizing	2.19	Destabilizing	-6.92	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-1.49	Pathogenic	0.00	Affected			-1	-3	-4.6	-42.08
c.1582C>A	P528T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P528T 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, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tools predict a benign outcome. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic. 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	GAP	0.225814	Structured	0.020396	Uncertain	0.909	0.403	0.000							-13.782	Likely Pathogenic	0.798	Likely Pathogenic	Ambiguous	0.673	Likely Pathogenic	0.1367	0.4360		2.05	Destabilizing	0.3	1.01	Ambiguous	1.53	Ambiguous	0.66	Ambiguous	-7.69	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	2.49	Pathogenic	0.00	Affected			0	-1	0.9	3.99
c.1582C>G	P528A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized, while the remaining pathogenic‑predicting tools are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; the remaining tools (FoldX, Rosetta, Foldetta, premPS) are uncertain. High‑accuracy methods give AlphaMissense‑Optimized a benign score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) a pathogenic prediction, and Foldetta an uncertain result. Overall, the majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment is not contradicted by 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	GAP	0.225814	Structured	0.020396	Uncertain	0.909	0.403	0.000							-11.562	Likely Pathogenic	0.607	Likely Pathogenic	Likely Benign	0.548	Likely Pathogenic	0.3146	0.3914		1.57	Ambiguous	0.1	1.49	Ambiguous	1.53	Ambiguous	0.69	Ambiguous	-7.69	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.52	Benign	0.01	Affected			1	-1	3.4	-26.04
c.1582C>T	P528S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528S missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Only FATHMM predicts a benign outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) remains Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is inconclusive. No folding‑stability metrics (FoldX, Rosetta, premPS) provide definitive evidence. Overall, the preponderance of pathogenic predictions suggests 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	GAP	0.225814	Structured	0.020396	Uncertain	0.909	0.403	0.000							-11.729	Likely Pathogenic	0.819	Likely Pathogenic	Ambiguous	0.617	Likely Pathogenic	0.3115	0.3982		1.88	Ambiguous	0.1	1.28	Ambiguous	1.58	Ambiguous	0.80	Ambiguous	-7.65	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.52	Benign	0.01	Affected			1	-1	0.8	-10.04
c.1583C>A	P528H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P528H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the change as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely pathogenic. No tool predicts a benign outcome; the remaining predictions (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are uncertain or inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence supports a pathogenic interpretation, and this is consistent with the absence of a ClinVar entry; there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.225814	Structured	0.020396	Uncertain	0.909	0.403	0.000							-15.365	Likely Pathogenic	0.940	Likely Pathogenic	Ambiguous	0.565	Likely Pathogenic	0.1434	0.3523		1.93	Ambiguous	0.1	0.74	Ambiguous	1.34	Ambiguous	0.61	Ambiguous	-8.61	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.47	Pathogenic	0.00	Affected			0	-2	-1.6	40.02
c.1583C>G	P528R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528R missense variant is not reported in ClinVar and is absent from gnomAD. No in silico predictor classifies it as benign; the following tools predict pathogenicity: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions that are uncertain or inconclusive (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, 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	GAP	0.225814	Structured	0.020396	Uncertain	0.909	0.403	0.000							-16.367	Likely Pathogenic	0.952	Likely Pathogenic	Ambiguous	0.615	Likely Pathogenic	0.1261	0.2543		0.76	Ambiguous	0.4	0.67	Ambiguous	0.72	Ambiguous	0.73	Ambiguous	-8.58	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.49	Pathogenic	0.01	Affected			0	-2	-2.9	59.07
c.1583C>T	P528L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P528L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only premPS, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently 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. Because the majority of evidence points to a deleterious effect and no ClinVar annotation exists 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	GAP	0.225814	Structured	0.020396	Uncertain	0.909	0.403	0.000							-13.752	Likely Pathogenic	0.853	Likely Pathogenic	Ambiguous	0.555	Likely Pathogenic	0.1975	0.5574		1.31	Ambiguous	0.1	0.61	Ambiguous	0.96	Ambiguous	0.19	Likely Benign	-9.65	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.48	Pathogenic	0.00	Affected			-3	-3	5.4	16.04
c.1585A>C	I529L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529L is listed in gnomAD (variant ID 6‑33438828‑A‑C) but has no ClinVar entry. 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. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. No prediction or folding result is missing or inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely benign, 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	GAP	0.318242	Structured	0.019545	Uncertain	0.901	0.403	0.000				6-33438828-A-C	1	6.20e-7	0.920	Likely Benign	0.066	Likely Benign	Likely Benign	0.309	Likely Benign	0.0819	0.3789		-0.13	Likely Benign	0.0	-0.11	Likely Benign	-0.12	Likely Benign	-0.21	Likely Benign	0.00	Neutral	0.001	Benign	0.022	Benign	-1.24	Pathogenic	0.48	Tolerated	3.37	35	2	2	-0.7	0.00
c.1585A>G	I529V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529V is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID 6‑33438828‑A‑G). Prediction tools that uniformly indicate 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. 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 is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. Based on the collective predictions, the variant is most likely benign, 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	GAP	0.318242	Structured	0.019545	Uncertain	0.901	0.403	0.000				6-33438828-A-G	1	6.20e-7	-2.342	Likely Benign	0.068	Likely Benign	Likely Benign	0.230	Likely Benign	0.1043	0.3526		0.18	Likely Benign	0.0	0.03	Likely Benign	0.11	Likely Benign	0.36	Likely Benign	-0.21	Neutral	0.019	Benign	0.014	Benign	-1.24	Pathogenic	1.00	Tolerated	3.37	35	3	4	-0.3	-14.03
c.1585A>T	I529F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529F is not reported in ClinVar and is present in gnomAD (variant ID 6‑33438828‑A‑T). Consensus from most in‑silico predictors classifies the change as benign: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic effect. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Overall, the preponderance of evidence indicates that I529F is most likely benign, 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	GAP	0.318242	Structured	0.019545	Uncertain	0.901	0.403	0.000				6-33438828-A-T	4	2.48e-6	-5.669	Likely Benign	0.235	Likely Benign	Likely Benign	0.320	Likely Benign	0.0522	0.2713		-0.21	Likely Benign	0.0	0.06	Likely Benign	-0.08	Likely Benign	0.06	Likely Benign	-0.97	Neutral	0.266	Benign	0.054	Benign	-1.30	Pathogenic	0.23	Tolerated	3.37	35	0	1	-1.7	34.02
c.1586T>A	I529N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529N 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 (Likely Benign) all predict a neutral impact. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign effect. Taken together, the preponderance of evidence from both general and high‑accuracy predictors 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	GAP	0.318242	Structured	0.019545	Uncertain	0.901	0.403	0.000							-4.478	Likely Benign	0.283	Likely Benign	Likely Benign	0.378	Likely Benign	0.0722	0.0700		0.12	Likely Benign	0.2	-0.05	Likely Benign	0.04	Likely Benign	0.46	Likely Benign	-0.31	Neutral	0.997	Probably Damaging	0.952	Probably Damaging	-1.24	Pathogenic	0.20	Tolerated			-2	-3	-8.0	0.94
c.1586T>C	I529T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign” call. Tools that predict a pathogenic outcome 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) also yields a benign prediction; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” classification—there is no contradiction between the predictions and the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.318242	Structured	0.019545	Uncertain	0.901	0.403	0.000	Uncertain		1				-0.539	Likely Benign	0.336	Likely Benign	Likely Benign	0.343	Likely Benign	0.0897	0.0989		0.22	Likely Benign	0.2	0.16	Likely Benign	0.19	Likely Benign	0.17	Likely Benign	0.24	Neutral	0.872	Possibly Damaging	0.820	Possibly Damaging	-1.23	Pathogenic	0.55	Tolerated	3.37	35	0	-1	-5.2	-12.05	207.2	29.8	0.2	0.0	0.2	0.1						X		Potentially Benign	Ile529 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the sec-butyl side chain of Ile529 faces the membrane interface and shows no specific interactions. In the variant simulations, the hydroxyl group of Thr529 forms a hydrogen bond with the carboxylate side chain of Asp527, but no negative structural changes are observed. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations.
c.1586T>G	I529S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529S 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 indicate 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) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of evidence supports a benign classification and is consistent with the absence of a ClinVar assertion. Therefore, 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	GAP	0.318242	Structured	0.019545	Uncertain	0.901	0.403	0.000							-0.171	Likely Benign	0.197	Likely Benign	Likely Benign	0.383	Likely Benign	0.2402	0.0887		0.13	Likely Benign	0.3	-0.53	Ambiguous	-0.20	Likely Benign	0.00	Likely Benign	1.62	Neutral	0.979	Probably Damaging	0.820	Possibly Damaging	-1.14	Pathogenic	0.40	Tolerated			-1	-2	-5.3	-26.08
c.1587C>G	I529M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529M 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, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome; Rosetta is uncertain and therefore treated as unavailable. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta outputs)—all uniformly indicate a benign effect. Consequently, the variant is most likely benign based on the collective predictions, 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 Benign	GAP	0.318242	Structured	0.019545	Uncertain	0.901	0.403	0.000							1.489	Likely Benign	0.063	Likely Benign	Likely Benign	0.215	Likely Benign	0.0673	0.2876		0.10	Likely Benign	0.1	0.68	Ambiguous	0.39	Likely Benign	-0.17	Likely Benign	0.71	Neutral	0.035	Benign	0.063	Benign	-1.27	Pathogenic	0.15	Tolerated			2	1	-2.6	18.03
c.610T>A	S204T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S204T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic effect. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of reliable predictors classify S204T as benign, and this conclusion does not contradict the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.268042	Structured	0.420667	Uncertain	0.816	0.405	0.125							-4.164	Likely Benign	0.167	Likely Benign	Likely Benign	0.104	Likely Benign	0.0857	0.5063		0.75	Ambiguous	0.1	1.19	Ambiguous	0.97	Ambiguous	-0.52	Ambiguous	0.55	Neutral	0.462	Possibly Damaging	0.173	Benign	4.19	Benign	1.00	Tolerated			1	1	0.1	14.03
c.610T>C	S204P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S204P 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, and polyPhen‑2 HumVar, whereas a separate group predicts a pathogenic effect: FoldX, Rosetta, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The remaining tools (premPS) are inconclusive and are not counted in either group. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain (treated as unavailable), the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie and therefore unavailable, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Overall, the majority of consensus predictions lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.268042	Structured	0.420667	Uncertain	0.816	0.405	0.125							-8.855	Likely Pathogenic	0.820	Likely Pathogenic	Ambiguous	0.137	Likely Benign	0.1430	0.4815		3.71	Destabilizing	0.4	4.61	Destabilizing	4.16	Destabilizing	0.61	Ambiguous	-1.28	Neutral	0.808	Possibly Damaging	0.382	Benign	4.13	Benign	0.12	Tolerated			1	-1	-0.8	10.04
c.610T>G	S204A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S204A 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, 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 Rosetta, Foldetta, and premPS, which are treated as unavailable evidence. 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 Uncertain. Overall, 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	PH	0.268042	Structured	0.420667	Uncertain	0.816	0.405	0.125							-3.330	Likely Benign	0.084	Likely Benign	Likely Benign	0.091	Likely Benign	0.3706	0.3495		-0.09	Likely Benign	0.0	-1.17	Ambiguous	-0.63	Ambiguous	-0.83	Ambiguous	0.65	Neutral	0.004	Benign	0.004	Benign	4.28	Benign	0.27	Tolerated			1	1	2.6	-16.00
c.611C>A	S204Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S204Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus (SGM Consensus) is inconclusive because it receives an equal split between pathogenic and benign calls. AlphaMissense‑Optimized, a high‑accuracy model, predicts benign, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts pathogenic. Overall, the majority of evidence points to 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.		PH	0.268042	Structured	0.420667	Uncertain	0.816	0.405	0.125							-10.518	Likely Pathogenic	0.782	Likely Pathogenic	Likely Benign	0.170	Likely Benign	0.0452	0.5625		8.99	Destabilizing	3.8	5.20	Destabilizing	7.10	Destabilizing	-0.03	Likely Benign	-0.96	Neutral	0.978	Probably Damaging	0.694	Possibly Damaging	4.14	Benign	0.03	Affected			-3	-2	-0.5	76.10
c.611C>G	S204C 2D 3DClick to see structure in 3D Viewer AISynGAP1 S204C is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. FoldX and Rosetta individually report uncertain stability changes. Overall, the majority of computational evidence supports a benign effect, 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	PH	0.268042	Structured	0.420667	Uncertain	0.816	0.405	0.125	Uncertain		1				-6.613	Likely Benign	0.127	Likely Benign	Likely Benign	0.148	Likely Benign	0.0665	0.5237		0.65	Ambiguous	0.4	-1.13	Ambiguous	-0.24	Likely Benign	0.10	Likely Benign	-0.64	Neutral	0.978	Probably Damaging	0.753	Possibly Damaging	4.13	Benign	0.05	Affected	3.44	10	0	-1	3.3	16.06	223.6	-13.8	0.6	0.3	0.0	0.2	X							Uncertain	The hydroxyl-containing Ser204, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by the thiol-containing cysteine. In the WT simulations, Ser204 simultaneously forms hydrogen bonds with the backbone carbonyl of Asp201 and the hydroxyl group of Thr224, helping to stabilize the two anti-parallel β strands (res. Ile205-Lys207 and Cys219-Thr223) at the end of the β sheet. Since the thiol group of cysteine forms weaker hydrogen bonds than the hydroxyl group of serine, Cys204 does not maintain the hydrogen bond network as stably as Ser204 in the variant simulations. However, because the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.611C>T	S204F 2D AIThe SynGAP1 missense variant S204F 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, and FATHMM, whereas a majority of tools (FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding‑stability method combining FoldX‑MD and Rosetta outputs, predicts a pathogenic effect. Overall, the balance of evidence—seven pathogenic versus four benign predictions, with high‑accuracy tools supporting pathogenicity—suggests that the variant is most likely pathogenic. 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.		PH	0.268042	Structured	0.420667	Uncertain	0.816	0.405	0.125							-8.693	Likely Pathogenic	0.842	Likely Pathogenic	Ambiguous	0.161	Likely Benign	0.0468	0.5764		7.35	Destabilizing	6.1	4.21	Destabilizing	5.78	Destabilizing	-0.09	Likely Benign	-0.88	Neutral	0.978	Probably Damaging	0.694	Possibly Damaging	4.16	Benign	0.03	Affected			-3	-2	3.6	60.10
c.607G>A	D203N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D203N is reported in gnomAD (variant ID 6-33435249‑G‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar; ESM1b is uncertain. The high‑accuracy consensus methods give a consistent benign signal: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No prediction or folding stability result is missing or inconclusive. Based on the aggregate 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	PH	0.314870	Structured	0.427620	Uncertain	0.740	0.407	0.125				6-33435249-G-A	1	6.20e-7	-7.465	In-Between	0.159	Likely Benign	Likely Benign	0.121	Likely Benign	0.0800	0.4296		-0.19	Likely Benign	0.1	-0.12	Likely Benign	-0.16	Likely Benign	-0.03	Likely Benign	-2.26	Neutral	0.970	Probably Damaging	0.749	Possibly Damaging	4.06	Benign	0.06	Tolerated	3.44	10	1	2	0.0	-0.98
c.607G>C	D203H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203H 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, 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) as benign. No prediction or folding result is missing or inconclusive. Overall, the predictions are mixed, but the two high‑accuracy tools favor a benign outcome, giving a slight bias toward benign. Thus, the variant is most likely benign, 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	PH	0.314870	Structured	0.427620	Uncertain	0.740	0.407	0.125							-9.130	Likely Pathogenic	0.593	Likely Pathogenic	Likely Benign	0.218	Likely Benign	0.0962	0.4815		0.00	Likely Benign	0.1	0.18	Likely Benign	0.09	Likely Benign	-0.04	Likely Benign	-3.28	Deleterious	0.999	Probably Damaging	0.936	Probably Damaging	3.98	Benign	0.02	Affected			1	-1	0.3	22.05
c.607G>T	D203Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203Y missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, 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) as benign. No prediction or folding result is missing or inconclusive. Overall, the majority of individual tools lean toward benign, and two of the three high‑accuracy methods also predict benign, so the variant is most likely benign. This assessment 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	PH	0.314870	Structured	0.427620	Uncertain	0.740	0.407	0.125							-11.651	Likely Pathogenic	0.597	Likely Pathogenic	Likely Benign	0.260	Likely Benign	0.0382	0.4436		-0.36	Likely Benign	0.0	0.09	Likely Benign	-0.14	Likely Benign	0.05	Likely Benign	-4.38	Deleterious	0.999	Probably Damaging	0.936	Probably Damaging	3.96	Benign	0.01	Affected			-4	-3	2.2	48.09
c.608A>C	D203A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203A 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, premPS, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar; AlphaMissense‑Default 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 (combining FoldX‑MD and Rosetta outputs) as benign. All available predictions and stability analyses point to a benign impact. Therefore, 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.		PH	0.314870	Structured	0.427620	Uncertain	0.740	0.407	0.125							-6.807	Likely Benign	0.373	Ambiguous	Likely Benign	0.174	Likely Benign	0.2527	0.4128		0.07	Likely Benign	0.1	0.49	Likely Benign	0.28	Likely Benign	0.12	Likely Benign	-3.34	Deleterious	0.941	Possibly Damaging	0.607	Possibly Damaging	4.05	Benign	0.17	Tolerated			0	-2	5.3	-44.01
c.608A>G	D203G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203G 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, FoldX, premPS, ESM1b, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools give uncertain results: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign (two benign vs. one pathogenic, one uncertain); and Foldetta also predicts benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence supports a benign effect, and this is consistent with the lack of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.314870	Structured	0.427620	Uncertain	0.740	0.407	0.125							-6.332	Likely Benign	0.350	Ambiguous	Likely Benign	0.231	Likely Benign	0.2708	0.4312		0.07	Likely Benign	0.1	0.72	Ambiguous	0.40	Likely Benign	0.03	Likely Benign	-3.42	Deleterious	0.990	Probably Damaging	0.681	Possibly Damaging	4.01	Benign	0.04	Affected			1	-1	3.1	-58.04
c.608A>T	D203V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203V 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, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b; AlphaMissense‑Default remains 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 tools and the SGM Consensus lean toward a pathogenic interpretation, whereas two high‑accuracy methods (AlphaMissense‑Optimized and Foldetta) suggest benign. Because ClinVar contains no entry for this variant, there is no contradiction between the predictions and existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.314870	Structured	0.427620	Uncertain	0.740	0.407	0.125							-10.660	Likely Pathogenic	0.523	Ambiguous	Likely Benign	0.289	Likely Benign	0.0534	0.4084		0.32	Likely Benign	0.0	0.44	Likely Benign	0.38	Likely Benign	0.05	Likely Benign	-4.07	Deleterious	0.991	Probably Damaging	0.781	Possibly Damaging	3.98	Benign	0.02	Affected			-2	-3	7.7	-15.96
c.609T>A	D203E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203E 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 SGM‑Consensus, 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 methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all uniformly classify the variant as benign. No prediction or folding‑stability result is missing or inconclusive. Based on the consensus of the majority of tools and the unanimous high‑accuracy 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	PH	0.314870	Structured	0.427620	Uncertain	0.740	0.407	0.125							-4.067	Likely Benign	0.201	Likely Benign	Likely Benign	0.152	Likely Benign	0.0975	0.4189		0.10	Likely Benign	0.0	0.08	Likely Benign	0.09	Likely Benign	-0.07	Likely Benign	-0.93	Neutral	0.990	Probably Damaging	0.675	Possibly Damaging	4.15	Benign	0.81	Tolerated			3	2	0.0	14.03
c.609T>G	D203E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203E 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 SGM‑Consensus, 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 methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all uniformly classify the variant as benign. No prediction or folding‑stability result is missing or inconclusive. Based on the consensus of the majority of tools and the unanimous high‑accuracy 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	PH	0.314870	Structured	0.427620	Uncertain	0.740	0.407	0.125							-4.067	Likely Benign	0.201	Likely Benign	Likely Benign	0.152	Likely Benign	0.0975	0.4189		0.10	Likely Benign	0.0	0.08	Likely Benign	0.09	Likely Benign	-0.07	Likely Benign	-0.93	Neutral	0.990	Probably Damaging	0.675	Possibly Damaging	4.15	Benign	0.81	Tolerated			3	2	0.0	14.03
c.1579G>A	D527N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D527N 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 FoldX, Rosetta, Foldetta, and premPS, whereas a majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. The high‑accuracy consensus methods give mixed results: AlphaMissense‑Optimized is uncertain, SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign outcome. Overall, the preponderance of evidence points 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.	Likely Pathogenic	GAP	0.139895	Structured	0.021908	Uncertain	0.913	0.408	0.000							-12.645	Likely Pathogenic	0.884	Likely Pathogenic	Ambiguous	0.730	Likely Pathogenic	0.0910	0.3754		0.31	Likely Benign	1.0	0.09	Likely Benign	0.20	Likely Benign	0.22	Likely Benign	-4.87	Deleterious	0.992	Probably Damaging	0.990	Probably Damaging	-2.13	Pathogenic	0.01	Affected			2	1	0.0	-0.98
c.1579G>C	D527H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D527H is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX and premPS, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. Uncertain results come from Rosetta and Foldetta. 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, SGM Consensus as pathogenic, and Foldetta as inconclusive. Based on the preponderance of pathogenic predictions and the lack of benign 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	GAP	0.139895	Structured	0.021908	Uncertain	0.913	0.408	0.000							-13.334	Likely Pathogenic	0.986	Likely Pathogenic	Likely Pathogenic	0.901	Likely Pathogenic	0.1092	0.4346		0.40	Likely Benign	1.2	1.26	Ambiguous	0.83	Ambiguous	0.49	Likely Benign	-6.80	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	-2.39	Pathogenic	0.00	Affected			1	-1	0.3	22.05
c.1579G>T	D527Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D527Y is listed in ClinVar with an uncertain significance (ClinVar ID 1698369.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: the single benign prediction from premPS versus a consensus of pathogenic predictions from the remaining 12 tools (REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized). High‑accuracy assessments further support a deleterious effect: 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 inconclusive. Protein‑stability calculations from FoldX and Rosetta are also uncertain. Overall, the preponderance of evidence indicates that D527Y is most likely pathogenic, which does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.139895	Structured	0.021908	Uncertain	0.913	0.408	0.000	Uncertain		1				-15.386	Likely Pathogenic	0.978	Likely Pathogenic	Likely Pathogenic	0.905	Likely Pathogenic	0.0554	0.4229		-0.77	Ambiguous	0.2	1.89	Ambiguous	0.56	Ambiguous	-0.14	Likely Benign	-8.79	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	-2.41	Pathogenic	0.00	Affected	3.37	35	-4	-3	2.2	48.09	270.9	-45.7	0.1	0.1	-0.1	0.0		X						Potentially Pathogenic	Asp527 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the carboxylate group of the Asp527 side chain forms hydrogen bonds with the backbone atoms of loop residues (e.g., Ile529, Lys530) facing the membrane surface. In the variant simulations, Tyr527 is a bulkier residue that faces away from the loop and stacks with Phe646 in a nearby α-helix (res. Ser614-Ser668). Regardless, no negative structural effects are observed during the variant simulations. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations.
c.1580A>C	D527A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D527A 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 premPS, while the remaining evaluated methods (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict pathogenicity. FoldX, Rosetta, and Foldetta are inconclusive and are treated as unavailable. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta remains uncertain. Overall, the variant is most likely pathogenic based on the consensus of predictive tools, 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	GAP	0.139895	Structured	0.021908	Uncertain	0.913	0.408	0.000							-15.473	Likely Pathogenic	0.970	Likely Pathogenic	Likely Pathogenic	0.929	Likely Pathogenic	0.2850	0.3799		0.81	Ambiguous	0.9	1.75	Ambiguous	1.28	Ambiguous	-0.24	Likely Benign	-7.79	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	-2.39	Pathogenic	0.00	Affected			0	-2	5.3	-44.01
c.1580A>G	D527G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D527G is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools cluster into two groups: the single benign prediction comes from premPS, while all other evaluated algorithms—SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—indicate pathogenicity. FoldX is uncertain and therefore not counted as evidence for either side. High‑accuracy methods reinforce the pathogenic assessment: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No contradictory evidence exists in ClinVar. **Thus, the variant is most likely pathogenic based on the collective predictions, with no ClinVar status to contradict this assessment.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.139895	Structured	0.021908	Uncertain	0.913	0.408	0.000							-15.177	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.933	Likely Pathogenic	0.2847	0.4366		1.71	Ambiguous	1.0	4.22	Destabilizing	2.97	Destabilizing	0.33	Likely Benign	-6.86	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	-2.39	Pathogenic	0.01	Affected			1	-1	3.1	-58.04
c.1580A>T	D527V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D527V 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 pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that are uncertain (FoldX, Rosetta, Foldetta, premPS) provide no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, while Foldetta remains uncertain. Overall, the majority of reliable predictors classify the variant as pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Thus, based on current computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.139895	Structured	0.021908	Uncertain	0.913	0.408	0.000							-16.844	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	0.938	Likely Pathogenic	0.0659	0.3984		0.71	Ambiguous	0.7	0.84	Ambiguous	0.78	Ambiguous	-0.55	Ambiguous	-8.78	Deleterious	0.998	Probably Damaging	0.997	Probably Damaging	-2.40	Pathogenic	0.00	Affected			-2	-3	7.7	-15.96
c.1581C>A	D527E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D527E missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a strong bias toward pathogenicity: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a deleterious effect, whereas only FoldX and premPS predict a benign 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 are mixed: AlphaMissense‑Optimized is inconclusive, Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain, and the SGM Consensus remains Likely Pathogenic. Overall, the preponderance of evidence points to a pathogenic impact, 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	GAP	0.139895	Structured	0.021908	Uncertain	0.913	0.408	0.000							-11.125	Likely Pathogenic	0.884	Likely Pathogenic	Ambiguous	0.740	Likely Pathogenic	0.1103	0.3428		0.36	Likely Benign	0.8	2.29	Destabilizing	1.33	Ambiguous	0.50	Likely Benign	-3.74	Deleterious	0.929	Possibly Damaging	0.938	Probably Damaging	-2.31	Pathogenic	0.02	Affected			3	2	0.0	14.03
c.1581C>G	D527E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D527E missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a strong bias toward pathogenicity: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a deleterious effect, whereas only FoldX and premPS predict a benign 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 are mixed: AlphaMissense‑Optimized is inconclusive, Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain, and the SGM Consensus remains Likely Pathogenic. Overall, the preponderance of evidence points to a pathogenic impact, 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	GAP	0.139895	Structured	0.021908	Uncertain	0.913	0.408	0.000							-11.125	Likely Pathogenic	0.884	Likely Pathogenic	Ambiguous	0.740	Likely Pathogenic	0.1103	0.3428		0.36	Likely Benign	0.8	2.29	Destabilizing	1.33	Ambiguous	0.50	Likely Benign	-3.74	Deleterious	0.929	Possibly Damaging	0.938	Probably Damaging	-2.31	Pathogenic	0.02	Affected			3	2	0.0	14.03
c.1588A>C	K530Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530Q 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, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (13/16) predict pathogenicity, whereas only three predict benign. Therefore, the variant is most likely pathogenic based on current 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	GAP	0.308712	Structured	0.018455	Uncertain	0.891	0.409	0.000							-10.593	Likely Pathogenic	0.574	Likely Pathogenic	Likely Benign	0.524	Likely Pathogenic	0.3001	0.0941		0.31	Likely Benign	0.0	0.87	Ambiguous	0.59	Ambiguous	0.13	Likely Benign	-3.18	Deleterious	0.698	Possibly Damaging	0.694	Possibly Damaging	-1.61	Pathogenic	0.01	Affected			1	1	0.4	-0.04
c.1588A>G	K530E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K530E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and polyPhen‑2 HumVar, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus remains Likely Pathogenic, and Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for K530E. 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	GAP	0.308712	Structured	0.018455	Uncertain	0.891	0.409	0.000							-14.450	Likely Pathogenic	0.951	Likely Pathogenic	Ambiguous	0.581	Likely Pathogenic	0.2505	0.0810		0.79	Ambiguous	0.2	1.27	Ambiguous	1.03	Ambiguous	0.43	Likely Benign	-3.45	Deleterious	0.703	Possibly Damaging	0.276	Benign	-1.57	Pathogenic	0.00	Affected			0	1	0.4	0.94
c.1589A>C	K530T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530T missense variant 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 only premPS, whereas the remaining nine tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of the pathogenic‑predominant tools) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a deleterious impact. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently contains no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.308712	Structured	0.018455	Uncertain	0.891	0.409	0.000							-11.506	Likely Pathogenic	0.852	Likely Pathogenic	Ambiguous	0.610	Likely Pathogenic	0.1351	0.2780		1.06	Ambiguous	0.3	1.06	Ambiguous	1.06	Ambiguous	0.27	Likely Benign	-5.17	Deleterious	0.921	Possibly Damaging	0.950	Probably Damaging	-1.63	Pathogenic	0.00	Affected			0	-1	3.2	-27.07
c.1589A>G	K530R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K530R is catalogued in gnomAD (6‑33438832‑A‑G) but has no ClinVar entry. 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. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. Overall, the preponderance of evidence indicates that the variant is most likely benign, 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	GAP	0.308712	Structured	0.018455	Uncertain	0.891	0.409	0.000				6-33438832-A-G	1	6.19e-7	-3.836	Likely Benign	0.081	Likely Benign	Likely Benign	0.234	Likely Benign	0.3297	0.0716		-0.02	Likely Benign	0.1	0.18	Likely Benign	0.08	Likely Benign	0.33	Likely Benign	-1.39	Neutral	0.000	Benign	0.002	Benign	-1.54	Pathogenic	0.08	Tolerated	3.37	35	2	3	-0.6	28.01
c.1589A>T	K530M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530M 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 premPS. Tools that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Based on the predominance of pathogenic predictions and the SGM Consensus result, the variant is most likely pathogenic. This assessment 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	GAP	0.308712	Structured	0.018455	Uncertain	0.891	0.409	0.000							-12.235	Likely Pathogenic	0.953	Likely Pathogenic	Ambiguous	0.671	Likely Pathogenic	0.0745	0.3123		0.51	Ambiguous	0.0	1.26	Ambiguous	0.89	Ambiguous	0.24	Likely Benign	-5.17	Deleterious	0.999	Probably Damaging	0.988	Probably Damaging	-1.69	Pathogenic	0.00	Affected			0	-1	5.8	3.02
c.1590G>C	K530N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530N missense variant 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 FoldX, Rosetta, and Foldetta, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—predict a pathogenic or likely pathogenic outcome; premPS is uncertain. 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 benign. Overall, the majority of predictions (10/13) support pathogenicity, with only three tools indicating benign. Therefore, the variant is most likely pathogenic based on the available 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	GAP	0.308712	Structured	0.018455	Uncertain	0.891	0.409	0.000							-12.459	Likely Pathogenic	0.960	Likely Pathogenic	Likely Pathogenic	0.553	Likely Pathogenic	0.2350	0.1086		0.42	Likely Benign	0.1	0.23	Likely Benign	0.33	Likely Benign	0.56	Ambiguous	-4.18	Deleterious	0.950	Possibly Damaging	0.703	Possibly Damaging	-1.65	Pathogenic	0.00	Affected			1	0	0.4	-14.07
c.1590G>T	K530N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530N missense variant 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 FoldX, Rosetta, and Foldetta, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—predict a pathogenic or likely pathogenic outcome; premPS is uncertain. 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 benign. Overall, the majority of predictions (10/13) support pathogenicity, with only three tools indicating benign. Therefore, the variant is most likely pathogenic based on the available 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	GAP	0.308712	Structured	0.018455	Uncertain	0.891	0.409	0.000							-12.459	Likely Pathogenic	0.960	Likely Pathogenic	Likely Pathogenic	0.553	Likely Pathogenic	0.2350	0.1086		0.42	Likely Benign	0.1	0.23	Likely Benign	0.33	Likely Benign	0.56	Ambiguous	-4.18	Deleterious	0.950	Possibly Damaging	0.703	Possibly Damaging	-1.65	Pathogenic	0.00	Affected			1	0	0.4	-14.07
c.1069C>A	H357N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H357N 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 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while ESM1b remains uncertain. 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 overwhelming majority of evidence points to a benign impact. There is no ClinVar annotation to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.203355	Structured	0.399052	Uncertain	0.861	0.413	0.250							-7.617	In-Between	0.103	Likely Benign	Likely Benign	0.126	Likely Benign	0.2052	0.3266		0.14	Likely Benign	0.2	0.31	Likely Benign	0.23	Likely Benign	0.31	Likely Benign	-1.47	Neutral	0.495	Possibly Damaging	0.169	Benign	4.25	Benign	0.15	Tolerated			2	1	-0.3	-23.04
c.1069C>G	H357D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H357D 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 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta also predicts a benign outcome. No prediction or folding‑stability result is 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	0.203355	Structured	0.399052	Uncertain	0.861	0.413	0.250							-12.013	Likely Pathogenic	0.559	Ambiguous	Likely Benign	0.208	Likely Benign	0.2782	0.1976		-0.23	Likely Benign	0.4	-0.27	Likely Benign	-0.25	Likely Benign	0.48	Likely Benign	-1.90	Neutral	0.495	Possibly Damaging	0.169	Benign	4.22	Benign	0.08	Tolerated			1	-1	-0.3	-22.05
c.1069C>T	H357Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H357Y is reported in gnomAD (variant ID 6‑33437974‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely benign. High‑accuracy assessments reinforce this view: 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 (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.203355	Structured	0.399052	Uncertain	0.861	0.413	0.250				6-33437974-C-T	1	6.21e-7	-5.888	Likely Benign	0.168	Likely Benign	Likely Benign	0.140	Likely Benign	0.1010	0.4658		-0.33	Likely Benign	0.2	0.08	Likely Benign	-0.13	Likely Benign	-0.07	Likely Benign	-1.71	Neutral	0.936	Possibly Damaging	0.388	Benign	4.19	Benign	0.14	Tolerated	3.39	22	2	0	1.9	26.03
c.1070A>C	H357P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H357P 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Two tools give uncertain results: Foldetta (protein‑folding stability) and ESM1b. 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. Thus, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.203355	Structured	0.399052	Uncertain	0.861	0.413	0.250							-7.953	In-Between	0.267	Likely Benign	Likely Benign	0.197	Likely Benign	0.2433	0.4468		0.17	Likely Benign	0.9	3.52	Destabilizing	1.85	Ambiguous	-0.06	Likely Benign	-2.70	Deleterious	0.936	Possibly Damaging	0.469	Possibly Damaging	4.18	Benign	0.17	Tolerated			0	-2	1.6	-40.02
c.1070A>G	H357R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H357R 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, PROVEAN, SIFT, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. Two tools remain uncertain: Rosetta and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority; and Foldetta also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of 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.		C2	0.203355	Structured	0.399052	Uncertain	0.861	0.413	0.250							-9.212	Likely Pathogenic	0.348	Ambiguous	Likely Benign	0.107	Likely Benign	0.2147	0.2818		-0.10	Likely Benign	0.3	1.07	Ambiguous	0.49	Likely Benign	0.32	Likely Benign	-1.03	Neutral	0.495	Possibly Damaging	0.095	Benign	4.22	Benign	0.59	Tolerated			2	0	-1.3	19.05
c.1070A>T	H357L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H357L 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, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv, while polyPhen‑2 HumVar and ESM1b are benign or uncertain, respectively. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign (3 benign vs 1 pathogenic), and Foldetta also predicts benign. No predictions are missing or inconclusive. Overall, the variant is most likely benign based on the majority of computational evidence, 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.		C2	0.203355	Structured	0.399052	Uncertain	0.861	0.413	0.250							-7.281	In-Between	0.140	Likely Benign	Likely Benign	0.203	Likely Benign	0.1084	0.5971		-0.18	Likely Benign	0.1	0.14	Likely Benign	-0.02	Likely Benign	0.10	Likely Benign	-3.39	Deleterious	0.704	Possibly Damaging	0.169	Benign	4.20	Benign	0.25	Tolerated			-2	-3	7.0	-23.98
c.1071C>A	H357Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H357Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess sequence conservation, structural impact, or functional effect all converge on a benign outcome: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: 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, also reports a benign effect. Based on the uniform predictions, 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	C2	0.203355	Structured	0.399052	Uncertain	0.861	0.413	0.250							-4.370	Likely Benign	0.163	Likely Benign	Likely Benign	0.025	Likely Benign	0.1716	0.3850		0.06	Likely Benign	0.2	-0.03	Likely Benign	0.02	Likely Benign	-0.35	Likely Benign	1.42	Neutral	0.013	Benign	0.007	Benign	4.49	Benign	1.00	Tolerated			3	0	-0.3	-9.01
c.1071C>G	H357Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H357Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess sequence conservation, structural impact, or functional effect all converge on a benign outcome: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: 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, also reports a benign effect. Based on the uniform predictions, 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	C2	0.203355	Structured	0.399052	Uncertain	0.861	0.413	0.250							-4.370	Likely Benign	0.163	Likely Benign	Likely Benign	0.025	Likely Benign	0.1716	0.3850		0.06	Likely Benign	0.2	-0.03	Likely Benign	0.02	Likely Benign	-0.35	Likely Benign	1.42	Neutral	0.013	Benign	0.007	Benign	4.49	Benign	1.00	Tolerated			3	0	-0.3	-9.01
c.1000A>C	K334Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K334Q is not reported in ClinVar and is absent from gnomAD. 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. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as 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 seven tools favoring pathogenicity versus five favoring benign, the overall prediction leans toward pathogenic. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.377384	Structured	0.325972	Uncertain	0.544	0.414	0.500							-8.185	Likely Pathogenic	0.810	Likely Pathogenic	Ambiguous	0.357	Likely Benign	0.4519	0.1062		0.08	Likely Benign	0.0	0.10	Likely Benign	0.09	Likely Benign	0.46	Likely Benign	-3.67	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.74	Pathogenic	0.03	Affected			1	1	0.4	-0.04
c.1000A>G	K334E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K334E 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, and premPS. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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 Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of evidence points toward a pathogenic impact, 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	0.377384	Structured	0.325972	Uncertain	0.544	0.414	0.500							-12.770	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.372	Likely Benign	0.3929	0.0882		0.30	Likely Benign	0.2	-0.07	Likely Benign	0.12	Likely Benign	0.42	Likely Benign	-3.67	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.74	Pathogenic	0.02	Affected			0	1	0.4	0.94
c.1001A>C	K334T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K334T 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, and premPS. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive or uncertain are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts a likely pathogenic outcome, AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain. Overall, the majority of evidence points to a pathogenic impact. 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	0.377384	Structured	0.325972	Uncertain	0.544	0.414	0.500							-8.313	Likely Pathogenic	0.943	Likely Pathogenic	Ambiguous	0.320	Likely Benign	0.2062	0.2978		0.78	Ambiguous	0.3	0.21	Likely Benign	0.50	Ambiguous	0.17	Likely Benign	-5.51	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.78	Pathogenic	0.02	Affected			0	-1	3.2	-27.07
c.1001A>G	K334R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K334R 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; Rosetta is 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‑vs‑2 split. Overall, the majority of evidence points to a benign impact. Thus, 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	0.377384	Structured	0.325972	Uncertain	0.544	0.414	0.500							-5.384	Likely Benign	0.162	Likely Benign	Likely Benign	0.247	Likely Benign	0.4647	0.0976		-0.37	Likely Benign	0.1	-0.53	Ambiguous	-0.45	Likely Benign	0.39	Likely Benign	-2.62	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.76	Pathogenic	0.07	Tolerated			3	2	-0.6	28.01
c.1001A>T	K334M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K334M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, and premPS. In contrast, the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as deleterious. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as Likely Pathogenic. Foldetta and Rosetta provide uncertain results. Focusing on high‑accuracy methods, AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus confirms a Likely Pathogenic status, and Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for K334M, 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	C2	0.377384	Structured	0.325972	Uncertain	0.544	0.414	0.500							-10.530	Likely Pathogenic	0.973	Likely Pathogenic	Likely Pathogenic	0.323	Likely Benign	0.1027	0.3690		0.44	Likely Benign	0.0	0.56	Ambiguous	0.50	Ambiguous	0.14	Likely Benign	-5.51	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.77	Pathogenic	0.01	Affected			0	-1	5.8	3.02
c.1002G>C	K334N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K334N 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, and premPS. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” Separately, the high‑accuracy AlphaMissense‑Optimized tool predicts pathogenicity, the SGM‑Consensus also predicts pathogenicity, while the Foldetta stability assessment predicts a benign effect. Overall, the majority of predictions (8 pathogenic vs. 5 benign) and the high‑accuracy consensus suggest that K334N 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	0.377384	Structured	0.325972	Uncertain	0.544	0.414	0.500							-9.581	Likely Pathogenic	0.982	Likely Pathogenic	Likely Pathogenic	0.249	Likely Benign	0.3716	0.0958		0.15	Likely Benign	0.1	-0.25	Likely Benign	-0.05	Likely Benign	0.18	Likely Benign	-4.59	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.77	Pathogenic	0.02	Affected			1	0	0.4	-14.07
c.1002G>T	K334N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K334N 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, and premPS. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” Separately, the high‑accuracy AlphaMissense‑Optimized tool predicts pathogenicity, the SGM‑Consensus also predicts pathogenicity, while the Foldetta stability assessment predicts a benign effect. Overall, the majority of predictions (8 pathogenic vs. 5 benign) and the high‑accuracy consensus suggest that K334N 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	0.377384	Structured	0.325972	Uncertain	0.544	0.414	0.500							-9.581	Likely Pathogenic	0.982	Likely Pathogenic	Likely Pathogenic	0.249	Likely Benign	0.3716	0.0958		0.15	Likely Benign	0.1	-0.25	Likely Benign	-0.05	Likely Benign	0.18	Likely Benign	-4.59	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.77	Pathogenic	0.02	Affected			1	0	0.4	-14.07
c.1042G>A	V348M 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V348M is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that report a clear outcome fall into two groups: benign calls come from REVEL, Foldetta, PROVEAN, and AlphaMissense‑Optimized; pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools (FoldX, Rosetta, premPS, AlphaMissense‑Default, ESM1b) give uncertain results, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to no majority. High‑accuracy methods specifically show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus is not available. With four benign and four pathogenic predictions, the evidence is evenly split, providing no definitive direction. Therefore, the variant is not clearly benign or pathogenic based on current predictions, and this lack of consensus does not contradict its ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.170161	Structured	0.346556	Uncertain	0.951	0.414	0.000	Uncertain		1				-7.076	In-Between	0.546	Ambiguous	Likely Benign	0.191	Likely Benign	0.0903	0.4748		-1.19	Ambiguous	0.1	0.72	Ambiguous	-0.24	Likely Benign	0.76	Ambiguous	-1.62	Neutral	0.966	Probably Damaging	0.564	Possibly Damaging	1.58	Pathogenic	0.03	Affected	3.37	25	2	1	-2.3	32.06	253.8	-47.4	-0.3	0.1	0.2	0.1						X		Potentially Benign	The iso-propyl side chain of Val348, located in an anti-parallel β sheet strand (res. Gly341-Pro349), packs against multiple hydrophobic C2 domain residues (e.g., Leu353, Leu323, Leu402). In the variant simulations, the thioether side chain of Met348 can form similar interactions as valine due to its comparable hydrophobic profile. In fact, the thioether group of methionine can even stack favorably with the phenol ring of Tyr363 in the anti-parallel β sheet strand (res. Ala399-Ile411). Overall, the residue swap does not appear to cause negative effects on the protein structure based on the simulations.
c.1042G>C	V348L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). 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 other high‑confidence tools provide conflicting evidence. Based on the preponderance of 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	0.170161	Structured	0.346556	Uncertain	0.951	0.414	0.000							-4.842	Likely Benign	0.270	Likely Benign	Likely Benign	0.072	Likely Benign	0.1088	0.4953		-0.58	Ambiguous	0.0	0.04	Likely Benign	-0.27	Likely Benign	0.24	Likely Benign	-0.75	Neutral	0.264	Benign	0.030	Benign	1.89	Pathogenic	0.62	Tolerated			2	1	-0.4	14.03
c.1042G>T	V348L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). 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 other high‑confidence tools provide conflicting evidence. Based on the preponderance of 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	0.170161	Structured	0.346556	Uncertain	0.951	0.414	0.000							-4.842	Likely Benign	0.270	Likely Benign	Likely Benign	0.072	Likely Benign	0.1088	0.4953		-0.58	Ambiguous	0.0	0.04	Likely Benign	-0.27	Likely Benign	0.24	Likely Benign	-0.75	Neutral	0.264	Benign	0.030	Benign	1.89	Pathogenic	0.62	Tolerated			2	1	-0.4	14.03
c.1043T>A	V348E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348E 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) indicate pathogenicity. 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, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for V348E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.170161	Structured	0.346556	Uncertain	0.951	0.414	0.000							-11.135	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.470	Likely Benign	0.1089	0.1922		2.41	Destabilizing	0.1	2.20	Destabilizing	2.31	Destabilizing	2.14	Destabilizing	-5.26	Deleterious	0.989	Probably Damaging	0.637	Possibly Damaging	1.56	Pathogenic	0.01	Affected			-2	-2	-7.7	29.98
c.1043T>C	V348A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further highlight the discrepancy: AlphaMissense‑Optimized predicts a benign effect, 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. Taken together, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict ClinVar status, which currently has no entry for V348A. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.170161	Structured	0.346556	Uncertain	0.951	0.414	0.000							-9.993	Likely Pathogenic	0.767	Likely Pathogenic	Likely Benign	0.175	Likely Benign	0.3223	0.2437		2.46	Destabilizing	0.1	3.13	Destabilizing	2.80	Destabilizing	2.23	Destabilizing	-3.42	Deleterious	0.622	Possibly Damaging	0.152	Benign	1.59	Pathogenic	0.14	Tolerated			0	0	-2.4	-28.05
c.1043T>G	V348G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348G 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 REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods reinforce this assessment: 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) indicates a pathogenic effect. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among pathogenic predictions and the lack of a benign consensus, 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.		C2	0.170161	Structured	0.346556	Uncertain	0.951	0.414	0.000							-12.793	Likely Pathogenic	0.964	Likely Pathogenic	Likely Pathogenic	0.419	Likely Benign	0.2229	0.2082		3.97	Destabilizing	0.2	5.70	Destabilizing	4.84	Destabilizing	2.23	Destabilizing	-6.18	Deleterious	0.637	Possibly Damaging	0.989	Probably Damaging	1.56	Pathogenic	0.00	Affected			-1	-3	-4.6	-42.08
c.613A>C	I205L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I205L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: 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) all classify the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No contradictory evidence exists. Based on the collective predictions, the variant is most likely benign, 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 Benign	PH	0.264545	Structured	0.409933	Uncertain	0.821	0.414	0.125							-5.474	Likely Benign	0.105	Likely Benign	Likely Benign	0.112	Likely Benign	0.0682	0.2702		0.07	Likely Benign	0.2	0.02	Likely Benign	0.05	Likely Benign	0.30	Likely Benign	-0.86	Neutral	0.004	Benign	0.012	Benign	4.17	Benign	0.34	Tolerated			2	2	-0.7	0.00
c.613A>G	I205V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I205V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: 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) all classify the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the consensus of all available predictions, the variant is most likely benign, 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 Benign	PH	0.264545	Structured	0.409933	Uncertain	0.821	0.414	0.125							-2.232	Likely Benign	0.063	Likely Benign	Likely Benign	0.113	Likely Benign	0.0897	0.2791		0.45	Likely Benign	0.0	-0.18	Likely Benign	0.14	Likely Benign	0.11	Likely Benign	-0.11	Neutral	0.001	Benign	0.007	Benign	4.20	Benign	0.84	Tolerated			4	3	-0.3	-14.03
c.613A>T	I205F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I205F missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, and polyPhen‑2 HumVar all classify it as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. Uncertain results from Foldetta, premPS, ESM1b, and Rosetta are 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 likely benign, while Foldetta remains uncertain. Overall, the consensus of the majority of tools indicates that the variant is most likely benign, 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	0.264545	Structured	0.409933	Uncertain	0.821	0.414	0.125							-7.913	In-Between	0.271	Likely Benign	Likely Benign	0.113	Likely Benign	0.0461	0.2205		0.30	Likely Benign	0.3	0.89	Ambiguous	0.60	Ambiguous	0.52	Ambiguous	-1.80	Neutral	0.838	Possibly Damaging	0.368	Benign	4.08	Benign	0.10	Tolerated			1	0	-1.7	34.02
c.614T>A	I205N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I205N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) 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 uncertain. No evidence from these tools contradicts the lack of ClinVar annotation. Overall, the majority of predictions (five pathogenic vs. four benign) and the pathogenic SGM Consensus suggest the variant is most likely pathogenic, with no ClinVar status to conflict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.264545	Structured	0.409933	Uncertain	0.821	0.414	0.125							-10.928	Likely Pathogenic	0.552	Ambiguous	Likely Benign	0.138	Likely Benign	0.0802	0.0212		0.66	Ambiguous	0.1	1.16	Ambiguous	0.91	Ambiguous	1.57	Destabilizing	-3.56	Deleterious	0.940	Possibly Damaging	0.641	Possibly Damaging	4.06	Benign	0.07	Tolerated			-2	-3	-8.0	0.94
c.614T>C	I205T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I205T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the remaining predictions (FoldX, premPS, AlphaMissense‑Default) are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, classifies the variant as benign. Taken together, the consensus of both general and high‑accuracy predictors indicates that I205T 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.	Likely Benign	PH	0.264545	Structured	0.409933	Uncertain	0.821	0.414	0.125							-6.869	Likely Benign	0.450	Ambiguous	Likely Benign	0.118	Likely Benign	0.0933	0.0541		0.65	Ambiguous	0.0	0.28	Likely Benign	0.47	Likely Benign	0.81	Ambiguous	-2.19	Neutral	0.421	Benign	0.156	Benign	4.16	Benign	0.15	Tolerated			0	-1	-5.2	-12.05
c.614T>G	I205S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I205S 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, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and ESM1b. Tools with uncertain or inconclusive results (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) 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, the majority of available predictions lean toward a benign 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.		PH	0.264545	Structured	0.409933	Uncertain	0.821	0.414	0.125							-8.694	Likely Pathogenic	0.518	Ambiguous	Likely Benign	0.178	Likely Benign	0.2346	0.0800		1.17	Ambiguous	0.2	0.95	Ambiguous	1.06	Ambiguous	0.88	Ambiguous	-2.73	Deleterious	0.838	Possibly Damaging	0.368	Benign	4.12	Benign	0.24	Tolerated			-1	-2	-5.3	-26.08
c.615T>G	I205M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I205M 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. Uncertain results come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as benign. Based on the majority of predictions and the high‑accuracy 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	PH	0.264545	Structured	0.409933	Uncertain	0.821	0.414	0.125							-6.693	Likely Benign	0.142	Likely Benign	Likely Benign	0.119	Likely Benign	0.0593	0.2000		0.20	Likely Benign	0.2	0.63	Ambiguous	0.42	Likely Benign	0.65	Ambiguous	-1.16	Neutral	0.838	Possibly Damaging	0.467	Possibly Damaging	4.07	Benign	0.07	Tolerated			2	1	-2.6	18.03
c.604G>A	E202K 2D AIThe SynGAP1 E202K 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Rosetta and Foldetta give uncertain results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta’s stability assessment is uncertain. Overall, more tools (7 vs. 5) predict pathogenicity, and the high‑accuracy consensus leans toward pathogenic. 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	PH	0.363090	Structured	0.429450	Uncertain	0.712	0.415	0.125							-9.011	Likely Pathogenic	0.678	Likely Pathogenic	Likely Benign	0.231	Likely Benign	0.1963	0.6885		-0.24	Likely Benign	0.3	-0.76	Ambiguous	-0.50	Ambiguous	0.10	Likely Benign	-2.55	Deleterious	0.982	Probably Damaging	0.679	Possibly Damaging	4.07	Benign	0.03	Affected			0	1	-0.4	-0.94
c.604G>C	E202Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202Q 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and SIFT. Two tools, ESM1b and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while 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 points to a benign effect. 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.		PH	0.363090	Structured	0.429450	Uncertain	0.712	0.415	0.125							-7.129	In-Between	0.456	Ambiguous	Likely Benign	0.175	Likely Benign	0.0949	0.6792		-0.16	Likely Benign	0.0	0.23	Likely Benign	0.04	Likely Benign	-0.13	Likely Benign	-1.39	Neutral	0.995	Probably Damaging	0.747	Possibly Damaging	4.07	Benign	0.02	Affected			2	2	0.0	-0.98
c.605A>C	E202A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202A 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools (AlphaMissense‑Default and ESM1b) return uncertain results. 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 and therefore unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion 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.		PH	0.363090	Structured	0.429450	Uncertain	0.712	0.415	0.125							-7.222	In-Between	0.538	Ambiguous	Likely Benign	0.220	Likely Benign	0.3903	0.6468		0.13	Likely Benign	0.0	0.14	Likely Benign	0.14	Likely Benign	0.19	Likely Benign	-4.05	Deleterious	0.948	Possibly Damaging	0.484	Possibly Damaging	4.02	Benign	0.02	Affected			0	-1	5.3	-58.04
c.605A>G	E202G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202G 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, and FATHMM. Those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools with uncertain or inconclusive results are Rosetta, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward pathogenic (2 pathogenic, 1 benign, 1 uncertain). Foldetta remains uncertain. Overall, the majority of standard prediction tools suggest a benign effect, and this conclusion does not contradict the lack of ClinVar reporting. Thus, the variant is most likely benign based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.363090	Structured	0.429450	Uncertain	0.712	0.415	0.125							-8.310	Likely Pathogenic	0.495	Ambiguous	Likely Benign	0.259	Likely Benign	0.3061	0.5405		0.37	Likely Benign	0.0	0.74	Ambiguous	0.56	Ambiguous	0.27	Likely Benign	-4.70	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	4.01	Benign	0.07	Tolerated			0	-2	3.1	-72.06
c.605A>T	E202V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202V missense variant has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SIFT, PROVEAN, polyPhen‑2 HumDiv, ESM1b, 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 benign. Because the majority of tools (8 benign vs. 5 pathogenic) lean toward a benign outcome, the variant is most likely benign, although the SGM Consensus suggests pathogenicity. 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	PH	0.363090	Structured	0.429450	Uncertain	0.712	0.415	0.125							-8.990	Likely Pathogenic	0.783	Likely Pathogenic	Likely Benign	0.270	Likely Benign	0.0525	0.7007		0.48	Likely Benign	0.0	0.34	Likely Benign	0.41	Likely Benign	0.12	Likely Benign	-4.81	Deleterious	0.649	Possibly Damaging	0.259	Benign	3.96	Benign	0.01	Affected			-2	-2	7.7	-29.98
c.606A>C	E202D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202D 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, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy methods give a consistent benign verdict: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Rosetta alone is uncertain, but this inconclusive result does not alter the overall benign consensus. Based on the aggregate 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	PH	0.363090	Structured	0.429450	Uncertain	0.712	0.415	0.125							-5.646	Likely Benign	0.169	Likely Benign	Likely Benign	0.065	Likely Benign	0.1606	0.4051		0.35	Likely Benign	0.1	0.53	Ambiguous	0.44	Likely Benign	0.19	Likely Benign	-1.82	Neutral	0.982	Probably Damaging	0.581	Possibly Damaging	4.02	Benign	0.04	Affected			3	2	0.0	-14.03
c.606A>T	E202D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202D missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus score. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized returns a benign prediction; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign effect. Taken together, the majority of evidence points to a benign 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 Benign	PH	0.363090	Structured	0.429450	Uncertain	0.712	0.415	0.125							-5.646	Likely Benign	0.169	Likely Benign	Likely Benign	0.065	Likely Benign	0.1606	0.4051		0.35	Likely Benign	0.1	0.53	Ambiguous	0.44	Likely Benign	0.19	Likely Benign	-1.82	Neutral	0.982	Probably Damaging	0.581	Possibly Damaging	4.02	Benign	0.04	Affected			3	2	0.0	-14.03
c.2158G>A	D720N 2D 3DClick to see structure in 3D Viewer AISynGAP1 D720N is listed in ClinVar as benign (ClinVar ID 2837618.0) and is present in gnomAD (ID 6‑33441623‑G‑A). Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus as pathogenic. With seven pathogenic versus six benign predictions overall, the variant is most likely pathogenic according to in‑silico evidence, which contradicts the benign classification in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.374039	Structured	0.450695	Uncertain	0.955	0.417	0.125	Likely Benign		1	6-33441623-G-A	5	3.10e-6	-9.135	Likely Pathogenic	0.654	Likely Pathogenic	Likely Benign	0.289	Likely Benign	0.1216	0.5513		0.01	Likely Benign	0.0	-0.20	Likely Benign	-0.10	Likely Benign	0.46	Likely Benign	-3.74	Deleterious	1.000	Probably Damaging	0.995	Probably Damaging	2.18	Pathogenic	0.01	Affected	3.50	9	1	2	0.0	-0.98
c.2158G>C	D720H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D720H missense variant is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, and premPS. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and is labeled Likely Pathogenic. The high‑accuracy AlphaMissense‑Optimized score is Uncertain, while Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, indicates a Benign effect. Considering the overall distribution of predictions, 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	GAP	0.374039	Structured	0.450695	Uncertain	0.955	0.417	0.125							-12.355	Likely Pathogenic	0.947	Likely Pathogenic	Ambiguous	0.444	Likely Benign	0.1363	0.6198		0.03	Likely Benign	0.0	-0.87	Ambiguous	-0.42	Likely Benign	0.48	Likely Benign	-5.27	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.13	Pathogenic	0.01	Affected			1	-1	0.3	22.05
c.2158G>T	D720Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D720Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and premPS, while pathogenic predictions are made by SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. The high‑accuracy consensus (SGM Consensus) classifies the variant as Likely Pathogenic, and Foldetta likewise yields an uncertain stability change. AlphaMissense‑Optimized remains inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not conflict with any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.374039	Structured	0.450695	Uncertain	0.955	0.417	0.125							-14.771	Likely Pathogenic	0.946	Likely Pathogenic	Ambiguous	0.499	Likely Benign	0.0626	0.5973		-0.74	Ambiguous	0.1	-1.38	Ambiguous	-1.06	Ambiguous	0.20	Likely Benign	-7.05	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.11	Pathogenic	0.00	Affected			-4	-3	2.2	48.09
c.2159A>C	D720A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D720A 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, and SIFT, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show that the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome, whereas Foldetta (combining FoldX‑MD and Rosetta) predicts a benign impact, and AlphaMissense‑Optimized remains uncertain. Overall, the predictions are split, with a slight tilt toward pathogenicity from the consensus and high‑accuracy methods. Thus, the variant is most likely pathogenic based on the available predictions, and this 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	GAP	0.374039	Structured	0.450695	Uncertain	0.955	0.417	0.125							-10.999	Likely Pathogenic	0.871	Likely Pathogenic	Ambiguous	0.424	Likely Benign	0.3726	0.5551		-0.14	Likely Benign	0.0	-0.35	Likely Benign	-0.25	Likely Benign	0.40	Likely Benign	-6.20	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.16	Pathogenic	0.11	Tolerated			0	-2	5.3	-44.01
c.2159A>G	D720G 2D AISynGAP1 missense variant D720G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Foldetta, and premPS, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools remain inconclusive: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as benign. Overall, the balance of evidence favors 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	GAP	0.374039	Structured	0.450695	Uncertain	0.955	0.417	0.125							-11.130	Likely Pathogenic	0.911	Likely Pathogenic	Ambiguous	0.427	Likely Benign	0.4027	0.5011		0.45	Likely Benign	0.4	0.53	Ambiguous	0.49	Likely Benign	0.46	Likely Benign	-5.67	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.15	Pathogenic	0.01	Affected			1	-1	3.1	-58.04
c.2159A>T	D720V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D720V has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Foldetta, and premPS, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic. Overall, the majority of evidence points to 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	GAP	0.374039	Structured	0.450695	Uncertain	0.955	0.417	0.125							-12.730	Likely Pathogenic	0.941	Likely Pathogenic	Ambiguous	0.437	Likely Benign	0.0822	0.5708		0.08	Likely Benign	0.0	-0.78	Ambiguous	-0.35	Likely Benign	0.20	Likely Benign	-7.18	Deleterious	0.999	Probably Damaging	0.999	Probably Damaging	2.12	Pathogenic	0.00	Affected			-2	-3	7.7	-15.96
c.2160C>A	D720E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D720E 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, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority, and Foldetta also predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the variant is most likely benign based on the collective 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.		GAP	0.374039	Structured	0.450695	Uncertain	0.955	0.417	0.125							-5.527	Likely Benign	0.391	Ambiguous	Likely Benign	0.131	Likely Benign	0.1310	0.5275		-0.31	Likely Benign	0.1	-0.41	Likely Benign	-0.36	Likely Benign	0.23	Likely Benign	-2.46	Neutral	0.975	Probably Damaging	0.969	Probably Damaging	2.46	Pathogenic	0.15	Tolerated			3	2	0.0	14.03
c.2160C>G	D720E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D720E 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, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority, and Foldetta also predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the variant is most likely benign based on the collective 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.		GAP	0.374039	Structured	0.450695	Uncertain	0.955	0.417	0.125							-5.527	Likely Benign	0.391	Ambiguous	Likely Benign	0.131	Likely Benign	0.1310	0.5275		-0.31	Likely Benign	0.1	-0.41	Likely Benign	-0.36	Likely Benign	0.23	Likely Benign	-2.46	Neutral	0.975	Probably Damaging	0.969	Probably Damaging	2.46	Pathogenic	0.15	Tolerated			3	2	0.0	14.03
c.1201C>G	R401G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401G 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 algorithms—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 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, also predicts pathogenic. Based on the overwhelming agreement among these tools, 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	0.314870	Structured	0.424277	Uncertain	0.961	0.419	0.000							-13.353	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.741	Likely Pathogenic	0.3549	0.2866		3.06	Destabilizing	0.2	4.31	Destabilizing	3.69	Destabilizing	1.01	Destabilizing	-6.45	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	5.45	Benign	0.00	Affected			-3	-2	4.1	-99.14
c.1201C>T	R401W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401W is listed in gnomAD (ID 6‑33438106‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions are returned by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Only FATHMM predicts a benign outcome; all other tools are either pathogenic or inconclusive. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Taken together, the overwhelming majority of predictions support a pathogenic effect, and this conclusion is not contradicted by ClinVar data, which currently contains no classification for the variant. Based on the aggregate predictions, the variant is most likely pathogenic, 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	0.314870	Structured	0.424277	Uncertain	0.961	0.419	0.000				6-33438106-C-T	2	1.24e-6	-10.712	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	0.711	Likely Pathogenic	0.1252	0.3791		1.59	Ambiguous	0.2	1.04	Ambiguous	1.32	Ambiguous	0.73	Ambiguous	-7.34	Deleterious	1.000	Probably Damaging	0.993	Probably Damaging	5.40	Benign	0.00	Affected	3.38	27	-3	2	3.6	30.03
c.1202G>A	R401Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438107‑G‑A). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of algorithms (REVEL, premPS, 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 methods reinforce the pathogenic prediction: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic,” and Foldetta’s stability assessment is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.314870	Structured	0.424277	Uncertain	0.961	0.419	0.000	Uncertain		1	6-33438107-G-A			-11.213	Likely Pathogenic	0.969	Likely Pathogenic	Likely Pathogenic	0.780	Likely Pathogenic	0.3234	0.2269		0.96	Ambiguous	0.1	1.50	Ambiguous	1.23	Ambiguous	1.20	Destabilizing	-3.69	Deleterious	0.999	Probably Damaging	0.978	Probably Damaging	5.47	Benign	0.04	Affected	3.38	27	1	1	1.0	-28.06
c.1202G>C	R401P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401P 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 is the sole benign predictor, while the remaining twelve tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the collective evidence, 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	0.314870	Structured	0.424277	Uncertain	0.961	0.419	0.000							-14.090	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.892	Likely Pathogenic	0.2265	0.4064		9.69	Destabilizing	0.3	8.07	Destabilizing	8.88	Destabilizing	0.77	Ambiguous	-6.45	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	5.42	Benign	0.00	Affected			0	-2	2.9	-59.07
c.1202G>T	R401L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401L is not reported in ClinVar and is present in gnomAD (ID 6‑33438107‑G‑T). Prediction tools that classify the variant as benign include Rosetta, FATHMM, and premPS, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) indicate a pathogenic effect. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No evidence from FoldX alone is available. Based on the preponderance of pathogenic predictions and the corroborating high‑accuracy tools, R401L is most likely pathogenic; this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.314870	Structured	0.424277	Uncertain	0.961	0.419	0.000				6-33438107-G-T	1	6.20e-7	-12.280	Likely Pathogenic	0.972	Likely Pathogenic	Likely Pathogenic	0.858	Likely Pathogenic	0.1972	0.4263		-1.52	Ambiguous	0.1	-0.23	Likely Benign	-0.88	Ambiguous	0.22	Likely Benign	-6.42	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	5.44	Benign	0.02	Affected	3.38	27	-2	-3	8.3	-43.03
c.1003C>A	R335S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R335S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, premPS, and SIFT; pathogenic predictions from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No evidence from FoldX or Rosetta alone is available. Based on the preponderance of pathogenic predictions and the high‑accuracy tools, the variant is most likely pathogenic, which is consistent with the absence of ClinVar reporting and gnomAD data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.305330	Structured	0.331028	Uncertain	0.483	0.428	0.500							-9.286	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	0.184	Likely Benign	0.2598	0.4005		0.68	Ambiguous	0.1	0.72	Ambiguous	0.70	Ambiguous	0.14	Likely Benign	-3.30	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.89	Pathogenic	0.11	Tolerated			0	-1	3.7	-69.11
c.1003C>G	R335G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R335G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, and SIFT, whereas those that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, more tools predict pathogenicity than benignity, and the high‑accuracy consensus also leans pathogenic. Therefore, the variant is most likely pathogenic based on current 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	0.305330	Structured	0.331028	Uncertain	0.483	0.428	0.500							-11.860	Likely Pathogenic	0.880	Likely Pathogenic	Ambiguous	0.194	Likely Benign	0.3000	0.3554		1.01	Ambiguous	0.1	0.44	Likely Benign	0.73	Ambiguous	0.20	Likely Benign	-4.77	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	2.01	Pathogenic	0.10	Tolerated			-3	-2	4.1	-99.14
c.1003C>T	R335C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R335C is listed in ClinVar with an uncertain significance (ClinVar ID 2835865.0) and is present in gnomAD (ID 6‑33437908‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL and premPS, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are AlphaMissense‑Optimized, FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion aligns with the ClinVar designation of uncertain significance, which does not contradict the prediction that the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.305330	Structured	0.331028	Uncertain	0.483	0.428	0.500	Uncertain		1	6-33437908-C-T	1	6.20e-7	-14.354	Likely Pathogenic	0.938	Likely Pathogenic	Ambiguous	0.277	Likely Benign	0.2882	0.3290		0.53	Ambiguous	0.1	0.85	Ambiguous	0.69	Ambiguous	0.46	Likely Benign	-5.69	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.67	Pathogenic	0.01	Affected	3.38	22	-3	-4	7.0	-53.05
c.1004G>A	R335H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R335H is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33437909‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and Foldetta, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as pathogenic, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the preponderance of evidence points to a pathogenic impact, 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	0.305330	Structured	0.331028	Uncertain	0.483	0.428	0.500	Uncertain		1	6-33437909-G-A	2	1.24e-6	-12.521	Likely Pathogenic	0.831	Likely Pathogenic	Ambiguous	0.132	Likely Benign	0.2316	0.2330		0.58	Ambiguous	0.1	0.22	Likely Benign	0.40	Likely Benign	0.72	Ambiguous	-3.02	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.70	Pathogenic	0.03	Affected	3.38	22	2	0	1.3	-19.05	242.4	82.1	-2.4	0.6	-0.1	0.1								Uncertain	The guanidinium group of Arg335, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Ala322-Asp330, res. Gly341-Pro349), faces the post-synaptic inner membrane surface. In the WT simulations, the Arg335 side chain dynamically forms salt bridges with the carboxylate groups of Asp322, Asp338, and Asp616. In contrast, the imidazole ring of His335, which is not double protonated and thus not positively charged in the variant simulations, continues to move dynamically without forming any lasting or strong interactions. Importantly, the positively charged arginine residues of the C2 domain are ideal membrane anchors for ensuring SynGAP-membrane association. However, this phenomenon cannot be addressed using solvent-only simulations.
c.1004G>C	R335P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R335P has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and SIFT, whereas pathogenic predictions are reported by FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments give a more focused view: AlphaMissense‑Optimized is uncertain; 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, also predicts a pathogenic effect. Taken together, the majority of evidence points to a pathogenic impact for R335P, 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	0.305330	Structured	0.331028	Uncertain	0.483	0.428	0.500							-13.952	Likely Pathogenic	0.948	Likely Pathogenic	Ambiguous	0.250	Likely Benign	0.1866	0.4497		3.23	Destabilizing	0.8	5.73	Destabilizing	4.48	Destabilizing	0.43	Likely Benign	-4.22	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.69	Pathogenic	0.09	Tolerated			0	-2	2.9	-59.07
c.1004G>T	R335L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R335L is not listed in ClinVar (ClinVar ID None) and has no reported allele in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, and premPS. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized and FoldX are uncertain and are treated as unavailable for pathogenicity inference. High‑accuracy assessments: AlphaMissense‑Optimized is uncertain; 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, predicts benign. Overall, the majority of predictions (8 pathogenic vs. 4 benign) indicate that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.305330	Structured	0.331028	Uncertain	0.483	0.428	0.500							-13.226	Likely Pathogenic	0.938	Likely Pathogenic	Ambiguous	0.196	Likely Benign	0.1382	0.4753		0.51	Ambiguous	0.0	-0.19	Likely Benign	0.16	Likely Benign	0.40	Likely Benign	-4.77	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.73	Pathogenic	0.04	Affected			-3	-2	8.3	-43.03
c.1006A>C	K336Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K336Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, 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 pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as benign. Because the predictions are evenly split and the high‑accuracy methods give conflicting results, the variant is best classified as of uncertain significance. This assessment 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.	Likely Pathogenic	C2	0.318242	Structured	0.338219	Uncertain	0.396	0.428	0.500							-12.876	Likely Pathogenic	0.829	Likely Pathogenic	Ambiguous	0.211	Likely Benign	0.4698	0.1514		0.02	Likely Benign	0.0	-0.17	Likely Benign	-0.08	Likely Benign	0.18	Likely Benign	-3.30	Deleterious	0.801	Possibly Damaging	0.252	Benign	1.58	Pathogenic	0.02	Affected			1	1	0.4	-0.04
c.1006A>G	K336E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K336E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic impact for K336E, 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	0.318242	Structured	0.338219	Uncertain	0.396	0.428	0.500							-16.091	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.236	Likely Benign	0.4003	0.1082		-0.28	Likely Benign	0.0	0.19	Likely Benign	-0.05	Likely Benign	0.35	Likely Benign	-3.43	Deleterious	0.625	Possibly Damaging	0.192	Benign	1.60	Pathogenic	0.01	Affected			0	1	0.4	0.94
c.1007A>C	K336T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K336T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy assessment shows 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 toward a pathogenic impact for K336T, and 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	0.318242	Structured	0.338219	Uncertain	0.396	0.428	0.500							-13.468	Likely Pathogenic	0.971	Likely Pathogenic	Likely Pathogenic	0.212	Likely Benign	0.2014	0.4048		0.33	Likely Benign	0.1	-0.08	Likely Benign	0.13	Likely Benign	0.15	Likely Benign	-4.94	Deleterious	0.891	Possibly Damaging	0.315	Benign	1.58	Pathogenic	0.01	Affected			0	-1	3.2	-27.07
c.1007A>G	K336R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K336R is not reported in ClinVar (ClinVar status: not listed) but is present in the gnomAD database (gnomAD ID: 6‑33437912‑A‑G). 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; the only tool predicting a pathogenic outcome is 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 further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, the SGM‑Consensus is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. No predictions or folding‑stability results 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	C2	0.318242	Structured	0.338219	Uncertain	0.396	0.428	0.500				6-33437912-A-G	1	6.20e-7	-5.897	Likely Benign	0.089	Likely Benign	Likely Benign	0.038	Likely Benign	0.4899	0.1240		0.00	Likely Benign	0.0	-0.15	Likely Benign	-0.08	Likely Benign	0.52	Ambiguous	-2.01	Neutral	0.002	Benign	0.005	Benign	1.69	Pathogenic	0.12	Tolerated	3.38	22	2	3	-0.6	28.01
c.1007A>T	K336M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K336M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, premPS) and pathogenic predictions (SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized). The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Pathogenic.” Stability‑based assessments are inconclusive: Foldetta is uncertain, and Rosetta is also uncertain. High‑accuracy tools specifically indicate pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms pathogenic, while Foldetta remains uncertain. Based on the overall pattern of 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	0.318242	Structured	0.338219	Uncertain	0.396	0.428	0.500							-15.395	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	0.301	Likely Benign	0.1185	0.4760		0.34	Likely Benign	0.1	0.82	Ambiguous	0.58	Ambiguous	-0.23	Likely Benign	-5.07	Deleterious	0.989	Probably Damaging	0.832	Possibly Damaging	1.53	Pathogenic	0.00	Affected			0	-1	5.8	3.02
c.1008G>C	K336N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K336N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show discordant results: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and polyPhen‑2 HumVar, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome. High‑accuracy assessments further highlight this split: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus also predicts likely pathogenic, while Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. No prediction or stability result is missing. Overall, the majority of tools and the high‑accuracy methods lean toward pathogenicity, 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.318242	Structured	0.338219	Uncertain	0.396	0.428	0.500							-13.307	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	0.186	Likely Benign	0.3710	0.1599		0.20	Likely Benign	0.1	-0.02	Likely Benign	0.09	Likely Benign	0.20	Likely Benign	-4.09	Deleterious	0.801	Possibly Damaging	0.315	Benign	1.59	Pathogenic	0.01	Affected			1	0	0.4	-14.07
c.1008G>T	K336N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K336N is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (derived from the unanimous pathogenic 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 toward a pathogenic impact for K336N, and 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	0.318242	Structured	0.338219	Uncertain	0.396	0.428	0.500							-13.307	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	0.186	Likely Benign	0.3710	0.1599		0.20	Likely Benign	0.1	-0.02	Likely Benign	0.09	Likely Benign	0.20	Likely Benign	-4.09	Deleterious	0.801	Possibly Damaging	0.315	Benign	1.59	Pathogenic	0.01	Affected			1	0	0.4	-14.07
c.2164A>C	S722R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722R 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 REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, 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 tools and the high‑accuracy methods lean toward a pathogenic effect. Thus, the variant is most likely pathogenic based on current predictions, 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	GAP	0.468512	Structured	0.457186	Uncertain	0.950	0.431	0.375							-10.731	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	0.306	Likely Benign	0.0886	0.2797		0.05	Likely Benign	0.1	-0.03	Likely Benign	0.01	Likely Benign	0.72	Ambiguous	-2.66	Deleterious	0.999	Probably Damaging	0.948	Probably Damaging	2.52	Benign	0.09	Tolerated			0	-1	-3.7	69.11
c.2164A>G	S722G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722G is not reported in ClinVar and is present in gnomAD (ID 6‑33441629‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and the protein‑folding stability method Foldetta. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. The consensus predictor SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as benign. No evidence from the high‑accuracy tools contradicts the benign predictions, but the consensus and several individual pathogenic predictors suggest a potential deleterious impact. Based on the overall pattern of predictions, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and the presence of multiple pathogenic signals. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.468512	Structured	0.457186	Uncertain	0.950	0.431	0.375				6-33441629-A-G	2	1.24e-6	-9.141	Likely Pathogenic	0.214	Likely Benign	Likely Benign	0.270	Likely Benign	0.2202	0.3400		0.24	Likely Benign	0.1	0.67	Ambiguous	0.46	Likely Benign	0.50	Likely Benign	-2.72	Deleterious	0.998	Probably Damaging	0.863	Possibly Damaging	2.49	Pathogenic	0.14	Tolerated	3.50	8	0	1	0.4	-30.03
c.2164A>T	S722C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as benign. Overall, the majority of individual predictors and the high‑accuracy methods lean toward a benign impact, with only the SGM Consensus suggesting pathogenicity. Thus, the variant is most likely benign based on the available predictions, 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	GAP	0.468512	Structured	0.457186	Uncertain	0.950	0.431	0.375							-8.060	Likely Pathogenic	0.273	Likely Benign	Likely Benign	0.362	Likely Benign	0.1132	0.4306		0.22	Likely Benign	0.0	-0.23	Likely Benign	-0.01	Likely Benign	0.28	Likely Benign	-3.44	Deleterious	1.000	Probably Damaging	0.968	Probably Damaging	2.46	Pathogenic	0.05	Affected			0	-1	3.3	16.06
c.2165G>A	S722N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus classify the change as benign: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a neutral effect. No tool predicts pathogenicity; the only inconclusive results come from premPS and AlphaMissense‑Default, which are treated as unavailable evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign outcome, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a benign impact. Taken together, the evidence overwhelmingly supports a benign classification, 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	GAP	0.468512	Structured	0.457186	Uncertain	0.950	0.431	0.375							-4.399	Likely Benign	0.379	Ambiguous	Likely Benign	0.051	Likely Benign	0.1258	0.3452		0.18	Likely Benign	0.1	0.15	Likely Benign	0.17	Likely Benign	0.79	Ambiguous	-0.91	Neutral	0.072	Benign	0.028	Benign	2.58	Benign	0.27	Tolerated			1	1	-2.7	27.03
c.2165G>C	S722T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722T is reported in gnomAD (6‑33441630‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while FoldX is uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts 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 (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.468512	Structured	0.457186	Uncertain	0.950	0.431	0.375				6-33441630-G-C	1	6.20e-7	-5.734	Likely Benign	0.202	Likely Benign	Likely Benign	0.118	Likely Benign	0.1357	0.4363		0.53	Ambiguous	0.0	-0.32	Likely Benign	0.11	Likely Benign	-0.12	Likely Benign	-0.57	Neutral	0.921	Possibly Damaging	0.414	Benign	2.57	Benign	1.00	Tolerated	3.50	8	1	1	0.1	14.03
c.2165G>T	S722I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S722I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, premPS, SIFT, and the folding‑stability method Foldetta, whereas pathogenic predictions are reported by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are provided by AlphaMissense‑Optimized, FoldX, and Rosetta. High‑accuracy analyses further clarify the picture: AlphaMissense‑Optimized remains inconclusive; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign impact on protein stability. Overall, the majority of evidence leans toward a pathogenic interpretation, 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	GAP	0.468512	Structured	0.457186	Uncertain	0.950	0.431	0.375							-11.165	Likely Pathogenic	0.867	Likely Pathogenic	Ambiguous	0.232	Likely Benign	0.0776	0.4187		0.69	Ambiguous	0.1	-0.65	Ambiguous	0.02	Likely Benign	0.18	Likely Benign	-3.88	Deleterious	1.000	Probably Damaging	0.983	Probably Damaging	2.48	Pathogenic	0.07	Tolerated			-1	-2	5.3	26.08
c.2166C>A	S722R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. 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	GAP	0.468512	Structured	0.457186	Uncertain	0.950	0.431	0.375							-10.731	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	0.221	Likely Benign	0.0886	0.2797		0.05	Likely Benign	0.1	-0.03	Likely Benign	0.01	Likely Benign	0.72	Ambiguous	-2.66	Deleterious	0.999	Probably Damaging	0.948	Probably Damaging	2.52	Benign	0.09	Tolerated			0	-1	-3.7	69.11
c.2166C>G	S722R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign stability. Overall, the balance of evidence leans toward pathogenicity, and this conclusion does not contradict any ClinVar annotation (none is available). Thus, based on the current computational predictions, the S722R variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.468512	Structured	0.457186	Uncertain	0.950	0.431	0.375							-10.731	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	0.220	Likely Benign	0.0886	0.2797		0.05	Likely Benign	0.1	-0.03	Likely Benign	0.01	Likely Benign	0.72	Ambiguous	-2.66	Deleterious	0.999	Probably Damaging	0.948	Probably Damaging	2.52	Benign	0.09	Tolerated			0	-1	-3.7	69.11
c.1039A>C	T347P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T347P 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, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and FATHMM. Three tools (FoldX, premPS, AlphaMissense‑Default) give 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 evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. 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.		C2	0.268042	Structured	0.349915	Uncertain	0.951	0.434	0.000							-9.323	Likely Pathogenic	0.417	Ambiguous	Likely Benign	0.236	Likely Benign	0.2000	0.5350		0.55	Ambiguous	0.0	0.28	Likely Benign	0.42	Likely Benign	0.65	Ambiguous	-2.41	Neutral	0.627	Possibly Damaging	0.139	Benign	1.63	Pathogenic	0.12	Tolerated			0	-1	-0.9	-3.99
c.1039A>G	T347A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347A is catalogued in gnomAD (ID 6‑33437944‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated. Only FATHMM predicts a pathogenic outcome, while Foldetta, premPS, and Rosetta are inconclusive. 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: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta remains uncertain. Overall, the consensus of the majority of tools indicates the variant is most likely benign, 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	0.268042	Structured	0.349915	Uncertain	0.951	0.434	0.000				6-33437944-A-G	9	5.58e-6	-5.858	Likely Benign	0.086	Likely Benign	Likely Benign	0.093	Likely Benign	0.4032	0.4615		0.34	Likely Benign	0.1	0.70	Ambiguous	0.52	Ambiguous	0.70	Ambiguous	-1.52	Neutral	0.031	Benign	0.016	Benign	1.68	Pathogenic	0.42	Tolerated	3.37	25	0	1	2.5	-30.03
c.1039A>T	T347S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347S 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, 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). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictors indicate a benign effect, 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	C2	0.268042	Structured	0.349915	Uncertain	0.951	0.434	0.000							-3.342	Likely Benign	0.090	Likely Benign	Likely Benign	0.104	Likely Benign	0.3205	0.4707		0.65	Ambiguous	0.1	0.82	Ambiguous	0.74	Ambiguous	-0.10	Likely Benign	0.63	Neutral	0.002	Benign	0.001	Benign	1.75	Pathogenic	0.86	Tolerated			1	1	-0.1	-14.03
c.1040C>A	T347N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347N is listed in ClinVar with an uncertain significance (ClinVar ID 3672484.0) and is present in the gnomAD database (gnomAD ID 6‑33437945‑C‑A). Prediction tools that uniformly indicate 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. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments are consistent: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the collective evidence points to a benign effect, aligning with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.268042	Structured	0.349915	Uncertain	0.951	0.434	0.000	Uncertain		1	6-33437945-C-A	9	5.58e-6	-5.545	Likely Benign	0.165	Likely Benign	Likely Benign	0.059	Likely Benign	0.1070	0.4359		0.41	Likely Benign	0.1	0.46	Likely Benign	0.44	Likely Benign	-0.06	Likely Benign	1.96	Neutral	0.001	Benign	0.001	Benign	1.67	Pathogenic	0.60	Tolerated	3.37	25	0	0	-2.8	13.00
c.1040C>G	T347S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347S 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, 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). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictors indicate a benign effect, 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	C2	0.268042	Structured	0.349915	Uncertain	0.951	0.434	0.000							-3.342	Likely Benign	0.090	Likely Benign	Likely Benign	0.054	Likely Benign	0.3205	0.4707		0.65	Ambiguous	0.1	0.82	Ambiguous	0.74	Ambiguous	-0.10	Likely Benign	0.63	Neutral	0.002	Benign	0.001	Benign	1.75	Pathogenic	0.86	Tolerated			1	1	-0.1	-14.03
c.1040C>T	T347I 2D 3DClick to see structure in 3D Viewer AISynGAP1 T347I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that provide definitive calls cluster into two groups: benign predictions come from REVEL, premPS, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. Tools with inconclusive outputs (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) are treated as unavailable. High‑accuracy assessments further split the evidence: AlphaMissense‑Optimized predicts benign, while the SGM consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenic; Foldetta remains uncertain. Consequently, the variant’s pathogenicity is ambiguous, with an equal number of strong benign and pathogenic calls and no consensus from the most reliable methods. The variant is therefore most likely uncertain, 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	0.268042	Structured	0.349915	Uncertain	0.951	0.434	0.000							-10.148	Likely Pathogenic	0.387	Ambiguous	Likely Benign	0.079	Likely Benign	0.0885	0.6298		-0.79	Ambiguous	0.1	-0.94	Ambiguous	-0.87	Ambiguous	0.29	Likely Benign	-3.12	Deleterious	0.627	Possibly Damaging	0.139	Benign	1.70	Pathogenic	0.08	Tolerated			0	-1	5.2	12.05
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	0.306	Likely Benign	0.0934	0.3942		0.22	Likely Benign	0.0	2.04	Destabilizing	1.13	Ambiguous	1.05	Destabilizing	-0.86	Neutral	0.997	Probably Damaging	0.939	Probably Damaging	1.36	Pathogenic	0.01	Affected			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	0.183	Likely Benign	0.1571	0.3957		2.26	Destabilizing	0.1	1.27	Ambiguous	1.77	Ambiguous	-0.39	Likely Benign	0.16	Neutral	0.898	Possibly Damaging	0.472	Possibly Damaging	1.68	Pathogenic	1.00	Tolerated			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	0.547	Likely Pathogenic	0.1235	0.1405		3.23	Destabilizing	0.0	2.68	Destabilizing	2.96	Destabilizing	2.02	Destabilizing	-3.97	Deleterious	0.999	Probably Damaging	0.977	Probably Damaging	1.33	Pathogenic	0.00	Affected			-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	0.607	Likely Pathogenic	0.3393	0.1903		5.49	Destabilizing	0.3	7.27	Destabilizing	6.38	Destabilizing	1.89	Destabilizing	-4.37	Deleterious	0.999	Probably Damaging	0.977	Probably Damaging	1.33	Pathogenic	0.00	Affected			-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	0.551	Likely Pathogenic	0.1405	0.1047		4.34	Destabilizing	0.3	4.11	Destabilizing	4.23	Destabilizing	1.94	Destabilizing	-4.39	Deleterious	0.999	Probably Damaging	0.969	Probably Damaging	1.33	Pathogenic	0.00	Affected			-3	-2	-8.3	43.03
c.2161A>C	I721L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I721L 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, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are 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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the predictions are split, but the majority of high‑confidence tools lean toward a benign interpretation. Thus, the variant is most likely benign, and this assessment 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.		GAP	0.394753	Structured	0.454550	Uncertain	0.957	0.437	0.125							-7.843	In-Between	0.757	Likely Pathogenic	Likely Benign	0.188	Likely Benign	0.0627	0.3446		0.35	Likely Benign	0.0	0.34	Likely Benign	0.35	Likely Benign	0.65	Ambiguous	-1.83	Neutral	0.955	Possibly Damaging	0.985	Probably Damaging	2.37	Pathogenic	0.02	Affected			2	2	-0.7	0.00
c.2161A>G	I721V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721V 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, 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 and polyPhen‑2 HumVar. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the majority of reliable predictors classify the variant as benign, 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	GAP	0.394753	Structured	0.454550	Uncertain	0.957	0.437	0.125							-6.730	Likely Benign	0.380	Ambiguous	Likely Benign	0.098	Likely Benign	0.0976	0.3070		1.22	Ambiguous	0.0	1.11	Ambiguous	1.17	Ambiguous	0.48	Likely Benign	-0.40	Neutral	0.969	Probably Damaging	0.960	Probably Damaging	2.60	Benign	0.45	Tolerated			4	3	-0.3	-14.03
c.2161A>T	I721F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721F 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—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic impact, while premPS remains uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the overwhelming agreement among these 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	GAP	0.394753	Structured	0.454550	Uncertain	0.957	0.437	0.125							-12.559	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.295	Likely Benign	0.0420	0.2931		4.61	Destabilizing	0.1	2.74	Destabilizing	3.68	Destabilizing	0.66	Ambiguous	-3.74	Deleterious	0.999	Probably Damaging	0.993	Probably Damaging	2.22	Pathogenic	0.00	Affected			1	0	-1.7	34.02
c.2162T>A	I721N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the collective evidence, 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	GAP	0.394753	Structured	0.454550	Uncertain	0.957	0.437	0.125							-14.905	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.425	Likely Benign	0.0737	0.0340		2.82	Destabilizing	0.0	3.21	Destabilizing	3.02	Destabilizing	2.10	Destabilizing	-6.30	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.19	Pathogenic	0.00	Affected			-2	-3	-8.0	0.94
c.2162T>C	I721T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721T is not reported in ClinVar (ClinVar status: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that indicate a benign effect include only REVEL. All other evaluated tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote) yields Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts Pathogenic. No prediction or folding result is missing or inconclusive. Based on the collective evidence, 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	GAP	0.394753	Structured	0.454550	Uncertain	0.957	0.437	0.125							-10.374	Likely Pathogenic	0.989	Likely Pathogenic	Likely Pathogenic	0.417	Likely Benign	0.0918	0.1019		2.73	Destabilizing	0.0	2.56	Destabilizing	2.65	Destabilizing	2.11	Destabilizing	-4.18	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.22	Pathogenic	0.00	Affected			0	-1	-5.2	-12.05
c.2162T>G	I721S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess the variant’s effect fall 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 a pathogenic outcome. 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 predictions are missing or inconclusive. Based on the overwhelming consensus 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	GAP	0.394753	Structured	0.454550	Uncertain	0.957	0.437	0.125	Uncertain		1				-14.032	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.466	Likely Benign	0.2606	0.1110		3.91	Destabilizing	0.1	3.96	Destabilizing	3.94	Destabilizing	2.28	Destabilizing	-5.26	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	2.21	Pathogenic	0.00	Affected	3.50	9	-1	-2	-5.3	-26.08	203.3	49.3	-0.1	0.0	-1.1	0.0							X	Uncertain	The sec-butyl side chain of Ile721, located on an α-helix (res. Leu714-Arg726), engages in hydrophobic packing with other residues in the hydrophobic inter-helix space, such as Phe420, Tyr417, His693, and Leu717. In the variant simulations, the hydroxyl side chain of Ser721 forms hydrogen bonds with nearby residues, such as Leu717 and His693. Although no major structural changes are observed during the variant simulations, the hydrophilic residue Ser721 could disrupt the hydrophobic packing during folding. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations.
c.2163C>G	I721M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, and PROVEAN, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, premPS, and the SGM‑Consensus score (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No prediction or stability result is missing or inconclusive beyond these stated uncertainties. Overall, the preponderance of evidence points to a pathogenic effect for I721M, 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 Pathogenic	GAP	0.394753	Structured	0.454550	Uncertain	0.957	0.437	0.125							-9.767	Likely Pathogenic	0.872	Likely Pathogenic	Ambiguous	0.225	Likely Benign	0.0576	0.2726		0.71	Ambiguous	0.0	0.45	Likely Benign	0.58	Ambiguous	1.00	Destabilizing	-2.40	Neutral	1.000	Probably Damaging	1.000	Probably Damaging	2.30	Pathogenic	0.00	Affected			2	1	-2.6	18.03
c.1009A>C	K337Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K337Q 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, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of predictions (8 pathogenic vs. 4 benign) indicate 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	0.321458	Structured	0.348540	Uncertain	0.449	0.438	0.500							-9.944	Likely Pathogenic	0.934	Likely Pathogenic	Ambiguous	0.305	Likely Benign	0.3672	0.1219		0.00	Likely Benign	0.0	0.88	Ambiguous	0.44	Likely Benign	0.43	Likely Benign	-3.48	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.70	Pathogenic	0.01	Affected			1	1	0.4	-0.04
c.1009A>G	K337E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K337E missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic impact comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). The premPS score is uncertain and does not influence the overall assessment. High‑accuracy analyses show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as benign. Based on the majority of predictions, the variant 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	0.321458	Structured	0.348540	Uncertain	0.449	0.438	0.500							-13.673	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	0.316	Likely Benign	0.3102	0.1039		-0.05	Likely Benign	0.1	0.49	Likely Benign	0.22	Likely Benign	0.52	Ambiguous	-3.48	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.76	Pathogenic	0.02	Affected			0	1	0.4	0.94
c.1010A>C	K337T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K337T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, FoldX, and premPS, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Three tools report uncertainty: Rosetta, Foldetta, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Pathogenic. In the high‑accuracy subset, AlphaMissense‑Optimized remains uncertain, SGM‑Consensus is Likely Pathogenic, and Foldetta is uncertain. Taken together, the majority of evidence points toward a deleterious effect. Therefore, K337T is most likely pathogenic, 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	0.321458	Structured	0.348540	Uncertain	0.449	0.438	0.500							-10.896	Likely Pathogenic	0.953	Likely Pathogenic	Ambiguous	0.338	Likely Benign	0.1741	0.3354		0.45	Likely Benign	0.2	1.33	Ambiguous	0.89	Ambiguous	0.25	Likely Benign	-5.32	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.70	Pathogenic	0.01	Affected			0	-1	3.2	-27.07
c.1010A>G	K337R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K337R has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into benign and pathogenic groups: benign predictions come from REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta; pathogenic predictions come from polyPhen2_HumDiv, polyPhen2_HumVar, and FATHMM, while Rosetta remains uncertain. High‑accuracy methods reinforce the benign assessment: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign. Consequently, 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	0.321458	Structured	0.348540	Uncertain	0.449	0.438	0.500							-6.302	Likely Benign	0.249	Likely Benign	Likely Benign	0.142	Likely Benign	0.3913	0.1134		-0.30	Likely Benign	0.2	1.07	Ambiguous	0.39	Likely Benign	0.12	Likely Benign	-2.36	Neutral	0.997	Probably Damaging	0.992	Probably Damaging	1.70	Pathogenic	0.07	Tolerated			3	2	-0.6	28.01
c.1010A>T	K337M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K337M missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify it as benign include REVEL, FoldX, premPS, and the protein‑folding stability method Foldetta. In contrast, the majority of in‑silico predictors flag it as pathogenic: SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Pathogenic” verdict. For high‑accuracy assessment, AlphaMissense‑Optimized remains pathogenic, the SGM‑Consensus also indicates likely pathogenic, whereas Foldetta predicts benign stability. No prediction is inconclusive; Rosetta is uncertain but not counted as evidence. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar classification because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.321458	Structured	0.348540	Uncertain	0.449	0.438	0.500							-13.406	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	0.345	Likely Benign	0.0862	0.3871		0.28	Likely Benign	0.1	0.61	Ambiguous	0.45	Likely Benign	-0.24	Likely Benign	-5.32	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.66	Pathogenic	0.00	Affected			0	-1	5.8	3.02
c.1011G>C	K337N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K337N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, premPS, and SIFT. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions (seven pathogenic vs. five benign) and the high‑accuracy consensus lean toward a pathogenic impact. Thus, 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	C2	0.321458	Structured	0.348540	Uncertain	0.449	0.438	0.500							-13.095	Likely Pathogenic	0.986	Likely Pathogenic	Likely Pathogenic	0.280	Likely Benign	0.2945	0.1315		0.12	Likely Benign	0.1	0.36	Likely Benign	0.24	Likely Benign	-0.02	Likely Benign	-4.38	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.87	Pathogenic	0.11	Tolerated			1	0	0.4	-14.07
c.1011G>T	K337N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K337N is not reported in ClinVar and has no entries in 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, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With seven tools supporting pathogenicity versus five supporting benign, the overall prediction leans toward pathogenic. No ClinVar entry contradicts this assessment, and the variant is absent from gnomAD, so the pathogenic prediction is not challenged by population data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.321458	Structured	0.348540	Uncertain	0.449	0.438	0.500							-13.095	Likely Pathogenic	0.986	Likely Pathogenic	Likely Pathogenic	0.280	Likely Benign	0.2945	0.1315		0.12	Likely Benign	0.1	0.36	Likely Benign	0.24	Likely Benign	-0.02	Likely Benign	-4.38	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.87	Pathogenic	0.11	Tolerated			1	0	0.4	-14.07
c.1012G>A	D338N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D338N 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, premPS, and polyPhen‑2 HumVar, whereas a majority of tools predict pathogenicity: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. No evidence from FoldX, Rosetta, or Foldetta supports a benign outcome. Overall, the balance of evidence favors a pathogenic interpretation; this 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	C2	0.335645	Structured	0.363354	Uncertain	0.460	0.438	0.375							-9.520	Likely Pathogenic	0.809	Likely Pathogenic	Ambiguous	0.442	Likely Benign	0.1399	0.5970		0.95	Ambiguous	0.4	1.34	Ambiguous	1.15	Ambiguous	0.06	Likely Benign	-3.62	Deleterious	0.801	Possibly Damaging	0.315	Benign	1.71	Pathogenic	0.02	Affected			2	1	0.0	-0.98
c.1012G>C	D338H 2D AIThe SynGAP1 missense variant D338H is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to premPS, whereas the remaining 11 tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all 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, and PROVEAN) indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for D338H, 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	0.335645	Structured	0.363354	Uncertain	0.460	0.438	0.375							-12.325	Likely Pathogenic	0.975	Likely Pathogenic	Likely Pathogenic	0.515	Likely Pathogenic	0.1671	0.6654		1.32	Ambiguous	1.2	0.76	Ambiguous	1.04	Ambiguous	0.18	Likely Benign	-4.42	Deleterious	0.966	Probably Damaging	0.770	Possibly Damaging	1.71	Pathogenic	0.01	Affected			1	-1	0.3	22.05
c.1012G>T	D338Y 2D AIThe SynGAP1 D338Y missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools largely agree on a deleterious effect: premPS is the sole predictor labeling it benign, whereas the remaining seven tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—classify it as pathogenic. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments further support a pathogenic interpretation: the SGM Consensus (derived from a unanimous majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, AlphaMissense‑Optimized remains uncertain, and Foldetta is also uncertain. Overall, the preponderance of evidence indicates that D338Y 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	0.335645	Structured	0.363354	Uncertain	0.460	0.438	0.375							-14.190	Likely Pathogenic	0.945	Likely Pathogenic	Ambiguous	0.552	Likely Pathogenic	0.0687	0.5609		1.10	Ambiguous	1.3	0.91	Ambiguous	1.01	Ambiguous	0.22	Likely Benign	-6.49	Deleterious	0.989	Probably Damaging	0.832	Possibly Damaging	1.66	Pathogenic	0.00	Affected			-4	-3	2.2	48.09
c.1013A>C	D338A 2D 3DClick to see structure in 3D Viewer AISynGAP1 D338A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, polyPhen‑2 HumVar, and SIFT, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. 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 toward a pathogenic effect. 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	0.335645	Structured	0.363354	Uncertain	0.460	0.438	0.375							-10.639	Likely Pathogenic	0.902	Likely Pathogenic	Ambiguous	0.479	Likely Benign	0.3830	0.5988		1.22	Ambiguous	0.3	1.11	Ambiguous	1.17	Ambiguous	0.16	Likely Benign	-5.74	Deleterious	0.625	Possibly Damaging	0.192	Benign	1.73	Pathogenic	0.11	Tolerated			0	-2	5.3	-44.01
c.1013A>G	D338G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D338G missense variant is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, premPS, and polyPhen‑2 HumVar. Those that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Because the majority of available predictors (seven versus three) indicate a deleterious impact, the variant is most likely pathogenic, 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	0.335645	Structured	0.363354	Uncertain	0.460	0.438	0.375							-8.875	Likely Pathogenic	0.871	Likely Pathogenic	Ambiguous	0.487	Likely Benign	0.4014	0.5934		1.33	Ambiguous	0.5	1.75	Ambiguous	1.54	Ambiguous	0.15	Likely Benign	-5.51	Deleterious	0.771	Possibly Damaging	0.315	Benign	1.69	Pathogenic	0.01	Affected			1	-1	3.1	-58.04
c.1013A>T	D338V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D338V 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 premPS, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No prediction or folding‑stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that 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	0.335645	Structured	0.363354	Uncertain	0.460	0.438	0.375							-11.494	Likely Pathogenic	0.927	Likely Pathogenic	Ambiguous	0.553	Likely Pathogenic	0.0879	0.5745		1.64	Ambiguous	0.2	1.08	Ambiguous	1.36	Ambiguous	0.23	Likely Benign	-6.79	Deleterious	0.891	Possibly Damaging	0.492	Possibly Damaging	1.73	Pathogenic	0.01	Affected			-2	-3	7.7	-15.96
c.1014C>A	D338E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D338E 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 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates a likely benign classification, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support from high‑accuracy methods, the variant is most likely benign. 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 Benign	C2	0.335645	Structured	0.363354	Uncertain	0.460	0.438	0.375							-5.264	Likely Benign	0.254	Likely Benign	Likely Benign	0.080	Likely Benign	0.1584	0.5397		0.85	Ambiguous	0.3	0.31	Likely Benign	0.58	Ambiguous	-0.01	Likely Benign	-1.95	Neutral	0.002	Benign	0.005	Benign	1.85	Pathogenic	0.55	Tolerated			3	2	0.0	14.03
c.1014C>G	D338E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D338E 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 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates a likely benign classification, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support from high‑accuracy methods, the variant is most likely benign. 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 Benign	C2	0.335645	Structured	0.363354	Uncertain	0.460	0.438	0.375							-5.264	Likely Benign	0.254	Likely Benign	Likely Benign	0.080	Likely Benign	0.1584	0.5397		0.85	Ambiguous	0.3	0.31	Likely Benign	0.58	Ambiguous	-0.01	Likely Benign	-1.95	Neutral	0.002	Benign	0.005	Benign	1.85	Pathogenic	0.55	Tolerated			3	2	0.0	14.03
c.1072T>A	F358I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F358I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Five tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports an uncertain impact. Overall, the preponderance of evidence points to a pathogenic effect for F358I, 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	0.222385	Structured	0.407113	Uncertain	0.912	0.441	0.250							-10.636	Likely Pathogenic	0.884	Likely Pathogenic	Ambiguous	0.393	Likely Benign	0.2331	0.2821		0.93	Ambiguous	0.2	1.66	Ambiguous	1.30	Ambiguous	0.95	Ambiguous	-4.45	Deleterious	0.993	Probably Damaging	0.977	Probably Damaging	4.07	Benign	0.13	Tolerated			1	0	1.7	-34.02
c.1072T>C	F358L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F358L 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, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results are reported for Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta’s stability prediction is unavailable due to inconclusiveness. Overall, the majority of available evidence points to a pathogenic impact. 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.		C2	0.222385	Structured	0.407113	Uncertain	0.912	0.441	0.250							-7.865	In-Between	0.964	Likely Pathogenic	Likely Pathogenic	0.290	Likely Benign	0.2555	0.3602		0.18	Likely Benign	0.1	1.62	Ambiguous	0.90	Ambiguous	0.97	Ambiguous	-4.21	Deleterious	0.982	Probably Damaging	0.952	Probably Damaging	4.12	Benign	0.22	Tolerated			2	0	1.0	-34.02
c.1072T>G	F358V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F358V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Five tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for F358V, 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	0.222385	Structured	0.407113	Uncertain	0.912	0.441	0.250							-9.021	Likely Pathogenic	0.847	Likely Pathogenic	Ambiguous	0.408	Likely Benign	0.2222	0.2978		1.42	Ambiguous	0.2	1.68	Ambiguous	1.55	Ambiguous	0.93	Ambiguous	-5.32	Deleterious	0.993	Probably Damaging	0.968	Probably Damaging	4.09	Benign	0.18	Tolerated			-1	-1	1.4	-48.04
c.1073T>A	F358Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F358Y 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, ESM1b, FATHMM, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a Likely Benign result (3 benign vs. 1 pathogenic), and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a benign effect. premPS is uncertain and is treated as unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.222385	Structured	0.407113	Uncertain	0.912	0.441	0.250							-6.458	Likely Benign	0.606	Likely Pathogenic	Likely Benign	0.231	Likely Benign	0.1467	0.2697		0.42	Likely Benign	0.1	0.21	Likely Benign	0.32	Likely Benign	0.84	Ambiguous	-2.17	Neutral	0.993	Probably Damaging	0.952	Probably Damaging	4.05	Benign	0.36	Tolerated			7	3	-4.1	16.00
c.1073T>C	F358S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F358S variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of algorithms predict a pathogenic outcome: FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Rosetta’s assessment is uncertain and is not taken as evidence. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the preponderance of pathogenic predictions and the agreement of the high‑accuracy 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	C2	0.222385	Structured	0.407113	Uncertain	0.912	0.441	0.250							-9.316	Likely Pathogenic	0.977	Likely Pathogenic	Likely Pathogenic	0.493	Likely Benign	0.3891	0.1333		2.32	Destabilizing	0.2	1.97	Ambiguous	2.15	Destabilizing	1.14	Destabilizing	-6.48	Deleterious	0.998	Probably Damaging	0.986	Probably Damaging	4.07	Benign	0.20	Tolerated			-3	-2	-3.6	-60.10
c.1073T>G	F358C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F358C is not reported in ClinVar and is absent from gnomAD. Consensus from standard in‑silico predictors shows a split: benign calls come from REVEL, SIFT, and FATHMM, whereas pathogenic calls arise from Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default. High‑accuracy assessments are less definitive: AlphaMissense‑Optimized is inconclusive, Foldetta is inconclusive, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward pathogenic. Because the majority of available predictions favor a damaging effect, the variant is most likely pathogenic, 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.		C2	0.222385	Structured	0.407113	Uncertain	0.912	0.441	0.250							-7.966	In-Between	0.927	Likely Pathogenic	Ambiguous	0.460	Likely Benign	0.2364	0.1800		1.68	Ambiguous	0.1	2.19	Destabilizing	1.94	Ambiguous	1.18	Destabilizing	-6.36	Deleterious	0.999	Probably Damaging	0.993	Probably Damaging	4.02	Benign	0.06	Tolerated			-4	-2	-0.3	-44.04
c.1074C>A	F358L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F358L 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, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results are reported for Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta’s stability prediction is unavailable due to inconclusiveness. Overall, the majority of available evidence points to a pathogenic impact. 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.		C2	0.222385	Structured	0.407113	Uncertain	0.912	0.441	0.250							-7.865	In-Between	0.964	Likely Pathogenic	Likely Pathogenic	0.215	Likely Benign	0.2555	0.3602		0.18	Likely Benign	0.1	1.62	Ambiguous	0.90	Ambiguous	0.97	Ambiguous	-4.21	Deleterious	0.982	Probably Damaging	0.952	Probably Damaging	4.12	Benign	0.22	Tolerated			2	0	1.0	-34.02
c.1074C>G	F358L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F358L 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, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta’s stability prediction is unavailable. Overall, the majority of reliable tools predict a pathogenic impact for F358L. This conclusion does not contradict ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.222385	Structured	0.407113	Uncertain	0.912	0.441	0.250							-7.865	In-Between	0.964	Likely Pathogenic	Likely Pathogenic	0.215	Likely Benign	0.2555	0.3602		0.18	Likely Benign	0.1	1.62	Ambiguous	0.90	Ambiguous	0.97	Ambiguous	-4.21	Deleterious	0.982	Probably Damaging	0.952	Probably Damaging	4.12	Benign	0.22	Tolerated			2	0	1.0	-34.02
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	0.396	Likely Benign	0.0785	0.3963		1.20	Ambiguous	0.1	-0.16	Likely Benign	0.52	Ambiguous	0.49	Likely Benign	-4.14	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.32	Pathogenic	0.11	Tolerated			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	0.505	Likely Pathogenic	0.1005	0.4542		1.50	Ambiguous	0.4	-0.28	Likely Benign	0.61	Ambiguous	0.22	Likely Benign	-5.63	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.23	Pathogenic	0.01	Affected			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	0.485	Likely Benign	0.0372	0.4018		1.15	Ambiguous	0.6	-0.07	Likely Benign	0.54	Ambiguous	0.41	Likely Benign	-7.33	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.20	Pathogenic	0.00	Affected			-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	0.458	Likely Benign	0.2998	0.4176		1.19	Ambiguous	0.2	0.32	Likely Benign	0.76	Ambiguous	0.54	Ambiguous	-6.45	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.24	Pathogenic	0.02	Affected			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	0.539	Likely Pathogenic	0.3052	0.4765		1.78	Ambiguous	0.3	0.69	Ambiguous	1.24	Ambiguous	0.63	Ambiguous	-5.98	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.31	Pathogenic	0.07	Tolerated			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	0.484	Likely Benign	0.0573	0.4132		1.39	Ambiguous	0.1	-0.52	Ambiguous	0.44	Likely Benign	0.50	Likely Benign	-7.27	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.21	Pathogenic	0.03	Affected			-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	0.191	Likely Benign	0.0970	0.3915		0.50	Ambiguous	0.2	0.04	Likely Benign	0.27	Likely Benign	0.35	Likely Benign	-2.66	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.29	Pathogenic	0.24	Tolerated			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	0.188	Likely Benign	0.0970	0.3915		0.50	Ambiguous	0.2	0.04	Likely Benign	0.27	Likely Benign	0.35	Likely Benign	-2.66	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.29	Pathogenic	0.24	Tolerated			3	2	0.0	14.03
c.2167A>C	T723P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723P 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 REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity are SGM Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The 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 pathogenic. premPS is uncertain and does not influence the overall assessment. Overall, the majority of tools and the high‑accuracy methods support a pathogenic effect. Thus, 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	GAP	0.476583	Structured	0.458243	Uncertain	0.945	0.447	0.375							-9.231	Likely Pathogenic	0.741	Likely Pathogenic	Likely Benign	0.085	Likely Benign	0.1826	0.4406		3.98	Destabilizing	0.1	6.10	Destabilizing	5.04	Destabilizing	0.54	Ambiguous	-2.51	Deleterious	0.995	Probably Damaging	0.929	Probably Damaging	3.49	Benign	0.04	Affected			0	-1	-0.9	-3.99
c.2167A>G	T723A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess sequence conservation, structural impact, or functional effect all converge on a benign outcome: SIFT, PolyPhen‑2 (HumDiv and HumVar), PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, REVEL, and the protein‑stability predictors FoldX, Rosetta, premPS, and Foldetta all indicate a benign effect. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: 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. Based on the uniform predictions, the variant is most likely benign, 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 Benign	GAP	0.476583	Structured	0.458243	Uncertain	0.945	0.447	0.375							-4.572	Likely Benign	0.064	Likely Benign	Likely Benign	0.053	Likely Benign	0.3902	0.3639		-0.47	Likely Benign	0.0	0.16	Likely Benign	-0.16	Likely Benign	0.25	Likely Benign	-0.91	Neutral	0.161	Benign	0.045	Benign	3.51	Benign	0.06	Tolerated			1	0	2.5	-30.03
c.2167A>T	T723S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or tolerated. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The high‑accuracy consensus methods confirm the benign assessment: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Overall, the majority of evidence supports a benign impact for T723S, 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 Benign	GAP	0.476583	Structured	0.458243	Uncertain	0.945	0.447	0.375							-4.792	Likely Benign	0.091	Likely Benign	Likely Benign	0.037	Likely Benign	0.3171	0.3731		-0.26	Likely Benign	0.0	0.28	Likely Benign	0.01	Likely Benign	0.23	Likely Benign	-0.89	Neutral	0.673	Possibly Damaging	0.678	Possibly Damaging	3.55	Benign	0.06	Tolerated			1	1	-0.1	-14.03
c.2168C>A	T723K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723K 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 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, while FoldX and AlphaMissense‑Default are uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the preponderance of evidence supports a benign classification for T723K, 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	GAP	0.476583	Structured	0.458243	Uncertain	0.945	0.447	0.375							-4.624	Likely Benign	0.482	Ambiguous	Likely Benign	0.121	Likely Benign	0.0924	0.2798		-0.77	Ambiguous	0.1	-0.04	Likely Benign	-0.41	Likely Benign	0.25	Likely Benign	-1.40	Neutral	0.674	Possibly Damaging	0.118	Benign	3.46	Benign	0.51	Tolerated			0	-1	-3.2	27.07
c.2168C>G	T723R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify it as benign. Two tools (polyPhen‑2 HumDiv and HumVar) predict it to be pathogenic, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. 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, SGM Consensus as likely benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign impact for T723R, 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	GAP	0.476583	Structured	0.458243	Uncertain	0.945	0.447	0.375							-3.654	Likely Benign	0.408	Ambiguous	Likely Benign	0.146	Likely Benign	0.0794	0.2437		-0.90	Ambiguous	0.1	-0.13	Likely Benign	-0.52	Ambiguous	0.44	Likely Benign	-1.50	Neutral	0.931	Possibly Damaging	0.458	Possibly Damaging	3.51	Benign	0.29	Tolerated			-1	-1	-3.8	55.08
c.2168C>T	T723I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723I is listed in ClinVar as Benign (ClinVar ID 436924.0) and is observed in gnomAD (variant ID 6‑33441633‑C‑T). Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT classifies the change as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates a benign impact. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	GAP	0.476583	Structured	0.458243	Uncertain	0.945	0.447	0.375	Likely Benign		1	6-33441633-C-T	2	1.24e-6	-2.591	Likely Benign	0.120	Likely Benign	Likely Benign	0.045	Likely Benign	0.0708	0.5803		-0.39	Likely Benign	0.0	-0.20	Likely Benign	-0.30	Likely Benign	0.26	Likely Benign	-2.09	Neutral	0.088	Benign	0.030	Benign	3.39	Benign	0.03	Affected	3.50	8	0	-1	5.2	12.05	252.3	-31.6	0.0	0.0	-0.2	0.2						X		Uncertain	The hydroxyl group of Thr723, located on the outer surface of an α-helix (res. Leu714-Arg726), continuously forms hydrogen bonds with the backbone carbonyl of Asn719 in the WT simulations, potentially lowering the stability of the α-helix. In the variant simulations, the sec-butyl side chain of Ile723 cannot form any hydrogen bonds, which, in theory, could increase the helix stability. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations.
c.601G>A	D201N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201N 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, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The remaining tools—Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default—return uncertain results and are treated as unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is unavailable because two of the four inputs are uncertain. Foldetta also yields an uncertain result and is unavailable. Overall, the preponderance of evidence points to a benign impact for D201N, 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	0.366687	Structured	0.428570	Uncertain	0.698	0.447	0.125							-7.686	In-Between	0.525	Ambiguous	Likely Benign	0.160	Likely Benign	0.0911	0.5413		0.31	Likely Benign	0.0	1.21	Ambiguous	0.76	Ambiguous	-0.10	Likely Benign	-2.36	Neutral	0.996	Probably Damaging	0.877	Possibly Damaging	4.08	Benign	0.13	Tolerated			2	1	0.0	-0.98
c.601G>C	D201H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201H missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM. Those that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. 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 as uncertain. Overall, the majority of available predictions (seven pathogenic vs. three benign) indicate that the variant is most likely pathogenic. This conclusion is not contradicted by 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	0.366687	Structured	0.428570	Uncertain	0.698	0.447	0.125							-8.595	Likely Pathogenic	0.862	Likely Pathogenic	Ambiguous	0.284	Likely Benign	0.1152	0.5838		0.68	Ambiguous	0.2	1.43	Ambiguous	1.06	Ambiguous	0.44	Likely Benign	-3.45	Deleterious	1.000	Probably Damaging	0.960	Probably Damaging	4.04	Benign	0.03	Affected			1	-1	0.3	22.05
c.601G>T	D201Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201Y 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, premPS, and FATHMM. Those that predict a pathogenic effect comprise SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and Rosetta. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; SGM Consensus predicts likely pathogenic; Foldetta is uncertain. Because the majority of consensus and individual predictors (seven pathogenic vs four benign) lean toward a damaging outcome, the variant is most likely pathogenic. This assessment 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	0.366687	Structured	0.428570	Uncertain	0.698	0.447	0.125							-10.916	Likely Pathogenic	0.892	Likely Pathogenic	Ambiguous	0.334	Likely Benign	0.0431	0.5371		0.28	Likely Benign	0.2	2.39	Destabilizing	1.34	Ambiguous	0.31	Likely Benign	-4.93	Deleterious	1.000	Probably Damaging	0.960	Probably Damaging	4.02	Benign	0.02	Affected			-4	-3	2.2	48.09
c.602A>C	D201A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201A 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, and FATHMM, whereas a pathogenic consensus is reached by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain or unavailable results come from Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward pathogenic, and Foldetta remains inconclusive. Overall, the majority of standard tools favor a benign classification, but the high‑accuracy consensus indicates a pathogenic signal, leaving the variant’s impact uncertain. The predictions do 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.		PH	0.366687	Structured	0.428570	Uncertain	0.698	0.447	0.125							-7.793	In-Between	0.769	Likely Pathogenic	Likely Benign	0.261	Likely Benign	0.3177	0.5050		0.45	Likely Benign	0.1	1.86	Ambiguous	1.16	Ambiguous	0.23	Likely Benign	-3.81	Deleterious	0.989	Probably Damaging	0.828	Possibly Damaging	4.11	Benign	0.09	Tolerated			0	-2	5.3	-44.01
c.602A>G	D201G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201G 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, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence favors a pathogenic interpretation, with no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.366687	Structured	0.428570	Uncertain	0.698	0.447	0.125							-7.744	In-Between	0.603	Likely Pathogenic	Likely Benign	0.289	Likely Benign	0.3268	0.5047		0.71	Ambiguous	0.0	2.64	Destabilizing	1.68	Ambiguous	0.24	Likely Benign	-3.03	Deleterious	0.996	Probably Damaging	0.877	Possibly Damaging	4.09	Benign	0.39	Tolerated			1	-1	3.1	-58.04
c.602A>T	D201V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, while those that predict a pathogenic impact are SGM‑Consensus (Likely Pathogenic), Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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 Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. With the majority of tools indicating pathogenicity and no ClinVar record 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	PH	0.366687	Structured	0.428570	Uncertain	0.698	0.447	0.125							-10.283	Likely Pathogenic	0.906	Likely Pathogenic	Ambiguous	0.305	Likely Benign	0.0572	0.5207		0.87	Ambiguous	0.1	2.18	Destabilizing	1.53	Ambiguous	0.31	Likely Benign	-5.01	Deleterious	0.999	Probably Damaging	0.946	Probably Damaging	4.04	Benign	0.02	Affected			-2	-3	7.7	-15.96
c.603T>A	D201E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201E missense variant (ClinVar ID 3004688.0) is classified as **Benign** in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as **Benign**, the SGM‑Consensus as **Likely Benign**, and Foldetta as **Uncertain**. Taken together, the overwhelming majority of evidence points to a benign impact, and this conclusion aligns with the ClinVar designation. Thus, the variant is most likely benign, with no contradiction to its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.366687	Structured	0.428570	Uncertain	0.698	0.447	0.125	Benign		1				-2.640	Likely Benign	0.406	Ambiguous	Likely Benign	0.165	Likely Benign	0.1069	0.5505		0.42	Likely Benign	0.2	1.99	Ambiguous	1.21	Ambiguous	0.23	Likely Benign	-0.69	Neutral	0.633	Possibly Damaging	0.108	Benign	4.30	Benign	1.00	Tolerated	3.46	9	3	2	0.0	14.03	258.7	-24.8	0.9	0.1	-0.3	0.2						X		Uncertain	Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.603T>G	D201E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201E missense variant (gnomAD ID 6‑33435245‑T‑G) is listed in ClinVar with an uncertain significance. Across a broad panel of in silico predictors, the majority indicate a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score benign. Only polyPhen‑2 HumDiv predicts pathogenicity, while Rosetta, Foldetta, and AlphaMissense‑Default remain inconclusive. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “likely benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta is inconclusive. Taken together, the preponderance of evidence points to a benign impact, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.366687	Structured	0.428570	Uncertain	0.698	0.447	0.125	Conflicting		2	6-33435245-T-G	20	1.24e-5	-2.640	Likely Benign	0.406	Ambiguous	Likely Benign	0.165	Likely Benign	0.1069	0.5505		0.42	Likely Benign	0.2	1.99	Ambiguous	1.21	Ambiguous	0.23	Likely Benign	-0.69	Neutral	0.633	Possibly Damaging	0.108	Benign	4.30	Benign	1.00	Tolerated	3.46	9	3	2	0.0	14.03	258.7	-24.8	0.9	0.1	-0.3	0.2						X		Uncertain	Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.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	0.444	Likely Benign	0.4015	0.1219		0.00	Likely Benign	0.1	0.51	Ambiguous	0.26	Likely Benign	0.76	Ambiguous	-3.11	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.91	Pathogenic	0.08	Tolerated			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	0.488	Likely Benign	0.3429	0.1039		-0.06	Likely Benign	0.2	0.30	Likely Benign	0.12	Likely Benign	0.89	Ambiguous	-3.21	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.91	Pathogenic	0.09	Tolerated			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	0.506	Likely Pathogenic	0.1839	0.3354		0.51	Ambiguous	0.0	-0.15	Likely Benign	0.18	Likely Benign	0.46	Likely Benign	-4.82	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.96	Pathogenic	0.08	Tolerated			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	0.232	Likely Benign	0.4294	0.1134		-0.23	Likely Benign	0.0	0.15	Likely Benign	-0.04	Likely Benign	0.33	Likely Benign	-2.02	Neutral	0.999	Probably Damaging	0.995	Probably Damaging	2.01	Pathogenic	0.14	Tolerated			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	0.544	Likely Pathogenic	0.0931	0.3521		0.30	Likely Benign	0.0	0.95	Ambiguous	0.63	Ambiguous	0.43	Likely Benign	-6.49	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.89	Pathogenic	0.03	Affected			-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	0.359	Likely Benign	0.3267	0.1315		0.30	Likely Benign	0.1	0.42	Likely Benign	0.36	Likely Benign	0.55	Ambiguous	-4.03	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.91	Pathogenic	0.13	Tolerated			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	0.366	Likely Benign	0.3267	0.1315		0.30	Likely Benign	0.1	0.42	Likely Benign	0.36	Likely Benign	0.55	Ambiguous	-4.03	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.91	Pathogenic	0.13	Tolerated			1	0	0.4	-14.07
c.1198G>A	V400M 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V400M is reported in gnomAD (ID 6‑33438103‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. In contrast, only three tools—polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default—predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, SGM‑Consensus is likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No evidence from FoldX or premPS is available. Overall, the preponderance of predictions, including the high‑accuracy methods, supports a benign classification, which is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.398279	Structured	0.415488	Uncertain	0.951	0.451	0.000				6-33438103-G-A	3	1.86e-6	-5.438	Likely Benign	0.573	Likely Pathogenic	Likely Benign	0.443	Likely Benign	0.0851	0.4643		-1.12	Ambiguous	0.1	-0.16	Likely Benign	-0.64	Ambiguous	0.55	Ambiguous	-1.44	Neutral	0.868	Possibly Damaging	0.289	Benign	5.26	Benign	0.01	Affected	3.38	27	1	2	-2.3	32.06
c.1198G>C	V400L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400L is listed in ClinVar as Benign (ClinVar ID 1166313.0) and is present in gnomAD (variant ID 6‑33438103‑G‑C). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive result is from FoldX, which is treated as unavailable. High‑accuracy assessments confirm benignity: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Overall, the computational evidence strongly supports a benign classification, consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.398279	Structured	0.415488	Uncertain	0.951	0.451	0.000	Benign		1	6-33438103-G-C	22	1.36e-5	-1.000	Likely Benign	0.137	Likely Benign	Likely Benign	0.325	Likely Benign	0.1006	0.5242		-0.71	Ambiguous	0.2	0.39	Likely Benign	-0.16	Likely Benign	-0.29	Likely Benign	-0.60	Neutral	0.001	Benign	0.001	Benign	5.33	Benign	0.64	Tolerated	3.38	27	2	1	-0.4	14.03	251.0	-30.1	0.0	0.0	0.7	0.1						X		Potentially Benign	The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). Val400 is swapped for another hydrophobic residue, leucine, whose branched hydrocarbon side chain is of a comparable size and thus packs favorably within the C2 domain. In short, the residue swap has no apparent negative effect on the structure based on the variant simulations.	10.1016/j.ajhg.2020.11.011
c.1198G>T	V400L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools that agree on a benign effect include REVEL, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, premPS, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive result is from FoldX (Uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields 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 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	0.398279	Structured	0.415488	Uncertain	0.951	0.451	0.000							-1.000	Likely Benign	0.137	Likely Benign	Likely Benign	0.325	Likely Benign	0.1006	0.5242		-0.71	Ambiguous	0.2	0.39	Likely Benign	-0.16	Likely Benign	-0.29	Likely Benign	-0.60	Neutral	0.001	Benign	0.001	Benign	5.33	Benign	0.64	Tolerated	3.38	27	2	1	-0.4	14.03	251.0	-30.1	0.0	0.0	0.7	0.1						X		Potentially Benign	The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). Val400 is swapped for another hydrophobic residue, leucine, whose branched hydrocarbon side chain is of a comparable size and thus packs favorably within the C2 domain. In short, the residue swap has no apparent negative effect on the structure based on the variant simulations.	10.1016/j.ajhg.2020.11.011
c.1199T>A	V400E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400E is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate 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 the SGM‑Consensus) predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. 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	0.398279	Structured	0.415488	Uncertain	0.951	0.451	0.000	Uncertain		1				-13.686	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.810	Likely Pathogenic	0.1044	0.1922		3.70	Destabilizing	0.2	2.46	Destabilizing	3.08	Destabilizing	2.29	Destabilizing	-4.88	Deleterious	0.920	Possibly Damaging	0.335	Benign	5.31	Benign	0.00	Affected	3.38	27	-2	-2	-7.7	29.98	249.1	-38.8	-0.1	0.1	1.0	0.0	X		X				X	Potentially Pathogenic	The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). In the variant simulations, the negatively charged carboxylate group of the Glu400 side chain is not suitable for occupying the hydrophobic niche. Consequently, the side chain escapes the center of the C2 domain and interacts with the backbone amide groups of Leu402 in the same β strand and/or Ile269 and Glu270 in a neighboring β strand (res. Arg259-Arg272). This residue swap disrupts the hydrophobic packing and generally has extensive negative effects on the C2 domain structure. At a minimum, the residue swap could affect the C2 domain stability and membrane association.
c.1199T>C	V400A 2D 3DClick to see structure in 3D Viewer AISynGAP1 V400A is not reported in ClinVar and is absent from gnomAD. Consensus from standard predictors shows a split: benign calls from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls come from FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT and AlphaMissense‑Default. Two high‑accuracy tools give a clear signal: AlphaMissense‑Optimized is uncertain, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta also predicts pathogenic. With most evidence pointing to deleterious effects, the variant is most likely pathogenic, 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	0.398279	Structured	0.415488	Uncertain	0.951	0.451	0.000							-7.564	In-Between	0.871	Likely Pathogenic	Ambiguous	0.479	Likely Benign	0.3291	0.2767		3.14	Destabilizing	0.1	3.12	Destabilizing	3.13	Destabilizing	2.29	Destabilizing	-3.12	Deleterious	0.435	Benign	0.049	Benign	5.32	Benign	0.01	Affected			0	0	-2.4	-28.05
c.1199T>G	V400G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V400G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumDiv and FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome. 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, which integrates FoldX‑MD and Rosetta stability predictions, is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy 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.		C2	0.398279	Structured	0.415488	Uncertain	0.951	0.451	0.000							-11.508	Likely Pathogenic	0.969	Likely Pathogenic	Likely Pathogenic	0.819	Likely Pathogenic	0.2296	0.2522		4.84	Destabilizing	0.1	5.40	Destabilizing	5.12	Destabilizing	2.40	Destabilizing	-5.70	Deleterious	0.335	Benign	0.920	Probably Damaging	5.27	Benign	0.00	Affected			-1	-3	-4.6	-42.08
c.598T>A	L200M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L200M 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign outcome. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from the four high‑confidence predictors, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Taken together, the overwhelming majority of evidence supports a benign classification for L200M, and this conclusion is consistent with the absence of a ClinVar entry. Thus, the variant is most likely benign, and this assessment does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.366687	Structured	0.428168	Uncertain	0.687	0.453	0.125							-4.107	Likely Benign	0.215	Likely Benign	Likely Benign	0.139	Likely Benign	0.0751	0.3511		0.08	Likely Benign	0.1	0.41	Likely Benign	0.25	Likely Benign	-0.25	Likely Benign	0.47	Neutral	0.997	Probably Damaging	0.960	Probably Damaging	4.11	Benign	0.31	Tolerated			4	2	-1.9	18.03
c.598T>G	L200V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L200V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and the Foldetta stability assessment. Uncertain results come from Rosetta 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 as pathogenic. Overall, the majority of evidence points to a benign effect; there is no ClinVar annotation to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.366687	Structured	0.428168	Uncertain	0.687	0.453	0.125							-6.917	Likely Benign	0.213	Likely Benign	Likely Benign	0.098	Likely Benign	0.1593	0.3607		2.15	Destabilizing	0.2	1.85	Ambiguous	2.00	Destabilizing	0.92	Ambiguous	-1.07	Neutral	0.990	Probably Damaging	0.760	Possibly Damaging	4.09	Benign	0.24	Tolerated			2	1	0.4	-14.03
c.599T>C	L200S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L200S 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, and FATHMM. Those that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2). High‑accuracy methods give a pathogenic signal from Foldetta (protein‑folding stability analysis) while AlphaMissense‑Optimized is uncertain and thus not considered evidence. Overall, the majority of available predictions (10 pathogenic vs 4 benign) 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.		PH	0.366687	Structured	0.428168	Uncertain	0.687	0.453	0.125							-10.755	Likely Pathogenic	0.807	Likely Pathogenic	Ambiguous	0.141	Likely Benign	0.3279	0.0575		2.72	Destabilizing	0.1	3.38	Destabilizing	3.05	Destabilizing	1.43	Destabilizing	-1.96	Neutral	0.970	Probably Damaging	0.683	Possibly Damaging	4.05	Benign	0.06	Tolerated			-3	-2	-4.6	-26.08
c.599T>G	L200W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L200W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools (SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and Foldetta) predict a pathogenic impact. Two tools (AlphaMissense‑Optimized and Rosetta) provide inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as Pathogenic, the latter integrating stability predictions from FoldX‑MD and Rosetta. Overall, the preponderance of evidence indicates that 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	0.366687	Structured	0.428168	Uncertain	0.687	0.453	0.125							-11.550	Likely Pathogenic	0.824	Likely Pathogenic	Ambiguous	0.200	Likely Benign	0.0627	0.2893		2.90	Destabilizing	1.0	1.95	Ambiguous	2.43	Destabilizing	1.20	Destabilizing	-2.93	Deleterious	0.999	Probably Damaging	0.970	Probably Damaging	3.98	Benign	0.02	Affected			-2	-2	-4.7	73.05
c.600G>C	L200F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L200F is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33435242‑G‑C). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and ESM1b. 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, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.366687	Structured	0.428168	Uncertain	0.687	0.453	0.125	Uncertain		1	6-33435242-G-C	2	1.24e-6	-7.606	In-Between	0.592	Likely Pathogenic	Likely Benign	0.094	Likely Benign	0.0640	0.3120		1.00	Ambiguous	0.5	1.45	Ambiguous	1.23	Ambiguous	0.43	Likely Benign	-1.97	Neutral	0.997	Probably Damaging	0.916	Probably Damaging	4.02	Benign	0.17	Tolerated	3.46	9	2	0	-1.0	34.02	250.4	-15.1	0.6	0.2	0.5	0.0						X		Uncertain	Leu200, a hydrophobic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another hydrophobic residue, phenylalanine. Both the phenyl group of Phe200 and the branched iso-butyl hydrocarbon sidechain of Leu200 occupy an inward hydrophobic niche (e.g., Leu246, Val222, Phe231) during the simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.600G>T	L200F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L200F 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, ESM1b, Foldetta) returned uncertain results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (benign)—is benign; Foldetta remains uncertain and is treated as unavailable. Overall, the balance of evidence (six benign vs. three pathogenic predictions, with a benign consensus from high‑accuracy methods) indicates that 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.		PH	0.366687	Structured	0.428168	Uncertain	0.687	0.453	0.125							-7.606	In-Between	0.592	Likely Pathogenic	Likely Benign	0.094	Likely Benign	0.0640	0.3120		1.00	Ambiguous	0.5	1.45	Ambiguous	1.23	Ambiguous	0.43	Likely Benign	-1.97	Neutral	0.997	Probably Damaging	0.916	Probably Damaging	4.02	Benign	0.17	Tolerated	3.46	9	2	0	-1.0	34.02	250.4	-15.1	0.6	0.2	0.5	0.0						X		Uncertain	Leu200, a hydrophobic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another hydrophobic residue, phenylalanine. Both the phenyl group of Phe200 and the branched iso-butyl hydrocarbon sidechain of Leu200 occupy an inward hydrophobic niche (e.g., Leu246, Val222, Phe231) during the simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
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	0.409	Likely Benign	0.1929	0.2552		0.81	Ambiguous	0.2	1.48	Ambiguous	1.15	Ambiguous	0.97	Ambiguous	-5.63	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.95	Pathogenic	0.11	Tolerated			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	0.561	Likely Pathogenic	0.2612	0.1611		0.87	Ambiguous	0.6	2.00	Destabilizing	1.44	Ambiguous	0.96	Ambiguous	-7.67	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	2.04	Pathogenic	0.10	Tolerated			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	0.562	Likely Pathogenic	0.0796	0.4323		0.03	Likely Benign	0.4	0.25	Likely Benign	0.14	Likely Benign	0.07	Likely Benign	-5.32	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.92	Pathogenic	0.02	Affected			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	0.711	Likely Pathogenic	0.2383	0.4492		2.67	Destabilizing	0.3	2.59	Destabilizing	2.63	Destabilizing	0.88	Ambiguous	-8.73	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.92	Pathogenic	0.03	Affected			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	0.601	Likely Pathogenic	0.1832	0.2413		-0.65	Ambiguous	0.1	1.40	Ambiguous	0.38	Likely Benign	0.83	Ambiguous	-6.89	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.97	Pathogenic	0.10	Tolerated			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	0.627	Likely Pathogenic	0.0992	0.5799		-0.85	Ambiguous	0.2	0.36	Likely Benign	-0.25	Likely Benign	0.44	Likely Benign	-9.64	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.95	Pathogenic	0.08	Tolerated			-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	0.444	Likely Benign	0.1485	0.3500		0.46	Likely Benign	0.1	1.67	Ambiguous	1.07	Ambiguous	1.00	Destabilizing	-6.89	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	2.07	Pathogenic	0.10	Tolerated			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	0.444	Likely Benign	0.1485	0.3500		0.46	Likely Benign	0.1	1.67	Ambiguous	1.07	Ambiguous	1.00	Destabilizing	-6.89	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	2.07	Pathogenic	0.10	Tolerated			3	0	-0.3	-9.01
c.1036G>A	V346M 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V346M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL and FoldX, whereas the majority of other in silico methods (PolyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, PROVEAN, AlphaMissense‑Optimized, and the SGM‑Consensus score) indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, remains uncertain. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment 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	0.260850	Structured	0.350921	Uncertain	0.949	0.461	0.000							-10.218	Likely Pathogenic	0.963	Likely Pathogenic	Likely Pathogenic	0.367	Likely Benign	0.1050	0.4749		0.29	Likely Benign	0.1	2.52	Destabilizing	1.41	Ambiguous	0.67	Ambiguous	-2.72	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	1.48	Pathogenic	0.05	Affected			2	1	-2.3	32.06
c.1036G>C	V346L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346L is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and SIFT, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta) give uncertain or inconclusive results and are not used as evidence. 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 reliable predictors and the SGM‑Consensus support a pathogenic effect. Therefore, 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	0.260850	Structured	0.350921	Uncertain	0.949	0.461	0.000							-8.178	Likely Pathogenic	0.834	Likely Pathogenic	Ambiguous	0.384	Likely Benign	0.1237	0.5348		0.05	Likely Benign	0.2	1.10	Ambiguous	0.58	Ambiguous	0.60	Ambiguous	-2.68	Deleterious	0.994	Probably Damaging	0.970	Probably Damaging	1.58	Pathogenic	0.09	Tolerated			2	1	-0.4	14.03
c.1036G>T	V346L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and SIFT, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a deleterious effect. Therefore, the variant is most likely pathogenic, and 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	0.260850	Structured	0.350921	Uncertain	0.949	0.461	0.000							-8.178	Likely Pathogenic	0.834	Likely Pathogenic	Ambiguous	0.386	Likely Benign	0.1237	0.5348		0.05	Likely Benign	0.2	1.10	Ambiguous	0.58	Ambiguous	0.60	Ambiguous	-2.68	Deleterious	0.994	Probably Damaging	0.970	Probably Damaging	1.58	Pathogenic	0.09	Tolerated			2	1	-0.4	14.03
c.1037T>A	V346E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All evaluated in silico predictors classify the change 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 further support pathogenicity: AlphaMissense‑Optimized predicts a pathogenic outcome; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic impact. **Conclusion:** The variant is most likely pathogenic based on the unanimous computational evidence, and this assessment 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	0.260850	Structured	0.350921	Uncertain	0.949	0.461	0.000							-14.004	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.720	Likely Pathogenic	0.1088	0.1568		3.30	Destabilizing	0.4	4.79	Destabilizing	4.05	Destabilizing	2.13	Destabilizing	-5.52	Deleterious	0.999	Probably Damaging	0.991	Probably Damaging	1.47	Pathogenic	0.00	Affected			-2	-2	-7.7	29.98
c.1037T>C	V346A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346A is reported in gnomAD (6‑33437942‑T‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect are limited to REVEL, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) uniformly predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant 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	0.260850	Structured	0.350921	Uncertain	0.949	0.461	0.000				6-33437942-T-C	1	6.20e-7	-8.556	Likely Pathogenic	0.856	Likely Pathogenic	Ambiguous	0.477	Likely Benign	0.3341	0.2967		2.72	Destabilizing	0.2	2.73	Destabilizing	2.73	Destabilizing	1.92	Destabilizing	-3.68	Deleterious	0.994	Probably Damaging	0.970	Probably Damaging	1.70	Pathogenic	0.01	Affected	3.37	25	0	0	-2.4	-28.05
c.1037T>G	V346G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All available in‑silico predictors classify it 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 of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports pathogenic. With all evidence converging on a 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.		C2	0.260850	Structured	0.350921	Uncertain	0.949	0.461	0.000							-12.779	Likely Pathogenic	0.969	Likely Pathogenic	Likely Pathogenic	0.667	Likely Pathogenic	0.2378	0.2522		4.24	Destabilizing	0.2	4.62	Destabilizing	4.43	Destabilizing	2.15	Destabilizing	-6.03	Deleterious	0.991	Probably Damaging	0.999	Probably Damaging	1.50	Pathogenic	0.00	Affected			-1	-3	-4.6	-42.08
c.1015A>C	K339Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. 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. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evaluated tools (8 pathogenic vs. 4 benign) indicate a pathogenic effect. 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	0.447574	Structured	0.384153	Uncertain	0.535	0.465	0.250							-10.952	Likely Pathogenic	0.863	Likely Pathogenic	Ambiguous	0.458	Likely Benign	0.4041	0.1012		0.06	Likely Benign	0.0	-0.50	Ambiguous	-0.22	Likely Benign	-0.02	Likely Benign	-3.06	Deleterious	0.982	Probably Damaging	0.824	Possibly Damaging	1.90	Pathogenic	0.04	Affected			1	1	0.4	-0.04
c.1015A>G	K339E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339E 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, Rosetta, Foldetta, and premPS. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score, 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 (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact, and this conclusion 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	0.447574	Structured	0.384153	Uncertain	0.535	0.465	0.250							-14.284	Likely Pathogenic	0.983	Likely Pathogenic	Likely Pathogenic	0.482	Likely Benign	0.3421	0.0882		0.13	Likely Benign	0.1	-0.03	Likely Benign	0.05	Likely Benign	0.40	Likely Benign	-3.00	Deleterious	0.939	Possibly Damaging	0.670	Possibly Damaging	1.92	Pathogenic	0.03	Affected			0	1	0.4	0.94
c.1016A>C	K339T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339T missense variant is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools are split: benign calls come from FoldX, Rosetta, Foldetta, premPS, and SIFT, whereas pathogenic calls are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further highlight this discordance: the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect, whereas Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. AlphaMissense‑Optimized returned an uncertain result and is treated as unavailable. Overall, the majority of robust predictors lean toward pathogenicity, 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	0.447574	Structured	0.384153	Uncertain	0.535	0.465	0.250							-10.061	Likely Pathogenic	0.910	Likely Pathogenic	Ambiguous	0.512	Likely Pathogenic	0.1900	0.3020		0.32	Likely Benign	0.0	0.10	Likely Benign	0.21	Likely Benign	-0.04	Likely Benign	-4.73	Deleterious	0.991	Probably Damaging	0.795	Possibly Damaging	1.94	Pathogenic	0.10	Tolerated			0	-1	3.2	-27.07
c.1016A>G	K339R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K339R 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, 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 predictions or stability results are 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.	Likely Benign	C2	0.447574	Structured	0.384153	Uncertain	0.535	0.465	0.250							-5.773	Likely Benign	0.120	Likely Benign	Likely Benign	0.134	Likely Benign	0.4197	0.0976		-0.15	Likely Benign	0.1	0.46	Likely Benign	0.16	Likely Benign	0.08	Likely Benign	-2.05	Neutral	0.046	Benign	0.040	Benign	1.94	Pathogenic	0.48	Tolerated			3	2	-0.6	28.01
c.1016A>T	K339M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339M 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 FoldX and premPS, 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. Tools with uncertain or inconclusive results are Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for K339M. This conclusion is not contradicted by 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	0.447574	Structured	0.384153	Uncertain	0.535	0.465	0.250							-13.387	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	0.575	Likely Pathogenic	0.0967	0.3541		0.23	Likely Benign	0.0	0.88	Ambiguous	0.56	Ambiguous	-0.37	Likely Benign	-4.95	Deleterious	0.999	Probably Damaging	0.964	Probably Damaging	1.92	Pathogenic	0.01	Affected			0	-1	5.8	3.02
c.1017G>C	K339N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339N 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, and premPS. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of evidence points to a pathogenic impact for K339N, 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	0.447574	Structured	0.384153	Uncertain	0.535	0.465	0.250							-11.117	Likely Pathogenic	0.983	Likely Pathogenic	Likely Pathogenic	0.410	Likely Benign	0.3224	0.1158		0.20	Likely Benign	0.0	0.35	Likely Benign	0.28	Likely Benign	0.00	Likely Benign	-3.88	Deleterious	0.991	Probably Damaging	0.864	Possibly Damaging	1.91	Pathogenic	0.02	Affected			1	0	0.4	-14.07
c.1017G>T	K339N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K339N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and premPS. Tools that predict a pathogenic effect comprise 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 indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta stability outputs) predicts a benign effect. Overall, the majority of evidence points toward a pathogenic impact for K339N, and 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	0.447574	Structured	0.384153	Uncertain	0.535	0.465	0.250							-11.117	Likely Pathogenic	0.983	Likely Pathogenic	Likely Pathogenic	0.410	Likely Benign	0.3224	0.1158		0.20	Likely Benign	0.0	0.35	Likely Benign	0.28	Likely Benign	0.00	Likely Benign	-3.88	Deleterious	0.991	Probably Damaging	0.864	Possibly Damaging	1.91	Pathogenic	0.02	Affected			1	0	0.4	-14.07
c.595A>C	N199H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199H 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict 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 are missing or inconclusive. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which contains no pathogenic assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.390993	Structured	0.431347	Uncertain	0.571	0.473	0.125							-6.387	Likely Benign	0.136	Likely Benign	Likely Benign	0.064	Likely Benign	0.0879	0.5635		0.17	Likely Benign	0.1	0.15	Likely Benign	0.16	Likely Benign	0.20	Likely Benign	-1.99	Neutral	0.952	Possibly Damaging	0.496	Possibly Damaging	4.17	Benign	0.08	Tolerated			2	1	0.3	23.04
c.595A>G	N199D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach a consensus classify the variant as benign: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. The only inconclusive results come from ESM1b and Rosetta, which are treated as unavailable. 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, which integrates FoldX‑MD and Rosetta outputs, also predicts a benign outcome. 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	0.390993	Structured	0.431347	Uncertain	0.571	0.473	0.125							-7.874	In-Between	0.338	Likely Benign	Likely Benign	0.028	Likely Benign	0.1516	0.3514		-0.14	Likely Benign	0.1	-0.67	Ambiguous	-0.41	Likely Benign	0.13	Likely Benign	-1.41	Neutral	0.276	Benign	0.062	Benign	4.22	Benign	0.35	Tolerated			2	1	0.0	0.98
c.595A>T	N199Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N199Y is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 (HumVar), FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from SIFT, PROVEAN, polyPhen‑2 (HumDiv), and ESM1b. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates benign stability. Overall, the majority of conventional tools (8 benign vs. 4 pathogenic) favor a benign effect, and this interpretation does not conflict with the absence of ClinVar annotation. Therefore, the variant is most likely benign based on the current predictive evidence, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.390993	Structured	0.431347	Uncertain	0.571	0.473	0.125							-8.575	Likely Pathogenic	0.391	Ambiguous	Likely Benign	0.097	Likely Benign	0.0389	0.5630		-0.06	Likely Benign	0.1	0.14	Likely Benign	0.04	Likely Benign	0.20	Likely Benign	-3.12	Deleterious	0.952	Possibly Damaging	0.395	Benign	4.15	Benign	0.04	Affected			-2	-2	2.2	49.07
c.596A>C	N199T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: 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) all classify it as benign or likely benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus predicts 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 any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.390993	Structured	0.431347	Uncertain	0.571	0.473	0.125							-4.123	Likely Benign	0.115	Likely Benign	Likely Benign	0.025	Likely Benign	0.0862	0.6186		0.16	Likely Benign	0.2	-0.10	Likely Benign	0.03	Likely Benign	-0.04	Likely Benign	-0.82	Neutral	0.002	Benign	0.003	Benign	4.24	Benign	0.10	Tolerated			0	0	2.8	-13.00
c.596A>G	N199S 2D AIThe SynGAP1 missense variant N199S 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 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). No tool predicts pathogenicity. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote) indicates likely benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the variant is most likely benign, and this prediction does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.390993	Structured	0.431347	Uncertain	0.571	0.473	0.125							-0.268	Likely Benign	0.079	Likely Benign	Likely Benign	0.040	Likely Benign	0.2601	0.6023		0.08	Likely Benign	0.4	-0.08	Likely Benign	0.00	Likely Benign	-0.44	Likely Benign	0.09	Neutral	0.160	Benign	0.045	Benign	4.36	Benign	0.57	Tolerated			1	1	2.7	-27.03
c.596A>T	N199I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199I 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, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and ESM1b. 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. The variant is most likely benign, 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	0.390993	Structured	0.431347	Uncertain	0.571	0.473	0.125							-8.299	Likely Pathogenic	0.328	Likely Benign	Likely Benign	0.066	Likely Benign	0.0450	0.6009		0.27	Likely Benign	0.1	-0.11	Likely Benign	0.08	Likely Benign	0.20	Likely Benign	-3.27	Deleterious	0.316	Benign	0.045	Benign	4.16	Benign	0.01	Affected			-2	-3	8.0	-0.94
c.597C>A	N199K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N199K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign. Only ESM1b and AlphaMissense‑Default predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the preponderance of evidence supports 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.		PH	0.390993	Structured	0.431347	Uncertain	0.571	0.473	0.125	Uncertain		1				-8.198	Likely Pathogenic	0.686	Likely Pathogenic	Likely Benign	0.024	Likely Benign	0.1399	0.5218		-0.19	Likely Benign	0.1	0.03	Likely Benign	-0.08	Likely Benign	0.33	Likely Benign	-1.48	Neutral	0.276	Benign	0.083	Benign	4.27	Benign	0.13	Tolerated	3.47	9	1	0	-0.4	14.07	207.8	21.5	-0.1	1.5	0.1	0.0						X		Uncertain	Asn199, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by a positively charged lysine. On the protein surface, both the carboxamide group of Asn199 and the amino group of Lys199 side chains can form hydrogen bonds with the backbone carbonyl groups of residues (e.g., Ala249) at the end of an α helix (res. Ala236-Lys251). However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.597C>G	N199K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199K 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. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the majority of evidence (10 benign vs. 2 pathogenic) supports a benign classification. This consensus 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.		PH	0.390993	Structured	0.431347	Uncertain	0.571	0.473	0.125							-8.198	Likely Pathogenic	0.686	Likely Pathogenic	Likely Benign	0.024	Likely Benign	0.1399	0.5218		-0.19	Likely Benign	0.1	0.03	Likely Benign	-0.08	Likely Benign	0.33	Likely Benign	-1.48	Neutral	0.276	Benign	0.083	Benign	4.27	Benign	0.13	Tolerated	3.47	9	1	0	-0.4	14.07	207.8	21.5	-0.1	1.5	0.1	0.0						X		Uncertain	Asn199, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by a positively charged lysine. On the protein surface, both the carboxamide group of Asn199 and the amino group of Lys199 side chains can form hydrogen bonds with the backbone carbonyl groups of residues (e.g., Ala249) at the end of an α helix (res. Ala236-Lys251). However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.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	0.095	Likely Benign	0.1505	0.4552		0.60	Ambiguous	0.2	-0.10	Likely Benign	0.25	Likely Benign	-0.72	Ambiguous	1.13	Neutral	0.003	Benign	0.002	Benign	1.86	Pathogenic	0.98	Tolerated			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	0.186	Likely Benign	0.2306	0.4086		0.33	Likely Benign	0.2	2.35	Destabilizing	1.34	Ambiguous	0.44	Likely Benign	-1.81	Neutral	0.784	Possibly Damaging	0.390	Benign	1.83	Pathogenic	0.26	Tolerated			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	0.071	Likely Benign	0.5314	0.3008	Weaken	0.22	Likely Benign	0.1	-0.08	Likely Benign	0.07	Likely Benign	-0.15	Likely Benign	-0.44	Neutral	0.139	Benign	0.060	Benign	1.89	Pathogenic	0.67	Tolerated			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	0.090	Likely Benign	0.0953	0.4124		0.54	Ambiguous	0.0	1.06	Ambiguous	0.80	Ambiguous	0.07	Likely Benign	-1.72	Neutral	0.270	Benign	0.136	Benign	1.87	Pathogenic	0.58	Tolerated			-3	-2	4.6	26.08
c.1033C>A	L345M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L345M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a benign outcome; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is uncertain. Overall, the majority of evidence points to a benign impact for the L345M variant, 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	0.260850	Structured	0.354989	Uncertain	0.936	0.478	0.125							-3.918	Likely Benign	0.101	Likely Benign	Likely Benign	0.101	Likely Benign	0.0677	0.3246		0.75	Ambiguous	0.1	0.80	Ambiguous	0.78	Ambiguous	0.54	Ambiguous	-0.97	Neutral	0.802	Possibly Damaging	0.122	Benign	1.73	Pathogenic	0.07	Tolerated			4	2	-1.9	18.03
c.1033C>G	L345V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L345V missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, Rosetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans toward benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the majority of evidence points to a benign impact for this variant, 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	0.260850	Structured	0.354989	Uncertain	0.936	0.478	0.125							-6.594	Likely Benign	0.131	Likely Benign	Likely Benign	0.126	Likely Benign	0.1411	0.3455		1.31	Ambiguous	0.0	0.18	Likely Benign	0.75	Ambiguous	0.92	Ambiguous	-1.96	Neutral	0.802	Possibly Damaging	0.277	Benign	1.77	Pathogenic	0.06	Tolerated			2	1	0.4	-14.03
c.1034T>A	L345Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L345Q is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into benign (REVEL, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM). FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is unavailable. Overall, the majority of predictions lean toward pathogenicity, while the single high‑accuracy tool that is definitive is benign. Thus, the variant is most likely pathogenic based on the collective evidence, 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	0.260850	Structured	0.354989	Uncertain	0.936	0.478	0.125							-6.034	Likely Benign	0.213	Likely Benign	Likely Benign	0.218	Likely Benign	0.0937	0.0842		1.32	Ambiguous	0.1	0.86	Ambiguous	1.09	Ambiguous	1.26	Destabilizing	-3.67	Deleterious	0.993	Probably Damaging	0.844	Possibly Damaging	1.82	Pathogenic	0.03	Affected			-2	-2	-7.3	14.97
c.1034T>C	L345P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L345P 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 algorithms—FoldX, Rosetta, Foldetta, 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, the SGM‑Consensus (majority vote) 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 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	0.260850	Structured	0.354989	Uncertain	0.936	0.478	0.125							-10.994	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	0.335	Likely Benign	0.3581	0.1342		3.33	Destabilizing	0.2	3.26	Destabilizing	3.30	Destabilizing	1.27	Destabilizing	-4.80	Deleterious	0.998	Probably Damaging	0.889	Possibly Damaging	1.70	Pathogenic	0.02	Affected			-3	-3	-5.4	-16.04
c.1034T>G	L345R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L345R 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 REVEL and AlphaMissense‑Optimized, whereas the majority of tools predict pathogenicity: SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic prediction. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Consequently, the variant is most likely pathogenic based on the collective predictions, 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	0.260850	Structured	0.354989	Uncertain	0.936	0.478	0.125							-10.325	Likely Pathogenic	0.635	Likely Pathogenic	Likely Benign	0.247	Likely Benign	0.1140	0.0685		0.96	Ambiguous	0.1	1.66	Ambiguous	1.31	Ambiguous	1.28	Destabilizing	-3.98	Deleterious	0.993	Probably Damaging	0.796	Possibly Damaging	1.81	Pathogenic	0.04	Affected			-3	-2	-8.3	43.03
c.1021G>A	G341S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G341S 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, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Predictions that are inconclusive or uncertain are Rosetta, Foldetta, and premPS. 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 G341S, 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	0.356642	Structured	0.431164	Uncertain	0.745	0.479	0.250							-3.206	Likely Benign	0.090	Likely Benign	Likely Benign	0.343	Likely Benign	0.2416	0.4215		0.41	Likely Benign	0.3	-1.46	Ambiguous	-0.53	Ambiguous	-0.67	Ambiguous	0.73	Neutral	0.454	Possibly Damaging	0.192	Benign	0.37	Pathogenic	0.72	Tolerated			1	0	-0.4	30.03
c.1021G>C	G341R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G341R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, polyPhen‑2 HumVar, and Foldetta. Those that predict a pathogenic effect are SGM‑Consensus (Likely Pathogenic), polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts a likely pathogenic outcome, while Foldetta predicts a benign effect; AlphaMissense‑Optimized remains inconclusive. Overall, the majority of predictions lean toward a benign impact, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign, though the evidence is not definitive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.356642	Structured	0.431164	Uncertain	0.745	0.479	0.250							-8.263	Likely Pathogenic	0.945	Likely Pathogenic	Ambiguous	0.379	Likely Benign	0.0838	0.3618		0.28	Likely Benign	0.2	-1.25	Ambiguous	-0.49	Likely Benign	0.18	Likely Benign	-1.03	Neutral	0.801	Possibly Damaging	0.417	Benign	0.34	Pathogenic	0.17	Tolerated			-3	-2	-4.1	99.14
c.1021G>T	G341C 2D AIThe SynGAP1 missense variant G341C has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (likely benign). Tools that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; Rosetta remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) 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 assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.356642	Structured	0.431164	Uncertain	0.745	0.479	0.250							-6.156	Likely Benign	0.190	Likely Benign	Likely Benign	0.501	Likely Pathogenic	0.1285	0.3650		0.42	Likely Benign	1.2	-0.92	Ambiguous	-0.25	Likely Benign	0.24	Likely Benign	-2.40	Neutral	0.997	Probably Damaging	0.870	Possibly Damaging	0.34	Pathogenic	0.01	Affected			-3	-3	2.9	46.09
c.1022G>A	G341D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G341D is not reported in ClinVar (ClinVar ID: None) but is present in gnomAD (ID: 6-33437927‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, FATHMM, and AlphaMissense‑Default. The remaining tools—Foldetta, AlphaMissense‑Optimized, ESM1b, and Rosetta—return uncertain or inconclusive results and are treated as unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Considering the majority of standard tools lean benign but the high‑accuracy consensus indicates pathogenicity, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.356642	Structured	0.431164	Uncertain	0.745	0.479	0.250				6-33437927-G-A	6	3.72e-6	-7.402	In-Between	0.871	Likely Pathogenic	Ambiguous	0.295	Likely Benign	0.1727	0.2241		0.28	Likely Benign	0.1	-1.32	Ambiguous	-0.52	Ambiguous	-0.04	Likely Benign	-0.11	Neutral	0.454	Possibly Damaging	0.192	Benign	0.34	Pathogenic	0.25	Tolerated	3.42	13	-1	1	-3.1	58.04
c.1022G>C	G341A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G341A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come only from polyPhen‑2 HumDiv and FATHMM. Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains inconclusive. Overall, the preponderance of evidence indicates that G341A 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	0.356642	Structured	0.431164	Uncertain	0.745	0.479	0.250							-3.211	Likely Benign	0.109	Likely Benign	Likely Benign	0.239	Likely Benign	0.3562	0.3979		0.16	Likely Benign	0.4	-1.23	Ambiguous	-0.54	Ambiguous	-0.03	Likely Benign	-1.13	Neutral	0.625	Possibly Damaging	0.192	Benign	0.43	Pathogenic	0.15	Tolerated			1	0	2.2	14.03
c.1022G>T	G341V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G341V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, polyPhen‑2 HumVar, and the SGM‑Consensus score (derived from a majority of benign calls among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as uncertain. No evidence from FoldX or premPS is available. Overall, the majority of predictions support a benign classification, and this is consistent with the lack of ClinVar annotation. Therefore, the variant is most likely benign and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.356642	Structured	0.431164	Uncertain	0.745	0.479	0.250							-5.371	Likely Benign	0.247	Likely Benign	Likely Benign	0.459	Likely Benign	0.1019	0.3649		0.86	Ambiguous	0.3	-2.24	Stabilizing	-0.69	Ambiguous	-0.50	Ambiguous	-2.29	Neutral	0.801	Possibly Damaging	0.192	Benign	0.42	Pathogenic	0.05	Affected			-1	-3	4.6	42.08
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	0.192	Likely Benign	0.2886	0.3625		1.80	Ambiguous	0.3	0.78	Ambiguous	1.29	Ambiguous	0.78	Ambiguous	-3.36	Deleterious	0.653	Possibly Damaging	0.226	Benign	4.07	Benign	0.04	Affected			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	0.204	Likely Benign	0.3147	0.3037		2.21	Destabilizing	0.3	1.58	Ambiguous	1.90	Ambiguous	0.92	Ambiguous	-4.78	Deleterious	0.653	Possibly Damaging	0.293	Benign	4.03	Benign	0.04	Affected			-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	0.313	Likely Benign	0.3553	0.2921		0.44	Likely Benign	0.1	0.40	Likely Benign	0.42	Likely Benign	0.69	Ambiguous	-5.70	Deleterious	0.999	Probably Damaging	0.825	Possibly Damaging	3.98	Benign	0.00	Affected	3.41	15	-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	0.155	Likely Benign	0.2955	0.1961		2.53	Destabilizing	0.7	0.71	Ambiguous	1.62	Ambiguous	0.82	Ambiguous	-3.17	Deleterious	0.995	Probably Damaging	0.778	Possibly Damaging	4.04	Benign	0.05	Affected	3.41	15	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	0.350	Likely Benign	0.2215	0.4099		3.06	Destabilizing	0.2	4.99	Destabilizing	4.03	Destabilizing	0.73	Ambiguous	-4.28	Deleterious	0.902	Possibly Damaging	0.544	Possibly Damaging	4.00	Benign	0.01	Affected			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	0.219	Likely Benign	0.1827	0.4121		-0.09	Likely Benign	0.4	0.53	Ambiguous	0.22	Likely Benign	0.54	Ambiguous	-4.81	Deleterious	0.653	Possibly Damaging	0.361	Benign	4.02	Benign	0.01	Affected			-3	-2	8.3	-43.03
c.1075A>C	T359P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T359P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Uncertain or inconclusive results come from 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 benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. 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	0.281712	Structured	0.414952	Uncertain	0.939	0.480	0.250							-6.884	Likely Benign	0.319	Likely Benign	Likely Benign	0.248	Likely Benign	0.2352	0.5611		0.97	Ambiguous	0.1	1.27	Ambiguous	1.12	Ambiguous	0.68	Ambiguous	-2.36	Neutral	0.627	Possibly Damaging	0.091	Benign	1.78	Pathogenic	0.14	Tolerated			0	-1	-0.9	-3.99
c.1075A>G	T359A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T359A 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome, while Rosetta remains uncertain. 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) predicts benign. 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.	Likely Benign	C2	0.281712	Structured	0.414952	Uncertain	0.939	0.480	0.250							-2.948	Likely Benign	0.062	Likely Benign	Likely Benign	0.103	Likely Benign	0.4215	0.4713		0.09	Likely Benign	0.0	0.73	Ambiguous	0.41	Likely Benign	0.45	Likely Benign	-0.73	Neutral	0.000	Benign	0.001	Benign	1.79	Pathogenic	0.34	Tolerated			1	0	2.5	-30.03
c.1075A>T	T359S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T359S is not reported in ClinVar (no ClinVar ID) 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, while FoldX, Rosetta, Foldetta, and premPS are inconclusive. 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. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is uncertain. 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	0.281712	Structured	0.414952	Uncertain	0.939	0.480	0.250							-4.624	Likely Benign	0.091	Likely Benign	Likely Benign	0.100	Likely Benign	0.3637	0.4996		0.50	Ambiguous	0.0	0.73	Ambiguous	0.62	Ambiguous	0.66	Ambiguous	-1.87	Neutral	0.146	Benign	0.024	Benign	1.76	Pathogenic	0.27	Tolerated			1	1	-0.1	-14.03
c.1076C>A	T359K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T359K 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. The remaining tools—FoldX, Rosetta, premPS, and AlphaMissense‑Default—return 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 benign. Overall, the majority of predictions (seven benign vs. two pathogenic) support a benign classification, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.281712	Structured	0.414952	Uncertain	0.939	0.480	0.250							-10.822	Likely Pathogenic	0.517	Ambiguous	Likely Benign	0.163	Likely Benign	0.1618	0.3483		-0.65	Ambiguous	0.1	0.66	Ambiguous	0.01	Likely Benign	0.75	Ambiguous	-2.23	Neutral	0.255	Benign	0.045	Benign	1.79	Pathogenic	0.24	Tolerated			0	-1	-3.2	27.07
c.1076C>G	T359R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T359R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign effects include REVEL, Rosetta, Foldetta, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. Uncertain results come from FoldX, premPS, 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. Overall, more tools favor a benign outcome, but a significant minority predict pathogenicity, leaving the variant’s clinical significance unresolved. The variant is most likely benign based on the prevailing predictions, and this 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	0.281712	Structured	0.414952	Uncertain	0.939	0.480	0.250							-8.675	Likely Pathogenic	0.402	Ambiguous	Likely Benign	0.157	Likely Benign	0.1323	0.3748		-0.74	Ambiguous	0.1	-0.20	Likely Benign	-0.47	Likely Benign	0.54	Ambiguous	-2.86	Deleterious	0.627	Possibly Damaging	0.091	Benign	1.75	Pathogenic	0.23	Tolerated			-1	-1	-3.8	55.08
c.1076C>T	T359I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T359I is reported in gnomAD (variant ID 6‑33437981‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. Uncertain results are reported for 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 Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign effect. There is no ClinVar status to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.281712	Structured	0.414952	Uncertain	0.939	0.480	0.250				6-33437981-C-T	1	6.22e-7	-2.594	Likely Benign	0.181	Likely Benign	Likely Benign	0.085	Likely Benign	0.1123	0.5921		-0.66	Ambiguous	0.1	-0.64	Ambiguous	-0.65	Ambiguous	-0.63	Ambiguous	0.77	Neutral	0.070	Benign	0.006	Benign	1.80	Pathogenic	0.23	Tolerated	3.38	24	-1	0	5.2	12.05
c.2170G>A	A724T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A724T missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that indicate a benign effect include REVEL, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Predictions that are inconclusive are AlphaMissense‑Default, FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the 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 tools (seven pathogenic vs. three benign) suggest a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, as there is no existing classification to contradict. 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.	Likely Pathogenic	GAP	0.476583	Structured	0.458050	Uncertain	0.923	0.483	0.250							-8.047	Likely Pathogenic	0.456	Ambiguous	Likely Benign	0.273	Likely Benign	0.1149	0.5897		0.95	Ambiguous	0.1	1.10	Ambiguous	1.03	Ambiguous	0.40	Likely Benign	-2.87	Deleterious	0.998	Probably Damaging	0.993	Probably Damaging	2.09	Pathogenic	0.01	Affected			1	0	-2.5	30.03
c.2170G>C	A724P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A724P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: REVEL predicts a benign effect, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS [uncertain], PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a pathogenic score; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, classifies the variant as pathogenic. No tool suggests a benign outcome, and the single benign prediction (REVEL) is outweighed by the consensus of pathogenic predictions. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this mutation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.476583	Structured	0.458050	Uncertain	0.923	0.483	0.250							-12.817	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.391	Likely Benign	0.1642	0.4273		2.90	Destabilizing	0.3	6.35	Destabilizing	4.63	Destabilizing	0.52	Ambiguous	-3.88	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	2.04	Pathogenic	0.04	Affected			1	-1	-3.4	26.04
c.2170G>T	A724S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A724S 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, and AlphaMissense‑Optimized. 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 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 outputs, is uncertain. Overall, the majority of evidence points to a benign impact for A724S, 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	GAP	0.476583	Structured	0.458050	Uncertain	0.923	0.483	0.250							-6.893	Likely Benign	0.204	Likely Benign	Likely Benign	0.265	Likely Benign	0.2308	0.4518		0.93	Ambiguous	0.1	0.88	Ambiguous	0.91	Ambiguous	0.57	Ambiguous	-1.68	Neutral	0.983	Probably Damaging	0.993	Probably Damaging	2.20	Pathogenic	0.25	Tolerated			1	1	-2.6	16.00
c.2171C>A	A724D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A724D is not reported in ClinVar or gnomAD. Prediction tools that indicate a benign effect include REVEL, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. Four methods (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for A724D, 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	GAP	0.476583	Structured	0.458050	Uncertain	0.923	0.483	0.250							-12.233	Likely Pathogenic	0.977	Likely Pathogenic	Likely Pathogenic	0.335	Likely Benign	0.1596	0.1812		1.06	Ambiguous	0.2	0.86	Ambiguous	0.96	Ambiguous	0.60	Ambiguous	-4.44	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	2.03	Pathogenic	0.00	Affected			0	-2	-5.3	44.01
c.2171C>G	A724G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A724G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall distribution of 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	GAP	0.476583	Structured	0.458050	Uncertain	0.923	0.483	0.250							-8.908	Likely Pathogenic	0.580	Likely Pathogenic	Likely Benign	0.286	Likely Benign	0.2001	0.3609		1.45	Ambiguous	0.1	1.73	Ambiguous	1.59	Ambiguous	0.56	Ambiguous	-3.10	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	2.07	Pathogenic	0.08	Tolerated			1	0	-2.2	-14.03
c.2171C>T	A724V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A724V missense variant 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, Foldetta, premPS, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by 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, classifies the variant as likely pathogenic. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign, SGM Consensus predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. With no ClinVar annotation, there is no contradiction between the predictions and existing clinical data. Overall, the evidence is mixed, but the majority of high‑confidence tools lean toward a benign effect, suggesting the variant is most likely benign rather than pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	GAP	0.476583	Structured	0.458050	Uncertain	0.923	0.483	0.250							-9.000	Likely Pathogenic	0.471	Ambiguous	Likely Benign	0.241	Likely Benign	0.0872	0.5620		0.42	Likely Benign	0.1	0.35	Likely Benign	0.39	Likely Benign	0.24	Likely Benign	-3.28	Deleterious	0.999	Probably Damaging	0.988	Probably Damaging	2.07	Pathogenic	0.01	Affected			0	0	2.4	28.05
c.1018G>A	A340T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A340T is reported in gnomAD (ID 6‑33437923‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus all classify the change as benign or likely benign. Only two tools predict pathogenicity—polyPhen‑2 HumDiv and FATHMM—while stability‑based methods (FoldX, Rosetta, premPS, Foldetta) return uncertain or inconclusive results. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign, and Foldetta provides no definitive stability change. 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.	Likely Benign	C2	0.390993	Structured	0.410781	Uncertain	0.558	0.485	0.250				6-33437923-G-A			-3.286	Likely Benign	0.086	Likely Benign	Likely Benign	0.105	Likely Benign	0.1740	0.7297		0.84	Ambiguous	0.2	0.96	Ambiguous	0.90	Ambiguous	-0.54	Ambiguous	0.62	Neutral	0.454	Possibly Damaging	0.192	Benign	1.93	Pathogenic	0.47	Tolerated	3.42	13	0	1	-2.5	30.03
c.1018G>C	A340P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A340P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The high‑accuracy predictors—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta—each report a benign outcome. No prediction or folding‑stability result is missing or inconclusive; all available evidence points to a benign impact. Consequently, the variant is most likely benign 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 Benign	C2	0.390993	Structured	0.410781	Uncertain	0.558	0.485	0.250							-4.983	Likely Benign	0.264	Likely Benign	Likely Benign	0.279	Likely Benign	0.2178	0.5468		0.32	Likely Benign	0.5	-0.58	Ambiguous	-0.13	Likely Benign	0.46	Likely Benign	-1.48	Neutral	0.891	Possibly Damaging	0.575	Possibly Damaging	1.91	Pathogenic	0.25	Tolerated			1	-1	-3.4	26.04
c.1018G>T	A340S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A340S is reported in gnomAD (variant ID 6‑33437923‑G‑T) but has no ClinVar entry. 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, while only FATHMM predicts pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign majority (3 benign vs. 1 pathogenic). High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign; the SGM‑Consensus is benign; 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 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	0.390993	Structured	0.410781	Uncertain	0.558	0.485	0.250				6-33437923-G-T	1	6.20e-7	-0.705	Likely Benign	0.083	Likely Benign	Likely Benign	0.083	Likely Benign	0.2852	0.6309		0.15	Likely Benign	0.0	0.27	Likely Benign	0.21	Likely Benign	-0.46	Likely Benign	1.62	Neutral	0.007	Benign	0.008	Benign	1.93	Pathogenic	0.51	Tolerated	3.42	13	1	1	-2.6	16.00
c.1019C>A	A340E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A340E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic outcome, while the protein‑folding stability method Foldetta is uncertain. AlphaMissense‑Optimized also yields an uncertain result. Overall, the majority of evidence points toward a pathogenic impact, and this 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	0.390993	Structured	0.410781	Uncertain	0.558	0.485	0.250							-8.225	Likely Pathogenic	0.803	Likely Pathogenic	Ambiguous	0.138	Likely Benign	0.1418	0.2160		0.63	Ambiguous	0.4	1.55	Ambiguous	1.09	Ambiguous	0.06	Likely Benign	-0.33	Neutral	0.625	Possibly Damaging	0.252	Benign	1.91	Pathogenic	0.39	Tolerated			0	-1	-5.3	58.04
c.1019C>G	A340G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A340G 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, 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). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictors indicate a benign effect, 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	C2	0.390993	Structured	0.410781	Uncertain	0.558	0.485	0.250							-3.763	Likely Benign	0.099	Likely Benign	Likely Benign	0.044	Likely Benign	0.2355	0.4470		0.66	Ambiguous	0.2	1.44	Ambiguous	1.05	Ambiguous	0.50	Likely Benign	-0.34	Neutral	0.267	Benign	0.127	Benign	1.92	Pathogenic	0.42	Tolerated			1	0	-2.2	-14.03
c.1019C>T	A340V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A340V variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. 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, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) is uncertain and therefore unavailable for interpretation. 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.	Likely Benign	C2	0.390993	Structured	0.410781	Uncertain	0.558	0.485	0.250							-6.427	Likely Benign	0.174	Likely Benign	Likely Benign	0.102	Likely Benign	0.1197	0.5780		0.69	Ambiguous	0.3	0.32	Likely Benign	0.51	Ambiguous	0.40	Likely Benign	-1.81	Neutral	0.801	Possibly Damaging	0.315	Benign	2.09	Pathogenic	0.57	Tolerated			0	0	2.4	28.05
c.1030G>A	G344S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344S is listed in ClinVar (ID 981240.0) as Pathogenic and is not reported in gnomAD. Prediction tools that assess pathogenicity all agree: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic; the only inconclusive result is premPS, which is marked Uncertain. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is 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	0.264545	Structured	0.368110	Uncertain	0.913	0.485	0.250	Pathogenic		5				-11.254	Likely Pathogenic	0.986	Likely Pathogenic	Likely Pathogenic	0.790	Likely Pathogenic	0.2735	0.5324		9.02	Destabilizing	0.7	6.08	Destabilizing	7.55	Destabilizing	0.98	Ambiguous	-5.28	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-0.45	Pathogenic	0.04	Affected	3.37	25	1	0	-0.4	30.03	217.3	-51.7	0.0	0.1	0.2	0.1			X				X	Potentially Pathogenic	Because Gly344 lacks a proper side chain, it allows the anti-parallel β sheet strand (res. Gly341-Pro349) to have a slight twist. Within a β strand, side chains normally alternate between outward and inward positions, but glycine is an exception as it allows the alternating pattern to skip a residue. Introducing serine or any other residue with a side chain at position 344 prevents this unique skip in the alternating pattern, causing structural strain or likely preventing correct folding altogether. Additionally, Tyr342 shields Gly344 from the solvent, contributing to twist formation in the β sheet and stabilizing the β-strand.In the variant simulations, the side chain of Ser344 assumes the inward position. However, the hydrophobic niche formed by multiple C2 domain residues (e.g., Val365, Val343, Leu327) is not accommodating for its hydroxyl group. The outward position, not seen in the simulations, would be equally disadvantageous due to the presence of hydrophobic residues on that side as well (e.g., Leu345, Tyr342). Serine is also not well-suited for twist formation, as it tends to suppress twisting and bending in β sheets. At this position, the hydroxyl group of Ser344 could also form hydrogen bonds with the backbone atoms of the Gly-rich Ω loop in the C2 domain (e.g., Thr366, Leu367, Gly378; res. Pro364-Pro398), potentially adversely affecting membrane-loop dynamics and ultimately compromising the stability of the SynGAP-membrane association.
c.1030G>C	G344R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344R 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 the only inconclusive result is premPS, which is listed as uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. Consequently, the variant is most likely pathogenic, and this assessment 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	0.264545	Structured	0.368110	Uncertain	0.913	0.485	0.250							-12.609	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.801	Likely Pathogenic	0.0844	0.4614		14.84	Destabilizing	0.8	13.66	Destabilizing	14.25	Destabilizing	0.81	Ambiguous	-7.17	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-0.49	Pathogenic	0.01	Affected			-3	-2	-4.1	99.14
c.1030G>T	G344C 2D AIThe SynGAP1 missense variant G344C is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic outcome include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy methods specifically show pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No tool predicts a benign effect. Based on the unanimous pathogenic predictions and the absence of any ClinVar or gnomAD evidence, the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.264545	Structured	0.368110	Uncertain	0.913	0.485	0.250							-12.880	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.794	Likely Pathogenic	0.1184	0.4788		8.52	Destabilizing	2.9	7.52	Destabilizing	8.02	Destabilizing	0.59	Ambiguous	-8.02	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-0.47	Pathogenic	0.01	Affected			-3	-3	2.9	46.09
c.1031G>A	G344D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools 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 change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the unanimous pathogenic predictions and the absence of 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	0.264545	Structured	0.368110	Uncertain	0.913	0.485	0.250							-12.527	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.897	Likely Pathogenic	0.1572	0.1574		14.53	Destabilizing	1.5	11.36	Destabilizing	12.95	Destabilizing	1.13	Destabilizing	-6.30	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-0.49	Pathogenic	0.01	Affected			1	-1	-3.1	58.04
c.1031G>C	G344A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G344A 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, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default, while only SIFT predicts a benign outcome. Two tools report uncertainty: premPS 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 consensus of the majority of predictors indicates 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	0.264545	Structured	0.368110	Uncertain	0.913	0.485	0.250							-10.439	Likely Pathogenic	0.931	Likely Pathogenic	Ambiguous	0.873	Likely Pathogenic	0.3964	0.5685		5.11	Destabilizing	0.4	4.23	Destabilizing	4.67	Destabilizing	0.58	Ambiguous	-5.38	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	-0.32	Pathogenic	0.10	Tolerated			1	0	2.2	14.03
c.1031G>T	G344V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344V 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 the only inconclusive result is premPS, which is listed as uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic status; 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	0.264545	Structured	0.368110	Uncertain	0.913	0.485	0.250							-14.913	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.889	Likely Pathogenic	0.1244	0.4744		13.33	Destabilizing	1.5	14.51	Destabilizing	13.92	Destabilizing	0.53	Ambiguous	-7.97	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	-0.48	Pathogenic	0.03	Affected			-1	-3	4.6	42.08
c.592C>A	L198I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198I 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 REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain or inconclusive results come from AlphaMissense‑Default, FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, 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 does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.			0.444081	Structured	0.431715	Uncertain	0.572	0.485	0.125							-10.411	Likely Pathogenic	0.563	Ambiguous	Likely Benign	0.234	Likely Benign	0.0921	0.3307		0.59	Ambiguous	0.1	0.70	Ambiguous	0.65	Ambiguous	0.10	Likely Benign	-1.72	Neutral	0.990	Probably Damaging	0.760	Possibly Damaging	3.43	Benign	0.00	Affected			2	2	0.7	0.00
c.592C>G	L198V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L198V variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are 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, is labeled Likely Pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (3 pathogenic vs. 1 benign) indicates pathogenicity; Foldetta remains uncertain. Overall, the majority of evaluated tools predict a pathogenic impact, and this is not contradicted by any ClinVar annotation (none exists). Thus, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.444081	Structured	0.431715	Uncertain	0.572	0.485	0.125							-9.343	Likely Pathogenic	0.747	Likely Pathogenic	Likely Benign	0.265	Likely Benign	0.1520	0.3017		1.10	Ambiguous	0.2	1.24	Ambiguous	1.17	Ambiguous	0.34	Likely Benign	-2.54	Deleterious	0.990	Probably Damaging	0.675	Possibly Damaging	3.44	Benign	0.00	Affected			2	1	0.4	-14.03
c.592C>T	L198F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198F has no ClinVar entry and is absent from gnomAD. Functional prediction tools split into two consensus groups: benign predictions come from REVEL, Rosetta, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments are mixed: AlphaMissense‑Optimized and Foldetta report uncertain results, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect. No evidence from ClinVar contradicts these findings. Overall, the preponderance of pathogenic predictions and the SGM‑Consensus designation suggest that the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.444081	Structured	0.431715	Uncertain	0.572	0.485	0.125							-10.602	Likely Pathogenic	0.930	Likely Pathogenic	Ambiguous	0.282	Likely Benign	0.0586	0.3112		1.03	Ambiguous	0.2	0.27	Likely Benign	0.65	Ambiguous	0.00	Likely Benign	-3.33	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	3.39	Benign	0.00	Affected			2	0	-1.0	34.02
c.593T>A	L198H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain. 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 L198H. 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		0.444081	Structured	0.431715	Uncertain	0.572	0.485	0.125							-15.650	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	0.419	Likely Benign	0.1057	0.0519		1.09	Ambiguous	0.2	1.04	Ambiguous	1.07	Ambiguous	0.74	Ambiguous	-5.91	Deleterious	0.999	Probably Damaging	0.936	Probably Damaging	3.33	Benign	0.00	Affected			-2	-3	-7.0	23.98
c.593T>C	L198P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198P has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX, Foldetta, and premPS are inconclusive. 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 majority of evidence points toward a deleterious effect. Thus, 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		0.444081	Structured	0.431715	Uncertain	0.572	0.485	0.125							-12.250	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.491	Likely Benign	0.3882	0.1582		1.55	Ambiguous	0.3	0.40	Likely Benign	0.98	Ambiguous	0.65	Ambiguous	-5.87	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	3.33	Benign	0.00	Affected			-3	-3	-5.4	-16.04
c.593T>G	L198R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198R 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 and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from multiple in‑silico 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		0.444081	Structured	0.431715	Uncertain	0.572	0.485	0.125							-15.992	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	0.410	Likely Benign	0.1180	0.0719		0.74	Ambiguous	0.2	1.56	Ambiguous	1.15	Ambiguous	0.69	Ambiguous	-4.98	Deleterious	0.982	Probably Damaging	0.648	Possibly Damaging	3.34	Benign	0.00	Affected			-3	-2	-8.3	43.03
c.1024T>A	Y342N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y342N has no ClinVar entry (ClinVar status: None) and is not reported in gnomAD (gnomAD ID: None). Prediction tools that assess the variant’s effect are overwhelmingly in agreement that it is deleterious: SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Taken together, 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	0.366687	Structured	0.408200	Uncertain	0.866	0.487	0.250							-9.685	Likely Pathogenic	0.940	Likely Pathogenic	Ambiguous	0.554	Likely Pathogenic	0.2189	0.0862		1.76	Ambiguous	0.1	2.89	Destabilizing	2.33	Destabilizing	1.02	Destabilizing	-6.65	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.71	Pathogenic	0.03	Affected			-2	-2	-2.2	-49.07
c.1024T>C	Y342H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y342H is reported in gnomAD (ID 6‑33437929‑T‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. Five tools predict pathogenicity versus three predicting benign, with the remaining five (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) yielding uncertain or inconclusive results. High‑accuracy assessments further support a deleterious effect: 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 uncertain. Overall, the preponderance of evidence indicates that Y342H is most likely pathogenic, and this conclusion is not contradicted by 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	0.366687	Structured	0.408200	Uncertain	0.866	0.487	0.250				6-33437929-T-C	1	6.20e-7	-6.459	Likely Benign	0.944	Likely Pathogenic	Ambiguous	0.453	Likely Benign	0.2491	0.0862		1.63	Ambiguous	0.1	1.33	Ambiguous	1.48	Ambiguous	0.73	Ambiguous	-3.61	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.72	Pathogenic	0.06	Tolerated	3.37	25	2	0	-1.9	-26.03
c.1024T>G	Y342D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y342D is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and SIFT, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict it to be pathogenic. FoldX reports an uncertain effect, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta is pathogenic. Based on the preponderance of pathogenic predictions and the absence of benign evidence, the variant is most likely pathogenic, and this conclusion 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	0.366687	Structured	0.408200	Uncertain	0.866	0.487	0.250							-10.940	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	0.668	Likely Pathogenic	0.3925	0.0862		1.60	Ambiguous	0.1	2.70	Destabilizing	2.15	Destabilizing	0.13	Likely Benign	-7.19	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.71	Pathogenic	0.07	Tolerated			-4	-3	-2.2	-48.09
c.1025A>C	Y342S 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant Y342S is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of algorithms predict a pathogenic impact: FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and the Foldetta stability assessment (combining FoldX‑MD and Rosetta). Uncertain results come from premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy methods specifically give AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as pathogenic. Overall, the preponderance of evidence points to a pathogenic effect, which contradicts the ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.366687	Structured	0.408200	Uncertain	0.866	0.487	0.250	Uncertain		2				-7.996	In-Between	0.925	Likely Pathogenic	Ambiguous	0.407	Likely Benign	0.4617	0.2637		3.03	Destabilizing	0.1	2.87	Destabilizing	2.95	Destabilizing	0.93	Ambiguous	-6.60	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.75	Pathogenic	0.04	Affected	3.37	25	-3	-2	0.5	-76.10	200.1	77.8	0.0	0.0	-0.2	0.1								Potentially Pathogenic	The phenol ring of Tyr342, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), faces outward in the C2 domain. In the WT simulations, the phenol ring of Tyr342 contributes to a triple tyrosine stack (Tyr342, Tyr328, and Tyr281) that links together three anti-parallel β sheet strands. Additionally, it shields Gly344 from the solvent, reducing its exposure and providing stability for the β-sandwich. This motif also contributes to a twist formation in the β sheet.In the variant simulations, the Ser342 side chain cannot participate in the stack formation. Instead, the hydroxyl group of the Ser342 side chain forms a hydrogen bond with the imidazole ring of His326 in a neighboring β strand (res. Ala322-Asp330). This disrupts the formation of a hydrogen bond between His326 and the carboxylate group of the Glu283 side chain from another β strand (res. Arg279-Cys285). Although these changes in surface interactions could weaken the characteristic twist that strengthens the β sheet fold, no major structural effects are observed in the variant simulations. The residue swap could also affect the SynGAP-membrane association, as the hydroxyl group of Ser342 could form hydrogen bonds with membrane-facing loop residues. However, this phenomenon cannot be addressed using solvent-only simulations.
c.1025A>G	Y342C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y342C is listed in ClinVar as Benign (ClinVar ID 1213078.0) and is observed in gnomAD (ID 6‑33437930‑A‑G). Across general prediction tools, benign calls are made by REVEL and AlphaMissense‑Optimized, whereas pathogenic calls are made by FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by premPS and ESM1b. 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 Pathogenic. Overall, the majority of predictions support a pathogenic effect, contradicting the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.366687	Structured	0.408200	Uncertain	0.866	0.487	0.250	Benign/Likely benign		2	6-33437930-A-G	21	1.30e-5	-7.596	In-Between	0.682	Likely Pathogenic	Likely Benign	0.404	Likely Benign	0.2836	0.2870		2.48	Destabilizing	0.1	2.73	Destabilizing	2.61	Destabilizing	0.92	Ambiguous	-6.67	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.72	Pathogenic	0.02	Affected	3.37	25	0	-2	3.8	-60.04	242.4	62.8	0.1	0.0	-0.1	0.2								Potentially Pathogenic	The phenol ring of Tyr342, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), faces outward in the C2 domain. This phenol ring contributes to a triple tyrosine stack (Tyr342, Tyr328, and Tyr281) that links together three anti-parallel β sheet strands. Additionally, it shields Gly344 from the solvent, reducing its exposure and providing stability for the β-sandwich. This motif also contributes to a twist formation in the β sheet.In the variant simulations, the Cys342 side chain cannot participate in the stack formation. Instead, its thiol group forms a hydrogen bond with the backbone carbonyl group of Leu327. Although these changes in surface interactions could weaken the characteristic twist that strengthens the β sheet fold, no major structural effects are observed in the variant simulations. The residue swap could also affect the SynGAP-membrane association; however, this phenomenon cannot be addressed using solvent-only simulations. Notably, the thiol group of cysteine is not a particularly strong hydrogen-bonding partner, which could mitigate the negative effects of the residue swap.
c.1025A>T	Y342F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y342F 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 and therefore treated as unavailable. Overall, the majority of evidence points to a benign impact. 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.		C2	0.366687	Structured	0.408200	Uncertain	0.866	0.487	0.250							-6.987	Likely Benign	0.145	Likely Benign	Likely Benign	0.160	Likely Benign	0.2626	0.3615		-0.13	Likely Benign	0.1	0.42	Likely Benign	0.15	Likely Benign	0.05	Likely Benign	-2.67	Deleterious	0.999	Probably Damaging	0.992	Probably Damaging	2.03	Pathogenic	0.26	Tolerated			7	3	4.1	-16.00
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	0.350	Likely Benign	0.1252	0.4263		1.61	Ambiguous	0.2	0.59	Ambiguous	1.10	Ambiguous	0.59	Ambiguous	-3.46	Deleterious	0.980	Probably Damaging	0.721	Possibly Damaging	1.01	Pathogenic	0.02	Affected			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	0.425	Likely Benign	0.1608	0.4843		2.29	Destabilizing	0.6	1.32	Ambiguous	1.81	Ambiguous	0.61	Ambiguous	-4.67	Deleterious	0.998	Probably Damaging	0.961	Probably Damaging	0.96	Pathogenic	0.01	Affected			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	0.472	Likely Benign	0.0539	0.4689		1.98	Ambiguous	0.6	2.90	Destabilizing	2.44	Destabilizing	0.35	Likely Benign	-6.47	Deleterious	0.998	Probably Damaging	0.948	Probably Damaging	0.89	Pathogenic	0.00	Affected			-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	0.399	Likely Benign	0.4087	0.4476		1.75	Ambiguous	0.3	1.06	Ambiguous	1.41	Ambiguous	0.60	Ambiguous	-5.49	Deleterious	0.961	Probably Damaging	0.655	Possibly Damaging	0.93	Pathogenic	0.11	Tolerated			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	0.373	Likely Benign	0.3935	0.5015		2.69	Destabilizing	0.2	2.17	Destabilizing	2.43	Destabilizing	0.63	Ambiguous	-5.03	Deleterious	0.980	Probably Damaging	0.782	Possibly Damaging	0.94	Pathogenic	0.01	Affected			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	0.428	Likely Benign	0.0862	0.4633		2.06	Destabilizing	0.5	0.57	Ambiguous	1.32	Ambiguous	0.45	Likely Benign	-6.40	Deleterious	0.994	Probably Damaging	0.892	Possibly Damaging	0.89	Pathogenic	0.01	Affected			-2	-3	7.7	-15.96
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	0.073	Likely Benign	0.1464	0.4416		0.98	Ambiguous	0.2	2.31	Destabilizing	1.65	Ambiguous	0.39	Likely Benign	-1.38	Neutral	0.122	Benign	0.030	Benign	0.97	Pathogenic	0.67	Tolerated			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	0.075	Likely Benign	0.1464	0.4416		0.98	Ambiguous	0.2	2.31	Destabilizing	1.65	Ambiguous	0.39	Likely Benign	-1.38	Neutral	0.122	Benign	0.030	Benign	0.97	Pathogenic	0.67	Tolerated			3	2	0.0	14.03
c.1195G>A	A399T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399T is listed in ClinVar (ID 1990638.0) as Benign and is not reported in gnomAD. 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 evidence. 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 Uncertain. Overall, the variant is most likely benign, and this conclusion aligns with its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.394753	Structured	0.407674	Uncertain	0.939	0.490	0.125	Benign		1				-5.236	Likely Benign	0.114	Likely Benign	Likely Benign	0.272	Likely Benign	0.1335	0.6477		1.24	Ambiguous	0.1	0.91	Ambiguous	1.08	Ambiguous	0.49	Likely Benign	-0.40	Neutral	0.131	Benign	0.039	Benign	5.41	Benign	0.69	Tolerated	3.38	26	1	0	-2.5	30.03	211.4	-41.4	0.0	0.0	0.6	0.4		X						Potentially Pathogenic	The methyl group of Ala399, located in an anti-parallel β sheet strand (res. Ala399-Ile411), is swapped for a hydroxyl-containing threonine. In the variant simulations, the hydroxyl group of Thr399 can form H-bonds with the backbone atoms of the residues in the membrane-facing loops (e.g., Gly382) in the C2 domain. Consequently, the ability of the Thr399 side chain to form H-bonds with the membrane-facing loops could adversely affect the dynamics and stability of the SynGAP-membrane association. However, since the effects on the dynamics of the membrane-facing loops can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn.
c.1195G>C	A399P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A399P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, FATHMM, and polyPhen‑2 HumVar; pathogenic predictions come from FoldX, Rosetta, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a pathogenic effect. Overall, the majority of evidence points toward a deleterious impact. The variant is most likely pathogenic based on the available predictions, 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.		C2	0.394753	Structured	0.407674	Uncertain	0.939	0.490	0.125							-8.809	Likely Pathogenic	0.942	Likely Pathogenic	Ambiguous	0.498	Likely Benign	0.1847	0.5472		2.29	Destabilizing	0.1	4.00	Destabilizing	3.15	Destabilizing	0.74	Ambiguous	-1.82	Neutral	0.596	Possibly Damaging	0.188	Benign	5.56	Benign	0.10	Tolerated			1	-1	-3.4	26.04
c.1195G>T	A399S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect, while FoldX, Rosetta, and Foldetta are inconclusive. Grouping by agreement, all available predictors fall into the benign category; none predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, whereas Foldetta’s stability analysis remains uncertain. 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	0.394753	Structured	0.407674	Uncertain	0.939	0.490	0.125							-4.256	Likely Benign	0.100	Likely Benign	Likely Benign	0.161	Likely Benign	0.2494	0.4897		0.65	Ambiguous	0.1	1.13	Ambiguous	0.89	Ambiguous	-0.33	Likely Benign	0.81	Neutral	0.001	Benign	0.001	Benign	5.65	Benign	0.86	Tolerated			1	1	-2.6	16.00
c.1196C>A	A399D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399D 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 PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, FoldX, SIFT, ESM1b, and AlphaMissense‑Default. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized—return uncertain or inconclusive results. High‑accuracy methods give no definitive verdict: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie and thus unavailable, and Foldetta is uncertain. Overall, the majority of available predictions (five pathogenic vs. four benign) lean toward pathogenicity. 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.		C2	0.394753	Structured	0.407674	Uncertain	0.939	0.490	0.125							-10.441	Likely Pathogenic	0.943	Likely Pathogenic	Ambiguous	0.525	Likely Pathogenic	0.1533	0.1760		2.45	Destabilizing	0.2	1.17	Ambiguous	1.81	Ambiguous	0.91	Ambiguous	-1.84	Neutral	0.421	Benign	0.054	Benign	5.38	Benign	0.05	Affected			0	-2	-5.3	44.01
c.1196C>G	A399G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399G is not reported in ClinVar and is absent from gnomAD. Across a panel of in silico predictors, all available pathogenicity scores classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. Uncertain results from FoldX, Rosetta, Foldetta, and premPS are treated as unavailable. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore not considered evidence. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.394753	Structured	0.407674	Uncertain	0.939	0.490	0.125							-6.513	Likely Benign	0.215	Likely Benign	Likely Benign	0.153	Likely Benign	0.2174	0.4532		1.03	Ambiguous	0.1	1.77	Ambiguous	1.40	Ambiguous	0.74	Ambiguous	-1.59	Neutral	0.062	Benign	0.024	Benign	5.39	Benign	0.13	Tolerated			1	0	-2.2	-14.03
c.1196C>T	A399V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399V 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). No tool predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the evidence overwhelmingly supports a benign classification, and this is consistent with the lack of ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.394753	Structured	0.407674	Uncertain	0.939	0.490	0.125							-4.943	Likely Benign	0.170	Likely Benign	Likely Benign	0.305	Likely Benign	0.1145	0.6807		0.49	Likely Benign	0.2	0.56	Ambiguous	0.53	Ambiguous	0.22	Likely Benign	-1.18	Neutral	0.421	Benign	0.073	Benign	5.37	Benign	0.24	Tolerated			0	0	2.4	28.05
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	0.320	Likely Benign	0.0806	0.3807		0.20	Likely Benign	0.0	0.72	Ambiguous	0.46	Likely Benign	1.07	Destabilizing	-1.61	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.53	Pathogenic	0.01	Affected			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	0.208	Likely Benign	0.1648	0.4206		1.38	Ambiguous	0.1	0.67	Ambiguous	1.03	Ambiguous	1.31	Destabilizing	-1.87	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	2.66	Benign	0.13	Tolerated	3.38	23	1	2	0.4	-14.03
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	0.605	Likely Pathogenic	0.1131	0.1042		3.03	Destabilizing	0.1	2.17	Destabilizing	2.60	Destabilizing	2.11	Destabilizing	-5.26	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.52	Pathogenic	0.00	Affected			-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	0.658	Likely Pathogenic	0.3921	0.1703		5.38	Destabilizing	0.1	4.00	Destabilizing	4.69	Destabilizing	2.62	Destabilizing	-5.97	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.52	Pathogenic	0.01	Affected	3.38	23	-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	0.619	Likely Pathogenic	0.1281	0.1085		4.46	Destabilizing	0.3	4.75	Destabilizing	4.61	Destabilizing	1.95	Destabilizing	-5.28	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.52	Pathogenic	0.00	Affected			-3	-2	-8.3	43.03
c.2173C>A	L725M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L725M 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 REVEL, FoldX, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Uncertain or inconclusive predictions come from Foldetta, premPS, AlphaMissense‑Default, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic (2 pathogenic vs. 1 benign). Foldetta remains uncertain and is not used as evidence. Overall, the majority of tools, including the high‑accuracy consensus, predict 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.			0.557691	Disordered	0.455613	Uncertain	0.911	0.491	0.625							-9.531	Likely Pathogenic	0.436	Ambiguous	Likely Benign	0.172	Likely Benign	0.0854	0.4156		0.42	Likely Benign	0.1	1.05	Ambiguous	0.74	Ambiguous	0.80	Ambiguous	-1.81	Neutral	1.000	Probably Damaging	1.000	Probably Damaging	1.32	Pathogenic	0.04	Affected			4	2	-1.9	18.03
c.2173C>G	L725V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L725V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The remaining methods (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) are inconclusive. 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 provides no definitive stability change. Overall, the majority of evidence points toward 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.	Likely Pathogenic		0.557691	Disordered	0.455613	Uncertain	0.911	0.491	0.625							-8.291	Likely Pathogenic	0.461	Ambiguous	Likely Benign	0.183	Likely Benign	0.1739	0.3977		1.76	Ambiguous	0.1	1.87	Ambiguous	1.82	Ambiguous	0.77	Ambiguous	-2.69	Deleterious	0.993	Probably Damaging	0.992	Probably Damaging	1.36	Pathogenic	0.01	Affected			2	1	0.4	-14.03
c.2174T>A	L725Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L725Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to REVEL, which scores the variant as benign. The majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, Rosetta, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain or inconclusive results come from FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion 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		0.557691	Disordered	0.455613	Uncertain	0.911	0.491	0.625							-13.952	Likely Pathogenic	0.888	Likely Pathogenic	Ambiguous	0.319	Likely Benign	0.1198	0.1203		1.55	Ambiguous	0.1	2.09	Destabilizing	1.82	Ambiguous	1.88	Destabilizing	-5.43	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.28	Pathogenic	0.00	Affected			-2	-2	-7.3	14.97
c.2174T>C	L725P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L725P 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. All other evaluated tools—FoldX, Rosetta, Foldetta, 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)—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) indicates 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 collective predictions, 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		0.557691	Disordered	0.455613	Uncertain	0.911	0.491	0.625							-15.390	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.396	Likely Benign	0.3796	0.1664		4.91	Destabilizing	0.1	9.02	Destabilizing	6.97	Destabilizing	1.82	Destabilizing	-6.08	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.28	Pathogenic	0.00	Affected			-3	-3	-5.4	-16.04
c.2174T>G	L725R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L725R 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. All other evaluated algorithms—polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, premPS, Rosetta, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—classify the variant as pathogenic. FoldX and Foldetta report uncertain results and are therefore not considered evidence for either side. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, while Foldetta remains uncertain. Based on the overwhelming majority of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, which is consistent with the absence of a ClinVar entry and gnomAD observation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.557691	Disordered	0.455613	Uncertain	0.911	0.491	0.625							-15.383	Likely Pathogenic	0.961	Likely Pathogenic	Likely Pathogenic	0.345	Likely Benign	0.1374	0.0846		0.69	Ambiguous	0.3	2.16	Destabilizing	1.43	Ambiguous	1.49	Destabilizing	-5.46	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.28	Pathogenic	0.00	Affected			-3	-2	-8.3	43.03
c.589G>A	E197K 2D AIThe SynGAP1 missense variant E197K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, whereas pathogenic calls arise from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized. Grouping by consensus, the majority of high‑confidence predictors (AlphaMissense‑Optimized, SGM‑Consensus, PROVEAN, SIFT, ESM1b) indicate pathogenicity, while a minority (REVEL, polyPhen‑2, FATHMM) suggest benign impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN, is classified as Likely Pathogenic. AlphaMissense‑Optimized also predicts Pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for E197K, and this assessment 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		0.349426	Structured	0.431896	Uncertain	0.452	0.492	0.125							-11.045	Likely Pathogenic	0.962	Likely Pathogenic	Likely Pathogenic	0.198	Likely Benign	0.1824	0.5890											-2.50	Deleterious	0.118	Benign	0.037	Benign	4.09	Benign	0.02	Affected			0	1	-0.4	-0.94
c.589G>C	E197Q 2D AIThe SynGAP1 E197Q variant 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. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and therefore reports a likely benign outcome. 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 impact, 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 Benign		0.349426	Structured	0.431896	Uncertain	0.452	0.492	0.125							-6.347	Likely Benign	0.723	Likely Pathogenic	Likely Benign	0.145	Likely Benign	0.0867	0.5228											-1.75	Neutral	0.396	Benign	0.067	Benign	4.05	Benign	0.02	Affected			2	2	0.0	-0.98
c.590A>C	E197A 2D AIThe SynGAP1 E197A 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. Two tools give uncertain results: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows that the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while AlphaMissense‑Optimized remains uncertain and Foldetta (which would combine FoldX‑MD and Rosetta outputs) has no available result. Overall, the balance of evidence—including the pathogenic majority in the high‑accuracy consensus—suggests that 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.			0.349426	Structured	0.431896	Uncertain	0.452	0.492	0.125							-7.956	In-Between	0.787	Likely Pathogenic	Ambiguous	0.155	Likely Benign	0.3134	0.5290											-3.56	Deleterious	0.055	Benign	0.016	Benign	4.06	Benign	0.02	Affected			0	-1	5.3	-58.04
c.590A>G	E197G 2D AIThe SynGAP1 missense variant E197G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign impact include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Pathogenic, while AlphaMissense‑Optimized remains benign; Foldetta results are unavailable. Overall, the majority of individual predictors lean toward pathogenicity, and the SGM‑Consensus supports this view. Therefore, 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		0.349426	Structured	0.431896	Uncertain	0.452	0.492	0.125							-8.480	Likely Pathogenic	0.749	Likely Pathogenic	Likely Benign	0.165	Likely Benign	0.2638	0.4615											-3.13	Deleterious	0.118	Benign	0.037	Benign	4.03	Benign	0.01	Affected			0	-2	3.1	-72.06
c.590A>T	E197V 2D AIThe SynGAP1 missense variant E197V is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split opinion: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. When predictions are grouped by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Taken together, the preponderance of evidence from both general and high‑accuracy predictors indicates that E197V 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		0.349426	Structured	0.431896	Uncertain	0.452	0.492	0.125							-9.023	Likely Pathogenic	0.932	Likely Pathogenic	Ambiguous	0.247	Likely Benign	0.0490	0.6024											-4.51	Deleterious	0.396	Benign	0.099	Benign	4.01	Benign	0.00	Affected			-2	-2	7.7	-29.98
c.591G>C	E197D 2D AIThe SynGAP1 missense variant E197D 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. 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 “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions strongly supports a benign classification, and this 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		0.349426	Structured	0.431896	Uncertain	0.452	0.492	0.125							0.784	Likely Benign	0.130	Likely Benign	Likely Benign	0.066	Likely Benign	0.1579	0.3345											1.81	Neutral	0.000	Benign	0.000	Benign	4.66	Benign	1.00	Tolerated			3	2	0.0	-14.03
c.591G>T	E197D 2D AIThe SynGAP1 missense variant E197D 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. 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 results are unavailable. Overall, the consensus of all available predictions strongly supports a benign classification, and this 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		0.349426	Structured	0.431896	Uncertain	0.452	0.492	0.125							0.784	Likely Benign	0.130	Likely Benign	Likely Benign	0.066	Likely Benign	0.1579	0.3345											1.81	Neutral	0.000	Benign	0.000	Benign	4.66	Benign	1.00	Tolerated			3	2	0.0	-14.03
c.1027G>A	V343I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V343I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33437932‑G‑A). Prediction tools that uniformly indicate 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. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments are consistent: AlphaMissense‑Optimized is benign; the SGM‑Consensus is likely benign; and Foldetta, combining FoldX‑MD and Rosetta outputs, is benign. Overall, the collective evidence strongly supports a benign classification, and this does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.291804	Structured	0.383911	Uncertain	0.882	0.497	0.250	Uncertain		2	6-33437932-G-A	1	6.20e-7	-6.020	Likely Benign	0.117	Likely Benign	Likely Benign	0.020	Likely Benign	0.1095	0.4536		-0.27	Likely Benign	0.0	-0.04	Likely Benign	-0.16	Likely Benign	-0.39	Likely Benign	-0.14	Neutral	0.159	Benign	0.084	Benign	1.98	Pathogenic	0.27	Tolerated	3.37	25	4	3	0.3	14.03	240.2	-26.9	-0.2	0.2	-0.2	0.2						X		Potentially Benign	The iso-propyl side chain of Val343, located in an anti-parallel β sheet strand (res. Gly341-Pro349), is packing against multiple hydrophobic residues of the C2 domain (e.g., Leu327, Leu274, Val365). In the variant simulations, the sec-butyl side chain of Ile343 is basically able to form the same interactions as valine due to its similar hydrophobic profile. The residue swap also does not seem to cause negative effects on the protein structure based on the simulations.