Data | SynGAP Server

c.dna	Variant	SGM Consensus	Domain and Structure information: based on WT protein												Annotated databases						Deep learning-based pathogenicity predictions					Folding stability-based pathogenicity predictions									Sequence/structure-based pathogenicity predictions														Phase Separation			Evolutionary/physical properties				Molecular Dynamics-based analysis															DOI
			Domain	IUPred2		ANCHOR2		AlphaFold		MobiDB	PhosphoSitePlus				ClinVar			gnomAD			ESM1b		AlphaMissense			FoldX			Rosetta		Foldetta		PremPS		REVEL		PROVEAN		PolyPhen-2 HumDiv		PolyPhen-2 HumVar		FATHMM		SIFT				PSMutPred			PAM		Physical		SASA		Normalized B-factor backbone		Normalized B-factor sidechain		SynGAP Structural Annotation
			Domain	Score	Prediction	Score	Prediction	pLDDT	disorder	disorder	LTP	HTP	KL	PTM	Clinical Status	Review	Subm.	ID	Allele count	Allele freq.	LLR score	Prediction	Pathogenicity	Class	Optimized	Average ΔΔG	Prediction	StdDev	ΔΔG	Prediction	ΔΔG	Prediction	ΔΔG	Prediction	Score	Prediction	Score	Prediction	pph2_prob	Prediction	pph2_prob	Prediction	Nervous System Score	Prediction	Prediction	Status	Conservation	Sequences	IP RF	SP RF	Prediction	PAM250	PAM120	Hydropathy Δ	MW Δ	Average	Δ	Δ	StdDev	Δ	StdDev	Secondary	Tertiary bonds	Inside out	GAP-Ras interface	At membrane	No effect	MD Alert	Verdict	Description
c.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	2.35	Destabilizing	0.5	0.04	Likely Benign	1.20	Ambiguous	0.67	Ambiguous	0.466	Likely Benign	-8.49	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	3.75	Benign	0.01	Affected	3.44	12	0.2219	0.6191		-3	-3	5.4	16.04													MD Alert	Verdict	Description
c.625G>A	V209M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V209M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Five tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.247041	Structured	0.397624	Uncertain	0.874	0.331	0.125											-8.112	Likely Pathogenic	0.932	Likely Pathogenic	Ambiguous	0.70	Ambiguous	0.4	0.77	Ambiguous	0.74	Ambiguous	0.78	Ambiguous	0.115	Likely Benign	-1.48	Neutral	0.995	Probably Damaging	0.880	Possibly Damaging	3.68	Benign	0.02	Affected			0.0669	0.3982		2	1	-2.3	32.06
c.626T>A	V209E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V209E is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas 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 predict a pathogenic outcome. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, V209E 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	PH	0.247041	Structured	0.397624	Uncertain	0.874	0.331	0.125											-14.366	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	3.53	Destabilizing	1.3	2.35	Destabilizing	2.94	Destabilizing	1.52	Destabilizing	0.403	Likely Benign	-4.54	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	3.65	Benign	0.00	Affected			0.0826	0.1652		-2	-2	-7.7	29.98
c.626T>C	V209A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V209A is reported in gnomAD (ID 6‑33435268‑T‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL and FATHMM. In contrast, a majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Stability‑based methods FoldX, Rosetta, and the combined Foldetta score are uncertain and therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that V209A 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	0.247041	Structured	0.397624	Uncertain	0.874	0.331	0.125								6-33435268-T-C	1	6.20e-7	-9.796	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	1.56	Ambiguous	0.3	1.85	Ambiguous	1.71	Ambiguous	1.60	Destabilizing	0.236	Likely Benign	-2.79	Deleterious	0.958	Probably Damaging	0.581	Possibly Damaging	3.70	Benign	0.02	Affected	3.41	13	0.2237	0.1919		0	0	-2.4	-28.05
c.626T>G	V209G 2D AIThe SynGAP1 missense variant V209G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are 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 methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a pathogenic classification; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. Taken together, the overwhelming majority of computational evidence indicates that V209G is 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.		PH	0.247041	Structured	0.397624	Uncertain	0.874	0.331	0.125											-13.763	Likely Pathogenic	0.988	Likely Pathogenic	Likely Pathogenic	3.05	Destabilizing	0.5	3.99	Destabilizing	3.52	Destabilizing	1.27	Destabilizing	0.390	Likely Benign	-5.49	Deleterious	0.829	Possibly Damaging	0.995	Probably Damaging	3.65	Benign	0.04	Affected			0.1600	0.2035		-1	-3	-4.6	-42.08
c.628C>A	H210N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H210N missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and FATHMM, while pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus score (Likely Pathogenic). Two tools give uncertain results: Foldetta (combining FoldX‑MD and Rosetta outputs) and Rosetta alone. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points toward a pathogenic effect for H210N. 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	PH	0.144935	Structured	0.390904	Uncertain	0.872	0.298	0.125											-13.699	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.19	Likely Benign	0.3	1.24	Ambiguous	0.72	Ambiguous	1.12	Destabilizing	0.375	Likely Benign	-6.01	Deleterious	0.895	Possibly Damaging	0.533	Possibly Damaging	3.11	Benign	0.00	Affected			0.1166	0.1839		2	1	-0.3	-23.04
c.628C>G	H210D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210D is 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. In contrast, the majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain, and Rosetta alone 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 H210D, 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	0.144935	Structured	0.390904	Uncertain	0.872	0.298	0.125											-16.440	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.13	Likely Benign	0.4	1.23	Ambiguous	0.68	Ambiguous	1.23	Destabilizing	0.489	Likely Benign	-7.73	Deleterious	0.895	Possibly Damaging	0.533	Possibly Damaging	3.18	Benign	0.00	Affected			0.2025	0.1255		1	-1	-0.3	-22.05
c.628C>T	H210Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H210Y 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 FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” 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 impact, and this conclusion does not contradict any ClinVar classification because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.144935	Structured	0.390904	Uncertain	0.872	0.298	0.125											-12.828	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	0.27	Likely Benign	0.8	0.38	Likely Benign	0.33	Likely Benign	0.39	Likely Benign	0.427	Likely Benign	-5.12	Deleterious	0.963	Probably Damaging	0.628	Possibly Damaging	3.07	Benign	0.00	Affected			0.0497	0.3662		0	2	1.9	26.03
c.629A>C	H210P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210P 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; all other evaluated algorithms—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 from 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 overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.144935	Structured	0.390904	Uncertain	0.872	0.298	0.125											-14.634	Likely Pathogenic	0.983	Likely Pathogenic	Likely Pathogenic	2.26	Destabilizing	0.5	2.80	Destabilizing	2.53	Destabilizing	1.00	Destabilizing	0.512	Likely Pathogenic	-8.55	Deleterious	0.989	Probably Damaging	0.795	Possibly Damaging	3.09	Benign	0.00	Affected			0.1805	0.3175		0	-2	1.6	-40.02
c.629A>G	H210R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H210R 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, FATHMM, and FoldX, whereas a majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The high‑accuracy AlphaMissense‑Optimized result is pathogenic; the SGM Consensus, based on the same set of predictors, is also pathogenic; Foldetta’s stability assessment is uncertain and therefore not considered evidence. Overall, the balance of evidence points to a pathogenic effect for H210R. This prediction does not contradict the ClinVar “Uncertain” classification, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.144935	Structured	0.390904	Uncertain	0.872	0.298	0.125					Uncertain		1				-14.254	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.40	Likely Benign	0.4	3.05	Destabilizing	1.73	Ambiguous	1.12	Destabilizing	0.431	Likely Benign	-6.74	Deleterious	0.808	Possibly Damaging	0.452	Possibly Damaging	3.09	Benign	0.00	Affected			0.1427	0.1982		2	0	-1.3	19.05
c.629A>T	H210L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H210L missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools cluster into two groups: benign predictions come from REVEL, Foldetta, premPS, and FATHMM, while pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta provide uncertain results. High‑accuracy assessments further highlight the discrepancy: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, whereas Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence points to 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	0.144935	Structured	0.390904	Uncertain	0.872	0.298	0.125											-14.516	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	-0.71	Ambiguous	0.1	1.35	Ambiguous	0.32	Likely Benign	0.49	Likely Benign	0.421	Likely Benign	-9.41	Deleterious	0.895	Possibly Damaging	0.614	Possibly Damaging	3.09	Benign	0.00	Affected			0.0617	0.4452		-2	-3	7.0	-23.98
c.62T>A	F21Y 2D AIThe SynGAP1 missense variant F21Y is listed in gnomAD (ID 6‑33420326‑T‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also indicates a likely benign classification. No Foldetta (FoldX‑MD/Rosetta stability) result is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for F21Y, and this conclusion is not contradicted by any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.534167	Disordered	0.443284	Uncertain	0.369	0.897	0.500								6-33420326-T-A			-3.712	Likely Benign	0.352	Ambiguous	Likely Benign										0.088	Likely Benign	-0.23	Neutral	0.273	Benign	0.153	Benign	4.15	Benign	0.00	Affected	4.32	1	0.1698	0.2608		3	7	-4.1	16.00
c.62T>C	F21S 2D AIThe SynGAP1 missense variant F21S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. 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 ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.534167	Disordered	0.443284	Uncertain	0.369	0.897	0.500											-2.396	Likely Benign	0.745	Likely Pathogenic	Likely Benign										0.182	Likely Benign	-0.22	Neutral	0.462	Possibly Damaging	0.307	Benign	4.15	Benign	0.00	Affected			0.4793	0.1133		-3	-2	-3.6	-60.10
c.62T>G	F21C 2D AIThe SynGAP1 missense variant F21C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for F21C. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.534167	Disordered	0.443284	Uncertain	0.369	0.897	0.500											-3.698	Likely Benign	0.686	Likely Pathogenic	Likely Benign										0.151	Likely Benign	-0.31	Neutral	0.880	Possibly Damaging	0.759	Possibly Damaging	4.12	Benign	0.00	Affected			0.2873	0.2171		-4	-2	-0.3	-44.04
c.630C>A	H210Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H210Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign calls come from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar) and FATHMM, whereas pathogenic calls are made by premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN, favors a pathogenic outcome (3/4). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote) also predicts pathogenic. Foldetta, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta, is inconclusive and therefore not used as evidence. Overall, the majority of reliable predictors indicate a pathogenic effect for H210Q, and this conclusion 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	PH	0.144935	Structured	0.390904	Uncertain	0.872	0.298	0.125											-12.639	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.26	Likely Benign	0.3	1.96	Ambiguous	1.11	Ambiguous	1.20	Destabilizing	0.258	Likely Benign	-6.84	Deleterious	0.141	Benign	0.064	Benign	3.10	Benign	0.00	Affected			0.1016	0.2852		3	0	-0.3	-9.01
c.630C>G	H210Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar) and FATHMM, whereas pathogenic calls come from premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized. When predictions are grouped, five tools favor a benign effect and six favor a pathogenic effect. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenic, and the Foldetta stability analysis is inconclusive. No evidence from ClinVar contradicts these findings. Therefore, the variant is most likely pathogenic based on the aggregate computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.144935	Structured	0.390904	Uncertain	0.872	0.298	0.125											-12.639	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.26	Likely Benign	0.3	1.96	Ambiguous	1.11	Ambiguous	1.20	Destabilizing	0.258	Likely Benign	-6.84	Deleterious	0.141	Benign	0.064	Benign	3.10	Benign	0.00	Affected			0.1016	0.2852		3	0	-0.3	-9.01
c.631A>C	S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R 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, and FATHMM, whereas a pathogenic signal is reported by SGM‑Consensus, 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 as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of tools predict a pathogenic effect, and the high‑accuracy predictions reinforce this conclusion. 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	PH	0.209395	Structured	0.389893	Uncertain	0.846	0.300	0.125											-14.126	Likely Pathogenic	0.989	Likely Pathogenic	Likely Pathogenic	0.49	Likely Benign	1.0	0.20	Likely Benign	0.35	Likely Benign	0.97	Ambiguous	0.132	Likely Benign	-4.00	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	3.95	Benign	0.02	Affected			0.1003	0.3592		0	-1	-3.7	69.11
c.631A>T	S211C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211C is 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, AlphaMissense‑Optimized, and premPS, whereas a separate group predicts pathogenicity: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Two tools (Rosetta and AlphaMissense‑Default) 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. Because the consensus of the most reliable predictors is split (two benign, one pathogenic) and the overall tool distribution is evenly divided, the variant’s impact remains ambiguous. Based on the available predictions, the variant is most likely benign, 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.		PH	0.209395	Structured	0.389893	Uncertain	0.846	0.300	0.125											-10.567	Likely Pathogenic	0.547	Ambiguous	Likely Benign	0.28	Likely Benign	0.1	0.63	Ambiguous	0.46	Likely Benign	0.11	Likely Benign	0.263	Likely Benign	-4.14	Deleterious	0.999	Probably Damaging	0.908	Possibly Damaging	3.89	Benign	0.01	Affected			0.1292	0.5638		0	-1	3.3	16.06
c.632G>T	S211I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S211I missense variant 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; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, 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 Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. No evidence from FoldX or Rosetta is available. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.209395	Structured	0.389893	Uncertain	0.846	0.300	0.125											-17.090	Likely Pathogenic	0.973	Likely Pathogenic	Likely Pathogenic	1.06	Ambiguous	1.1	1.05	Ambiguous	1.06	Ambiguous	0.12	Likely Benign	0.251	Likely Benign	-4.94	Deleterious	0.995	Probably Damaging	0.767	Possibly Damaging	3.90	Benign	0.01	Affected			0.0909	0.5220		-1	-2	5.3	26.08
c.633C>A	S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, FATHMM, and Foldetta. Tools that predict a pathogenic effect are 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, is labeled “Likely Pathogenic.” The premPS score is uncertain. 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 and the two high‑accuracy pathogenic calls suggest that 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	PH	0.209395	Structured	0.389893	Uncertain	0.846	0.300	0.125											-14.126	Likely Pathogenic	0.989	Likely Pathogenic	Likely Pathogenic	0.49	Likely Benign	1.0	0.20	Likely Benign	0.35	Likely Benign	0.97	Ambiguous	0.144	Likely Benign	-4.00	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	3.95	Benign	0.02	Affected			0.1003	0.3592		0	-1	-3.7	69.11
c.633C>G	S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, FATHMM, and the protein‑stability integrator Foldetta, whereas 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, and premPS is uncertain. High‑accuracy assessments give conflicting signals: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus also predicts Likely Pathogenic, but Foldetta, which combines FoldX‑MD and Rosetta outputs, predicts Benign. Overall, the majority of tools and the consensus score point to a pathogenic effect, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.209395	Structured	0.389893	Uncertain	0.846	0.300	0.125											-14.126	Likely Pathogenic	0.989	Likely Pathogenic	Likely Pathogenic	0.49	Likely Benign	1.0	0.20	Likely Benign	0.35	Likely Benign	0.97	Ambiguous	0.144	Likely Benign	-4.00	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	3.95	Benign	0.02	Affected			0.1003	0.3592		0	-1	-3.7	69.11
c.634T>A	S212T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S212T is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show 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. With most evidence pointing to deleterious effects and no conflicting ClinVar annotation, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.158265	Structured	0.381517	Uncertain	0.846	0.278	0.125											-11.473	Likely Pathogenic	0.939	Likely Pathogenic	Ambiguous	0.32	Likely Benign	0.2	2.03	Destabilizing	1.18	Ambiguous	0.58	Ambiguous	0.767	Likely Pathogenic	-2.58	Deleterious	0.956	Probably Damaging	0.931	Probably Damaging	5.79	Benign	0.01	Affected			0.1077	0.6284		1	1	0.1	14.03
c.634T>C	S212P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX and FATHMM, whereas the remaining tools—REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic. High‑accuracy methods give consistent pathogenic results: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. With the overwhelming majority of tools supporting pathogenicity and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.158265	Structured	0.381517	Uncertain	0.846	0.278	0.125											-13.051	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.02	Likely Benign	0.9	6.30	Destabilizing	3.16	Destabilizing	0.90	Ambiguous	0.809	Likely Pathogenic	-4.13	Deleterious	0.995	Probably Damaging	0.979	Probably Damaging	5.75	Benign	0.01	Affected			0.1859	0.5679		1	-1	-0.8	10.04
c.634T>G	S212A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212A has no ClinVar record and is not listed in gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, PROVEAN, and FATHMM, while pathogenic predictions arise from REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta predicts benign stability. Overall, the majority of conventional tools lean toward pathogenicity, whereas the most reliable high‑accuracy methods are either benign or inconclusive. Thus, the variant is most likely pathogenic based on the prevailing predictions, 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.		PH	0.158265	Structured	0.381517	Uncertain	0.846	0.278	0.125											-8.890	Likely Pathogenic	0.869	Likely Pathogenic	Ambiguous	-0.13	Likely Benign	0.1	0.13	Likely Benign	0.00	Likely Benign	0.75	Ambiguous	0.752	Likely Pathogenic	-2.48	Neutral	0.956	Probably Damaging	0.931	Probably Damaging	5.83	Benign	0.01	Affected			0.4639	0.4509		1	1	2.6	-16.00
c.635C>A	S212Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212Y 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, FATHMM, and premPS. In contrast, a majority of tools predict a pathogenic impact: REVEL, SGM‑Consensus, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, is inconclusive for this variant. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence from multiple in silico predictors indicates that S212Y is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.158265	Structured	0.381517	Uncertain	0.846	0.278	0.125											-14.812	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.43	Likely Benign	0.5	2.32	Destabilizing	1.38	Ambiguous	0.22	Likely Benign	0.819	Likely Pathogenic	-5.15	Deleterious	0.995	Probably Damaging	0.986	Probably Damaging	5.76	Benign	0.00	Affected			0.0555	0.6120		-3	-2	-0.5	76.10
c.635C>G	S212C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include FoldX, premPS, and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are inconclusive are Rosetta and Foldetta. The high‑accuracy consensus methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.158265	Structured	0.381517	Uncertain	0.846	0.278	0.125											-11.656	Likely Pathogenic	0.981	Likely Pathogenic	Likely Pathogenic	0.16	Likely Benign	0.1	0.98	Ambiguous	0.57	Ambiguous	0.47	Likely Benign	0.840	Likely Pathogenic	-4.29	Deleterious	0.999	Probably Damaging	0.990	Probably Damaging	5.73	Benign	0.00	Affected			0.0785	0.6270		0	-1	3.3	16.06
c.635C>T	S212F 2D AIThe SynGAP1 missense variant S212F is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX, FATHMM, and premPS, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score (Likely Pathogenic) predict a pathogenic outcome. The remaining tools, Foldetta and Rosetta, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall consensus of the majority of predictors and the 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	PH	0.158265	Structured	0.381517	Uncertain	0.846	0.278	0.125											-14.029	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.11	Likely Benign	1.6	0.88	Ambiguous	0.50	Ambiguous	-0.02	Likely Benign	0.820	Likely Pathogenic	-5.15	Deleterious	0.995	Probably Damaging	0.986	Probably Damaging	5.76	Benign	0.00	Affected			0.0503	0.6259		-3	-2	3.6	60.10
c.637A>T	I213F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213F missense variant is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; FoldX and premPS are uncertain and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain and thus not considered. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.158265	Structured	0.372201	Uncertain	0.850	0.295	0.125											-12.212	Likely Pathogenic	0.980	Likely Pathogenic	Likely Pathogenic	0.96	Ambiguous	0.7	2.66	Destabilizing	1.81	Ambiguous	0.73	Ambiguous	0.815	Likely Pathogenic	-3.30	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	5.79	Benign	0.01	Affected			0.0473	0.2560		1	0	-1.7	34.02
c.638T>A	I213N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I213N is 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 evaluated algorithms—SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; FoldX is uncertain and is 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 ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.158265	Structured	0.372201	Uncertain	0.850	0.295	0.125											-15.069	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.71	Ambiguous	0.8	2.81	Destabilizing	2.26	Destabilizing	1.85	Destabilizing	0.862	Likely Pathogenic	-5.81	Deleterious	0.995	Probably Damaging	0.880	Possibly Damaging	5.83	Benign	0.00	Affected			0.0750	0.0412		-2	-3	-8.0	0.94
c.638T>C	I213T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213T missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining evidence—SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently indicates pathogenicity. FoldX, Rosetta, and Foldetta provide uncertain results. 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 remains uncertain. Overall, the preponderance of evidence supports a pathogenic classification for I213T, 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	0.158265	Structured	0.372201	Uncertain	0.850	0.295	0.125											-11.080	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	1.46	Ambiguous	0.8	1.32	Ambiguous	1.39	Ambiguous	1.49	Destabilizing	0.882	Likely Pathogenic	-3.99	Deleterious	0.948	Possibly Damaging	0.588	Possibly Damaging	5.82	Benign	0.00	Affected			0.0905	0.0708		0	-1	-5.2	-12.05
c.638T>G	I213S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment 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	PH	0.158265	Structured	0.372201	Uncertain	0.850	0.295	0.125											-12.858	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	2.00	Destabilizing	1.1	2.95	Destabilizing	2.48	Destabilizing	1.53	Destabilizing	0.879	Likely Pathogenic	-4.88	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	5.83	Benign	0.00	Affected			0.2290	0.0800		-1	-2	-5.3	-26.08
c.639C>G	I213M 2D AIThe SynGAP1 missense variant I213M 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 PROVEAN and FATHMM, while a larger group—REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) return uncertain or inconclusive results and are therefore treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.158265	Structured	0.372201	Uncertain	0.850	0.295	0.125											-10.777	Likely Pathogenic	0.906	Likely Pathogenic	Ambiguous	0.66	Ambiguous	0.5	1.58	Ambiguous	1.12	Ambiguous	0.85	Ambiguous	0.680	Likely Pathogenic	-2.31	Neutral	0.995	Probably Damaging	0.880	Possibly Damaging	5.85	Benign	0.01	Affected			0.0611	0.2524		2	1	-2.6	18.03
c.63C>A	F21L 2D AIThe SynGAP1 missense variant F21L is reported in gnomAD (ID 6‑33420327‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.534167	Disordered	0.443284	Uncertain	0.369	0.897	0.500								6-33420327-C-A			-2.480	Likely Benign	0.940	Likely Pathogenic	Ambiguous										0.103	Likely Benign	0.15	Neutral	0.140	Benign	0.153	Benign	4.34	Benign	0.00	Affected	4.32	1	0.2680	0.3250		0	2	1.0	-34.02
c.63C>G	F21L 2D AIThe SynGAP1 missense variant F21L is 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, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, while AlphaMissense‑Optimized remains uncertain and Foldetta is unavailable. Overall, the majority of evidence points to a benign impact. The predictions do not contradict the ClinVar status, which is currently unreported. Thus, based on the available computational predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.534167	Disordered	0.443284	Uncertain	0.369	0.897	0.500											-2.480	Likely Benign	0.940	Likely Pathogenic	Ambiguous										0.104	Likely Benign	0.15	Neutral	0.140	Benign	0.153	Benign	4.34	Benign	0.00	Affected	4.32	1	0.2680	0.3250		0	2	1.0	-34.02
c.640C>A	L214M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L214M 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 PROVEAN and FATHMM, whereas the majority of tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; the remaining tools (FoldX, Rosetta, Foldetta, premPS) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs two benign) and Foldetta is uncertain. Thus, the available evidence points to a pathogenic effect. 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	0.155435	Structured	0.372604	Uncertain	0.818	0.302	0.125											-9.347	Likely Pathogenic	0.958	Likely Pathogenic	Likely Pathogenic	0.74	Ambiguous	0.3	1.43	Ambiguous	1.09	Ambiguous	0.80	Ambiguous	0.646	Likely Pathogenic	-1.72	Neutral	0.997	Probably Damaging	0.916	Probably Damaging	5.73	Benign	0.01	Affected			0.0805	0.4054		4	2	-1.9	18.03
c.640C>G	L214V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L214V 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The remaining methods—FoldX, Rosetta, premPS, and AlphaMissense‑Optimized—yield uncertain results and are treated as unavailable evidence. 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. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.155435	Structured	0.372604	Uncertain	0.818	0.302	0.125											-9.913	Likely Pathogenic	0.950	Likely Pathogenic	Ambiguous	1.80	Ambiguous	0.4	0.54	Ambiguous	1.17	Ambiguous	0.89	Ambiguous	0.495	Likely Benign	-2.54	Deleterious	0.384	Benign	0.070	Benign	5.78	Benign	0.01	Affected			0.1469	0.3887		2	1	0.4	-14.03
c.641T>A	L214Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change at residue 214 (Leu→Gln) is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, the majority (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic effect, while only FATHMM predicts a benign outcome. Three tools (FoldX, Rosetta, Foldetta) return uncertain results. 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 is uncertain. Taken together, the overwhelming consensus of pathogenic predictions indicates that the variant is most likely pathogenic, with no ClinVar evidence contradicting this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.155435	Structured	0.372604	Uncertain	0.818	0.302	0.125											-10.119	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	1.60	Ambiguous	0.6	1.71	Ambiguous	1.66	Ambiguous	1.73	Destabilizing	0.912	Likely Pathogenic	-5.12	Deleterious	0.997	Probably Damaging	0.936	Probably Damaging	5.74	Benign	0.00	Affected			0.1140	0.0930		-2	-2	-7.3	14.97
c.641T>C	L214P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L214P 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, while the remaining 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and the consensus of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) uniformly 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, 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 predictive algorithms, 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	0.155435	Structured	0.372604	Uncertain	0.818	0.302	0.125											-11.348	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	3.38	Destabilizing	1.3	7.51	Destabilizing	5.45	Destabilizing	1.30	Destabilizing	0.930	Likely Pathogenic	-5.98	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	5.76	Benign	0.00	Affected			0.3448	0.1553		-3	-3	-5.4	-16.04
c.641T>G	L214R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L214R 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 majority of tools (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the evidence strongly favors a pathogenic effect for 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 Pathogenic	PH	0.155435	Structured	0.372604	Uncertain	0.818	0.302	0.125											-11.458	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	1.35	Ambiguous	0.6	0.92	Ambiguous	1.14	Ambiguous	1.68	Destabilizing	0.927	Likely Pathogenic	-4.98	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	5.75	Benign	0.00	Affected			0.1335	0.0772		-3	-2	-8.3	43.03
c.643G>A	G215S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining pathogenic predictors (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all indicate pathogenicity. Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is 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 annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.155435	Structured	0.382818	Uncertain	0.791	0.291	0.000											-9.067	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	2.30	Destabilizing	0.3	1.20	Ambiguous	1.75	Ambiguous	0.55	Ambiguous	0.864	Likely Pathogenic	-5.05	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	5.66	Benign	0.02	Affected			0.2701	0.5761		1	0	-0.4	30.03
c.643G>C	G215R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. Four methods (FoldX, Rosetta, Foldetta, premPS) return uncertain results and are not considered evidence for either side. 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’s stability prediction is inconclusive. Taken together, the preponderance of evidence points to a pathogenic effect for G215R. This conclusion is consistent with the absence of a ClinVar entry and does not contradict any existing database annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.155435	Structured	0.382818	Uncertain	0.791	0.291	0.000											-12.654	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.75	Ambiguous	0.1	1.25	Ambiguous	1.50	Ambiguous	0.56	Ambiguous	0.823	Likely Pathogenic	-6.84	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	5.71	Benign	0.01	Affected			0.1048	0.4890		-3	-2	-4.1	99.14
c.643G>T	G215C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are premPS and FATHMM; those that agree on a pathogenic effect include SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta gives an uncertain result and is listed separately. High‑accuracy methods all predict pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.155435	Structured	0.382818	Uncertain	0.791	0.291	0.000											-12.295	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	2.39	Destabilizing	0.2	1.76	Ambiguous	2.08	Destabilizing	0.33	Likely Benign	0.869	Likely Pathogenic	-7.69	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	5.56	Benign	0.00	Affected			0.1274	0.4640		-3	-3	2.9	46.09
c.644G>A	G215D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215D is 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—SIFT, PolyPhen‑2 (HumDiv and HumVar), PROVEAN, REVEL, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and FoldX—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta, which evaluates protein‑folding stability, yields an uncertain result. No other high‑confidence tool contradicts the pathogenic prediction. Consequently, the variant is most likely pathogenic based on the collective predictions, 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	PH	0.155435	Structured	0.382818	Uncertain	0.791	0.291	0.000											-9.884	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	2.23	Destabilizing	0.3	0.91	Ambiguous	1.57	Ambiguous	0.57	Ambiguous	0.807	Likely Pathogenic	-5.98	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	5.71	Benign	0.02	Affected			0.1888	0.2947		1	-1	-3.1	58.04
c.644G>C	G215A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215A is not reported in ClinVar (ClinVar ID: 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 and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tool predicting a benign outcome is FATHMM. Predictions that are uncertain or inconclusive are Foldetta, Rosetta, and premPS. 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 is uncertain. Overall, the majority of evidence indicates that G215A is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.155435	Structured	0.382818	Uncertain	0.791	0.291	0.000											-8.930	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	2.36	Destabilizing	0.2	1.35	Ambiguous	1.86	Ambiguous	0.59	Ambiguous	0.874	Likely Pathogenic	-5.08	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	5.61	Benign	0.02	Affected			0.3897	0.5525		1	0	2.2	14.03
c.644G>T	G215V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215V is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining twelve tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the variant as pathogenic. premPS is uncertain and does not influence the consensus. High‑accuracy methods reinforce this view: 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) 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 reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.155435	Structured	0.382818	Uncertain	0.791	0.291	0.000											-12.960	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.69	Destabilizing	0.2	5.41	Destabilizing	4.55	Destabilizing	0.53	Ambiguous	0.884	Likely Pathogenic	-7.66	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	5.56	Benign	0.00	Affected			0.1087	0.4777		-1	-3	4.6	42.08
c.647A>C	Q216P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216P 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. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic impact. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; SGM‑Consensus indicates likely pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. premPS is inconclusive and is treated as unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.206376	Structured	0.396100	Uncertain	0.804	0.274	0.000											-13.128	Likely Pathogenic	0.987	Likely Pathogenic	Likely Pathogenic	4.35	Destabilizing	0.8	4.05	Destabilizing	4.20	Destabilizing	0.53	Ambiguous	0.830	Likely Pathogenic	-4.69	Deleterious	0.989	Probably Damaging	0.737	Possibly Damaging	5.84	Benign	0.01	Affected			0.2603	0.5736		0	-1	1.9	-31.01
c.647A>T	Q216L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216L 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, premPS, and FATHMM, while those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain (treated as unavailable), SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. Overall, the majority of tools (8 pathogenic vs. 5 benign) and the consensus high‑accuracy prediction 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.	Likely Pathogenic	PH	0.206376	Structured	0.396100	Uncertain	0.804	0.274	0.000											-11.303	Likely Pathogenic	0.886	Likely Pathogenic	Ambiguous	-0.17	Likely Benign	0.3	0.28	Likely Benign	0.06	Likely Benign	0.30	Likely Benign	0.797	Likely Pathogenic	-5.58	Deleterious	0.963	Probably Damaging	0.452	Possibly Damaging	5.87	Benign	0.01	Affected			0.1036	0.6410		-2	-2	7.3	-14.97
c.648G>C	Q216H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas those that predict a pathogenic impact are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows 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; 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	PH	0.206376	Structured	0.396100	Uncertain	0.804	0.274	0.000											-10.532	Likely Pathogenic	0.951	Likely Pathogenic	Ambiguous	0.29	Likely Benign	0.0	0.30	Likely Benign	0.30	Likely Benign	0.50	Likely Benign	0.638	Likely Pathogenic	-3.84	Deleterious	0.989	Probably Damaging	0.809	Possibly Damaging	5.85	Benign	0.01	Affected			0.1909	0.4660		3	0	0.3	9.01
c.648G>T	Q216H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas a larger group predicts pathogenicity: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is 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 majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.206376	Structured	0.396100	Uncertain	0.804	0.274	0.000											-10.532	Likely Pathogenic	0.951	Likely Pathogenic	Ambiguous	0.29	Likely Benign	0.0	0.30	Likely Benign	0.30	Likely Benign	0.50	Likely Benign	0.638	Likely Pathogenic	-3.84	Deleterious	0.989	Probably Damaging	0.809	Possibly Damaging	5.85	Benign	0.01	Affected			0.1909	0.4660		3	0	0.3	9.01
c.64A>G	R22G 2D AIThe SynGAP1 missense variant R22G is reported in ClinVar as “Not submitted” and is present in gnomAD (ID 6‑33420328‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.441505	Uncertain	0.377	0.891	0.500								6-33420328-A-G			-3.628	Likely Benign	0.322	Likely Benign	Likely Benign										0.185	Likely Benign	-0.42	Neutral	0.462	Possibly Damaging	0.152	Benign	4.19	Benign	0.00	Affected	4.32	1	0.3590	0.4098		-2	-3	4.1	-99.14
c.650A>T	E217V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E217V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include Rosetta, FATHMM, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E217V. This conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.278302	Structured	0.404912	Uncertain	0.823	0.284	0.000											-10.194	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	0.76	Ambiguous	0.6	0.39	Likely Benign	0.58	Ambiguous	0.23	Likely Benign	0.723	Likely Pathogenic	-4.84	Deleterious	0.900	Possibly Damaging	0.461	Possibly Damaging	5.79	Benign	0.03	Affected			0.0919	0.8340		-2	-2	7.7	-29.98
c.653T>G	F218C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218C is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33435295‑T‑G). Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of tools (REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact. Results that are uncertain or unavailable are FoldX, ESM1b, AlphaMissense‑Optimized, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic prediction (2 pathogenic vs. 1 benign votes); and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for F218C, 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.		PH	0.281712	Structured	0.408725	Uncertain	0.848	0.272	0.000								6-33435295-T-G	1	6.20e-7	-7.234	In-Between	0.948	Likely Pathogenic	Ambiguous	1.49	Ambiguous	0.1	2.20	Destabilizing	1.85	Ambiguous	1.02	Destabilizing	0.744	Likely Pathogenic	-4.92	Deleterious	0.994	Probably Damaging	0.667	Possibly Damaging	5.78	Benign	0.03	Affected	3.41	13	0.2330	0.1321		-2	-4	-0.3	-44.04
c.655T>A	C219S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from FoldX, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. With the majority of evidence pointing to a damaging effect and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.254060	Structured	0.426845	Uncertain	0.903	0.279	0.000											-12.962	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.09	Likely Benign	0.4	1.53	Ambiguous	0.81	Ambiguous	1.56	Destabilizing	0.892	Likely Pathogenic	-8.35	Deleterious	0.900	Possibly Damaging	0.380	Benign	5.95	Benign	0.04	Affected			0.3568	0.1454		0	-1	-3.3	-16.06
c.655T>C	C219R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219R 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 FATHMM, while the remaining 13 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 or likely pathogenic impact. 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. No prediction or folding stability result is missing or inconclusive. 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	PH	0.254060	Structured	0.426845	Uncertain	0.903	0.279	0.000											-15.727	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.00	Destabilizing	1.5	2.20	Destabilizing	2.60	Destabilizing	1.33	Destabilizing	0.904	Likely Pathogenic	-9.90	Deleterious	0.969	Probably Damaging	0.680	Possibly Damaging	5.80	Benign	0.00	Affected			0.1381	0.1837		-4	-3	-7.0	53.05
c.655T>G	C219G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219G 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 11 tools—including REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized returns a pathogenic score, 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, is inconclusive. Taken together, the overwhelming majority of evidence points to a pathogenic effect for C219G. This conclusion aligns with the absence of a ClinVar entry and does not contradict any existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.254060	Structured	0.426845	Uncertain	0.903	0.279	0.000											-15.072	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.72	Ambiguous	0.3	1.98	Ambiguous	1.35	Ambiguous	1.18	Destabilizing	0.900	Likely Pathogenic	-10.09	Deleterious	0.900	Possibly Damaging	0.461	Possibly Damaging	5.83	Benign	0.02	Affected			0.2159	0.2169		-3	-3	-2.9	-46.09
c.656G>A	C219Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219Y is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized returns a pathogenic prediction; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Based on the preponderance of evidence, the variant is most likely pathogenic, a conclusion that 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	PH	0.254060	Structured	0.426845	Uncertain	0.903	0.279	0.000					Uncertain		1				-14.797	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	8.98	Destabilizing	2.0	2.84	Destabilizing	5.91	Destabilizing	0.55	Ambiguous	0.812	Likely Pathogenic	-9.09	Deleterious	0.990	Probably Damaging	0.758	Possibly Damaging	5.81	Benign	0.00	Affected			0.0772	0.3285		0	-2	-3.8	60.04
c.656G>C	C219S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219S is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, polyPhen‑2 HumVar, and FATHMM, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta’s stability analysis is inconclusive (treated as unavailable). Taken together, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic impact for C219S. This conclusion is not contradicted by 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	PH	0.254060	Structured	0.426845	Uncertain	0.903	0.279	0.000											-12.962	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.09	Likely Benign	0.4	1.53	Ambiguous	0.81	Ambiguous	1.56	Destabilizing	0.817	Likely Pathogenic	-8.35	Deleterious	0.900	Possibly Damaging	0.380	Benign	5.95	Benign	0.04	Affected			0.3568	0.1454		0	-1	-3.3	-16.06
c.656G>T	C219F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219F 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 premPS and FATHMM, while the remaining 13 tools—including 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. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized reports 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 outputs, also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.254060	Structured	0.426845	Uncertain	0.903	0.279	0.000											-14.322	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	7.31	Destabilizing	1.9	2.45	Destabilizing	4.88	Destabilizing	0.47	Likely Benign	0.814	Likely Pathogenic	-9.18	Deleterious	0.940	Possibly Damaging	0.505	Possibly Damaging	5.82	Benign	0.00	Affected			0.0959	0.3804		-4	-2	0.3	44.04
c.657T>G	C219W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219W is 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 (SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta and premPS are inconclusive. High‑accuracy methods give consistent pathogenic 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. Taken together, the overwhelming evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.254060	Structured	0.426845	Uncertain	0.903	0.279	0.000											-16.565	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	10.10	Destabilizing	3.6	1.20	Ambiguous	5.65	Destabilizing	0.52	Ambiguous	0.706	Likely Pathogenic	-9.23	Deleterious	0.997	Probably Damaging	0.808	Possibly Damaging	5.77	Benign	0.00	Affected			0.1131	0.3285		-8	-2	-3.4	83.07
c.658T>A	F220I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yielding 3 pathogenic versus 1 benign calls, thus supporting a pathogenic classification. High‑accuracy tools specifically report pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.219301	Structured	0.429422	Uncertain	0.898	0.295	0.000											-12.041	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	3.11	Destabilizing	0.1	2.35	Destabilizing	2.73	Destabilizing	1.03	Destabilizing	0.921	Likely Pathogenic	-4.98	Deleterious	0.300	Benign	0.098	Benign	4.06	Benign	0.01	Affected			0.2292	0.3127		1	0	1.7	-34.02
c.658T>C	F220L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—indicate a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic, 1 benign), thus supporting a pathogenic classification. High‑accuracy assessments further corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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	PH	0.219301	Structured	0.429422	Uncertain	0.898	0.295	0.000											-9.601	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	2.08	Destabilizing	0.1	2.24	Destabilizing	2.16	Destabilizing	1.33	Destabilizing	0.850	Likely Pathogenic	-4.95	Deleterious	0.003	Benign	0.005	Benign	4.24	Benign	0.02	Affected			0.2589	0.4108		2	0	1.0	-34.02
c.658T>G	F220V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220V is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. 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, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Based on the preponderance of pathogenic predictions, 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	PH	0.219301	Structured	0.429422	Uncertain	0.898	0.295	0.000											-11.599	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	3.83	Destabilizing	0.1	4.11	Destabilizing	3.97	Destabilizing	1.56	Destabilizing	0.911	Likely Pathogenic	-5.81	Deleterious	0.075	Benign	0.015	Benign	4.04	Benign	0.01	Affected			0.2351	0.3315		-1	-1	1.4	-48.04
c.659T>A	F220Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, FATHMM, and polyPhen‑2 HumVar. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is classified as pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain and therefore not considered evidence. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that F220Y 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	0.219301	Structured	0.429422	Uncertain	0.898	0.295	0.000											-12.541	Likely Pathogenic	0.989	Likely Pathogenic	Likely Pathogenic	2.25	Destabilizing	0.1	0.35	Likely Benign	1.30	Ambiguous	1.14	Destabilizing	0.879	Likely Pathogenic	-2.54	Deleterious	0.928	Possibly Damaging	0.395	Benign	4.07	Benign	0.00	Affected			0.1479	0.2661		7	3	-4.1	16.00
c.659T>C	F220S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: all available scores (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default) indicate pathogenicity, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also labels it pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.219301	Structured	0.429422	Uncertain	0.898	0.295	0.000											-15.258	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	4.06	Destabilizing	0.1	4.67	Destabilizing	4.37	Destabilizing	1.44	Destabilizing	0.954	Likely Pathogenic	-6.67	Deleterious	0.928	Possibly Damaging	0.477	Possibly Damaging	4.03	Benign	0.01	Affected			0.3813	0.1143		-3	-2	-3.6	-60.10
c.659T>G	F220C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220C 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—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among these 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	PH	0.219301	Structured	0.429422	Uncertain	0.898	0.295	0.000											-12.948	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.67	Destabilizing	0.0	5.03	Destabilizing	4.35	Destabilizing	2.22	Destabilizing	0.941	Likely Pathogenic	-6.72	Deleterious	0.994	Probably Damaging	0.753	Possibly Damaging	4.03	Benign	0.00	Affected			0.2264	0.2012		-4	-2	-0.3	-44.04
c.65G>A	R22K 2D AIThe SynGAP1 missense variant R22K is reported in gnomAD (variant ID 6‑33420329‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for R22K, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.441505	Uncertain	0.377	0.891	0.500								6-33420329-G-A			-4.736	Likely Benign	0.268	Likely Benign	Likely Benign										0.032	Likely Benign	-0.12	Neutral	0.140	Benign	0.067	Benign	4.27	Benign	0.00	Affected	4.32	1	0.6413	0.5384	Strenghten	2	3	0.6	-28.01
c.65G>C	R22T 2D AIThe SynGAP1 missense variant R22T is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools show a split: benign calls from REVEL, PROVEAN, polyPhen2_HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from polyPhen2_HumDiv and SIFT. The majority‑vote SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy predictors further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta predictions are not available. Given the preponderance of benign predictions and the lack of pathogenic evidence, the variant is most likely benign. This assessment aligns with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.441505	Uncertain	0.377	0.891	0.500											-4.079	Likely Benign	0.510	Ambiguous	Likely Benign										0.146	Likely Benign	-0.21	Neutral	0.462	Possibly Damaging	0.227	Benign	4.23	Benign	0.00	Affected			0.2140	0.5599		-1	-1	3.8	-55.08
c.65G>T	R22I 2D AIThe SynGAP1 missense variant R22I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.441505	Uncertain	0.377	0.891	0.500											-4.849	Likely Benign	0.692	Likely Pathogenic	Likely Benign										0.118	Likely Benign	0.06	Neutral	0.676	Possibly Damaging	0.308	Benign	4.20	Benign	0.00	Affected			0.2120	0.5048		-2	-3	9.0	-43.03
c.660T>A	F220L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—indicate a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic, 1 benign), thus supporting a pathogenic classification. High‑accuracy assessments further corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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	PH	0.219301	Structured	0.429422	Uncertain	0.898	0.295	0.000											-9.601	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	2.08	Destabilizing	0.1	2.24	Destabilizing	2.16	Destabilizing	1.33	Destabilizing	0.752	Likely Pathogenic	-4.95	Deleterious	0.003	Benign	0.005	Benign	4.24	Benign	0.02	Affected			0.2589	0.4108		2	0	1.0	-34.02
c.660T>G	F220L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—indicate a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic, 1 benign), thus supporting a pathogenic classification. High‑accuracy assessments further corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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	PH	0.219301	Structured	0.429422	Uncertain	0.898	0.295	0.000											-9.601	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	2.08	Destabilizing	0.1	2.24	Destabilizing	2.16	Destabilizing	1.33	Destabilizing	0.752	Likely Pathogenic	-4.95	Deleterious	0.003	Benign	0.005	Benign	4.24	Benign	0.02	Affected			0.2589	0.4108		2	0	1.0	-34.02
c.661G>A	E221K 2D AIThe SynGAP1 E221K 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 Rosetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. FoldX and Foldetta give uncertain results. High‑accuracy methods show AlphaMissense‑Optimized as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenic (3 pathogenic vs 1 benign). Foldetta remains uncertain. Overall, the majority of reliable predictors indicate 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	PH	0.127496	Structured	0.413334	Uncertain	0.891	0.283	0.000											-12.331	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	-1.01	Ambiguous	0.4	-0.18	Likely Benign	-0.60	Ambiguous	0.19	Likely Benign	0.815	Likely Pathogenic	-2.92	Deleterious	0.131	Benign	0.058	Benign	5.92	Benign	0.02	Affected			0.2491	0.8002		0	1	-0.4	-0.94
c.662A>C	E221A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221A 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as benign. Overall, the predictions are split, but the two high‑confidence pathogenic calls outweigh the single high‑confidence benign call, suggesting 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	PH	0.127496	Structured	0.413334	Uncertain	0.891	0.283	0.000											-12.906	Likely Pathogenic	0.964	Likely Pathogenic	Likely Pathogenic	0.31	Likely Benign	0.0	-0.11	Likely Benign	0.10	Likely Benign	0.52	Ambiguous	0.796	Likely Pathogenic	-4.70	Deleterious	0.231	Benign	0.081	Benign	5.82	Benign	0.01	Affected			0.3486	0.7335		0	-1	5.3	-58.04
c.662A>G	E221G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221G 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 polyPhen‑2 HumVar and FATHMM, while the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) indicate a pathogenic impact; FoldX, Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Based on the collective evidence, the variant is most likely pathogenic, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.413334	Uncertain	0.891	0.283	0.000					Uncertain		1				-12.221	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	1.40	Ambiguous	0.1	1.74	Ambiguous	1.57	Ambiguous	0.71	Ambiguous	0.863	Likely Pathogenic	-5.56	Deleterious	0.596	Possibly Damaging	0.201	Benign	5.79	Benign	0.00	Affected			0.2611	0.6370		0	-2	3.1	-72.06
c.662A>T	E221V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221V missense variant is reported in ClinVar as Pathogenic (ClinVar ID 2413181.0) and is not found in gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Benign predictions are limited to premPS, polyPhen‑2 HumVar, and FATHMM. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments reinforce the pathogenic interpretation: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus also indicates Likely Pathogenic, while Foldetta remains Uncertain. Taken together, the preponderance of evidence supports a pathogenic effect for E221V, and this conclusion aligns with the ClinVar classification, showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.413334	Uncertain	0.891	0.283	0.000					Likely Pathogenic		1				-14.954	Likely Pathogenic	0.987	Likely Pathogenic	Likely Pathogenic	-0.66	Ambiguous	0.2	-0.89	Ambiguous	-0.78	Ambiguous	0.49	Likely Benign	0.875	Likely Pathogenic	-5.54	Deleterious	0.596	Possibly Damaging	0.203	Benign	5.86	Benign	0.00	Affected	3.41	13	0.0806	0.8138		-2	-2	7.7	-29.98	234.5	50.6	0.0	0.0	-0.4	0.2		X						Uncertain	The introduced residue Val221 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the carboxylate group of Glu221, Val221 cannot form hydrogen bonds with Thr223 or a salt bridge with the amino group of the Lys207 side chain. Despite this, the WT simulations containing Glu221 do not show significant differences compared to the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.663G>C	E221D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221D 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 PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta remains uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.127496	Structured	0.413334	Uncertain	0.891	0.283	0.000											-12.237	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	1.59	Ambiguous	0.1	1.07	Ambiguous	1.33	Ambiguous	0.84	Ambiguous	0.750	Likely Pathogenic	-2.43	Neutral	0.421	Benign	0.107	Benign	5.80	Benign	0.02	Affected			0.1755	0.5228		3	2	0.0	-14.03
c.663G>T	E221D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221D 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 PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.127496	Structured	0.413334	Uncertain	0.891	0.283	0.000											-12.237	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	1.59	Ambiguous	0.1	1.07	Ambiguous	1.33	Ambiguous	0.84	Ambiguous	0.750	Likely Pathogenic	-2.43	Neutral	0.421	Benign	0.107	Benign	5.80	Benign	0.02	Affected			0.1755	0.5228		3	2	0.0	-14.03
c.664G>C	V222L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V222L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, FATHMM, and Foldetta, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (premPS and ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—also predicts pathogenic; Foldetta, a protein‑folding stability method, predicts benign. Overall, the majority of evidence (seven pathogenic vs. four benign) points to a pathogenic effect. The variant’s predicted pathogenicity is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.116183	Structured	0.402706	Uncertain	0.885	0.310	0.125											-7.626	In-Between	0.987	Likely Pathogenic	Likely Pathogenic	0.00	Likely Benign	0.3	0.06	Likely Benign	0.03	Likely Benign	0.60	Ambiguous	0.617	Likely Pathogenic	-2.59	Deleterious	0.984	Probably Damaging	0.956	Probably Damaging	5.49	Benign	0.05	Affected			0.0863	0.4349		2	1	-0.4	14.03
c.664G>T	V222L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V222L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, FATHMM, and Foldetta, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (premPS and ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—also predicts pathogenic; Foldetta, a protein‑folding stability method, predicts benign. Overall, the majority of evidence (seven pathogenic vs. four benign) points to a pathogenic effect. The variant’s predicted pathogenicity is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.116183	Structured	0.402706	Uncertain	0.885	0.310	0.125											-7.626	In-Between	0.987	Likely Pathogenic	Likely Pathogenic	0.00	Likely Benign	0.3	0.06	Likely Benign	0.03	Likely Benign	0.60	Ambiguous	0.617	Likely Pathogenic	-2.59	Deleterious	0.984	Probably Damaging	0.956	Probably Damaging	5.49	Benign	0.05	Affected			0.0863	0.4349		2	1	-0.4	14.03
c.665T>A	V222E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V222E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, 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). Only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is consistent with the lack of ClinVar reporting (i.e., no contradictory evidence). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.116183	Structured	0.402706	Uncertain	0.885	0.310	0.125											-18.017	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.04	Destabilizing	0.2	3.46	Destabilizing	3.75	Destabilizing	1.64	Destabilizing	0.960	Likely Pathogenic	-5.20	Deleterious	0.998	Probably Damaging	0.987	Probably Damaging	5.20	Benign	0.00	Affected			0.0833	0.1495		-2	-2	-7.7	29.98
c.665T>C	V222A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V222A missense variant 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 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	0.116183	Structured	0.402706	Uncertain	0.885	0.310	0.125											-10.248	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	2.89	Destabilizing	0.3	2.98	Destabilizing	2.94	Destabilizing	2.06	Destabilizing	0.894	Likely Pathogenic	-3.50	Deleterious	0.984	Probably Damaging	0.956	Probably Damaging	5.26	Benign	0.04	Affected			0.2386	0.2081		0	0	-2.4	-28.05
c.665T>G	V222G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V222G resides in the PH domain. ClinVar has no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining eleven tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Thus, the variant is most likely pathogenic based on the collective predictions, 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.		PH	0.116183	Structured	0.402706	Uncertain	0.885	0.310	0.125											-14.857	Likely Pathogenic	0.982	Likely Pathogenic	Likely Pathogenic	4.54	Destabilizing	0.4	5.25	Destabilizing	4.90	Destabilizing	2.05	Destabilizing	0.962	Likely Pathogenic	-6.05	Deleterious	0.987	Probably Damaging	0.998	Probably Damaging	5.21	Benign	0.00	Affected			0.1678	0.1996		-1	-3	-4.6	-42.08
c.667A>C	T223P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T223P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as Uncertain. No other high‑accuracy tools provide a definitive prediction. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.070400	Structured	0.382605	Uncertain	0.867	0.316	0.125											-13.707	Likely Pathogenic	0.974	Likely Pathogenic	Likely Pathogenic	0.42	Likely Benign	0.3	3.45	Destabilizing	1.94	Ambiguous	0.67	Ambiguous	0.898	Likely Pathogenic	-4.54	Deleterious	0.838	Possibly Damaging	0.367	Benign	5.72	Benign	0.01	Affected			0.1464	0.3728		0	-1	-0.9	-3.99
c.667A>T	T223S 2D 3DClick to see structure in 3D Viewer AISynGAP1 T223S is listed in ClinVar as a variant of uncertain significance and is present in the gnomAD database (ID 6‑33435518‑A‑T). Functional prediction tools that reach consensus classify the variant as benign: FoldX, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity include REVEL, PROVEAN, and SIFT. Predictions that are inconclusive or uncertain are Rosetta, premPS, AlphaMissense‑Default, and ESM1b. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, Foldetta is benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 1‑to‑1 split between benign and pathogenic calls. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.070400	Structured	0.382605	Uncertain	0.867	0.316	0.125					Conflicting		2	6-33435518-A-T	3	1.86e-6	-7.714	In-Between	0.410	Ambiguous	Likely Benign	0.26	Likely Benign	0.1	0.50	Ambiguous	0.38	Likely Benign	0.62	Ambiguous	0.535	Likely Pathogenic	-2.86	Deleterious	0.421	Benign	0.058	Benign	5.80	Benign	0.02	Affected	3.41	13	0.2388	0.2972		1	1	-0.1	-14.03	200.7	17.3	-0.2	0.2	0.0	0.0						X		Uncertain	The introduced residue Ser223 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Its hydroxyl group forms hydrogen bonds with nearby residues Thr228 and Lys207 in the variant simulations, similar to the hydroxyl group of Thr223 in the WT simulations. These hydrogen-bonding interactions at the β sheet surface contribute to the stability of the secondary structure element and may prevent it from unfolding. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.668C>A	T223K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T223K missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The remaining tools, premPS and AlphaMissense‑Optimized, are uncertain and therefore treated as unavailable evidence. 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 balance of evidence leans toward a benign impact, with no contradiction to the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.070400	Structured	0.382605	Uncertain	0.867	0.316	0.125											-12.084	Likely Pathogenic	0.853	Likely Pathogenic	Ambiguous	-0.30	Likely Benign	0.1	0.42	Likely Benign	0.06	Likely Benign	0.93	Ambiguous	0.810	Likely Pathogenic	-4.60	Deleterious	0.267	Benign	0.086	Benign	5.78	Benign	0.01	Affected			0.0793	0.2462		0	-1	-3.2	27.07
c.66A>C	R22S 2D AIThe SynGAP1 missense variant R22S 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, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; a Foldetta stability prediction is unavailable. 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		0.538167	Disordered	0.441505	Uncertain	0.377	0.891	0.500											-3.419	Likely Benign	0.602	Likely Pathogenic	Likely Benign										0.190	Likely Benign	0.01	Neutral	0.462	Possibly Damaging	0.227	Benign	4.28	Benign	0.00	Affected	4.32	1	0.3252	0.5187		-1	0	3.7	-69.11
c.66A>T	R22S 2D AIThe SynGAP1 missense variant R22S is listed in gnomAD (ID 6‑33420330‑A‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its stability impact is unavailable. Overall, the majority of evidence points to a benign effect, and this is not in conflict with ClinVar, which has no classification for R22S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.441505	Uncertain	0.377	0.891	0.500								6-33420330-A-T			-3.419	Likely Benign	0.602	Likely Pathogenic	Likely Benign										0.190	Likely Benign	0.01	Neutral	0.462	Possibly Damaging	0.227	Benign	4.28	Benign	0.00	Affected	4.32	1	0.3252	0.5187		-1	0	3.7	-69.11
c.676T>A	S226T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S226T 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, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while FoldX is uncertain and therefore 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) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. 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	PH	0.129801	Structured	0.334959	Uncertain	0.800	0.324	0.250											-5.066	Likely Benign	0.102	Likely Benign	Likely Benign	0.53	Ambiguous	0.2	0.12	Likely Benign	0.33	Likely Benign	-0.10	Likely Benign	0.326	Likely Benign	-1.47	Neutral	0.390	Benign	0.079	Benign	5.75	Benign	0.05	Affected			0.1991	0.6681		1	1	0.1	14.03
c.676T>C	S226P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S226P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) all predict a pathogenic or likely pathogenic outcome. Uncertain results are reported by FoldX, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Overall, the preponderance of evidence indicates that S226P 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	PH	0.129801	Structured	0.334959	Uncertain	0.800	0.324	0.250											-11.030	Likely Pathogenic	0.933	Likely Pathogenic	Ambiguous	1.51	Ambiguous	1.1	5.29	Destabilizing	3.40	Destabilizing	0.57	Ambiguous	0.776	Likely Pathogenic	-3.22	Deleterious	0.971	Probably Damaging	0.543	Possibly Damaging	5.74	Benign	0.04	Affected			0.2837	0.7038		1	-1	-0.8	10.04
c.677C>T	S226L 2D AIThe SynGAP1 missense variant S226L 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 FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, PROVEAN, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote) also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts benign. No prediction or folding 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	PH	0.129801	Structured	0.334959	Uncertain	0.800	0.324	0.250											-6.098	Likely Benign	0.239	Likely Benign	Likely Benign	-0.12	Likely Benign	0.5	-0.14	Likely Benign	-0.13	Likely Benign	0.36	Likely Benign	0.578	Likely Pathogenic	-3.87	Deleterious	0.437	Benign	0.048	Benign	5.73	Benign	0.03	Affected			0.1525	0.5907		-3	-2	4.6	26.08
c.679G>A	G227R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of other in silico predictors classify the variant as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized (premPS is inconclusive). 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) reports a pathogenic effect. Overall, the preponderance of evidence points to a pathogenic classification for G227R, with no conflict from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.106997	Structured	0.329995	Uncertain	0.800	0.329	0.250											-9.776	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	2.31	Destabilizing	0.3	5.29	Destabilizing	3.80	Destabilizing	0.90	Ambiguous	0.765	Likely Pathogenic	-6.49	Deleterious	0.020	Benign	0.018	Benign	6.02	Benign	0.01	Affected	3.43	12	0.0997	0.4195		-2	-3	-4.1	99.14
c.679G>C	G227R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227R is not reported in ClinVar (no ClinVar ID) but is present in gnomAD (ID 6‑33435530‑G‑C). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect comprise REVEL, FoldX, Rosetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. The premPS score is uncertain and does not influence the consensus. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Based on the overwhelming agreement among high‑confidence predictors, the variant is most likely pathogenic; this conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.106997	Structured	0.329995	Uncertain	0.800	0.329	0.250								6-33435530-G-C	1	6.20e-7	-9.776	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	2.31	Destabilizing	0.3	5.29	Destabilizing	3.80	Destabilizing	0.90	Ambiguous	0.765	Likely Pathogenic	-6.49	Deleterious	0.020	Benign	0.018	Benign	6.02	Benign	0.01	Affected	3.43	12	0.0997	0.4195		-2	-3	-4.1	99.14
c.67G>A	D23N 2D AIThe SynGAP1 D23N missense variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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 Benign		0.557691	Disordered	0.440341	Uncertain	0.369	0.892	0.375											-3.918	Likely Benign	0.719	Likely Pathogenic	Likely Benign										0.077	Likely Benign	-1.88	Neutral	0.805	Possibly Damaging	0.539	Possibly Damaging	3.52	Benign	0.00	Affected			0.2236	0.8784		2	1	0.0	-0.98
c.67G>C	D23H 2D AIThe SynGAP1 D23H missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.557691	Disordered	0.440341	Uncertain	0.369	0.892	0.375											-3.801	Likely Benign	0.867	Likely Pathogenic	Ambiguous										0.103	Likely Benign	-2.46	Neutral	0.972	Probably Damaging	0.861	Possibly Damaging	3.47	Benign	0.00	Affected			0.2644	0.9017		1	-1	0.3	22.05
c.67G>T	D23Y 2D AIThe SynGAP1 D23Y missense variant is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33420331‑G‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, 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 results are unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. 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.			0.557691	Disordered	0.440341	Uncertain	0.369	0.892	0.375								6-33420331-G-T			-4.191	Likely Benign	0.729	Likely Pathogenic	Likely Benign										0.142	Likely Benign	-2.87	Deleterious	0.972	Probably Damaging	0.861	Possibly Damaging	3.46	Benign	0.00	Affected	4.32	1	0.1013	0.7951		-3	-4	2.2	48.09
c.680G>A	G227E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227E is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33435531-G-A). Functional prediction tools largely agree on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report pathogenicity, while only polyPhen‑2 (HumVar) and FATHMM predict a benign outcome; premPS remains inconclusive. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Taken together, the overwhelming majority of evidence points to a pathogenic effect. This conclusion is consistent with the ClinVar “Uncertain” classification, which does not contradict the predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.106997	Structured	0.329995	Uncertain	0.800	0.329	0.250					Conflicting		2	6-33435531-G-A	3	1.86e-6	-9.186	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	2.56	Destabilizing	0.4	5.36	Destabilizing	3.96	Destabilizing	0.94	Ambiguous	0.792	Likely Pathogenic	-6.49	Deleterious	0.906	Possibly Damaging	0.360	Benign	5.72	Benign	0.01	Affected	3.43	12	0.1414	0.4049		0	-2	-3.1	72.06	237.7	-112.1	0.1	0.3	0.0	0.3		X				X		Uncertain	The introduced residue Glu227 is located in a β hairpin loop connecting two anti-parallel β sheet strands (res. Cys219-Thr224 and Thr228-Ala232). In the variant simulations, the carboxylate group of Glu227 frequently forms a salt bridge with the amino group of the neighboring residue Lys229. Despite this interaction, the integrity of the secondary structure element is not compromised. However, the β hairpins are potential nucleation sites during the initial stages of protein folding. Additionally, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.680G>C	G227A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, and AlphaMissense‑Default. Predictions that remain uncertain are premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic majority, 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 overall consensus of the majority of tools and the high‑accuracy predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.106997	Structured	0.329995	Uncertain	0.800	0.329	0.250											-7.344	In-Between	0.920	Likely Pathogenic	Ambiguous	2.45	Destabilizing	0.4	5.14	Destabilizing	3.80	Destabilizing	0.78	Ambiguous	0.682	Likely Pathogenic	-5.08	Deleterious	0.097	Benign	0.023	Benign	5.71	Benign	0.04	Affected			0.3987	0.5221		1	0	2.2	14.03
c.680G>T	G227V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227V 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 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 outputs, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.106997	Structured	0.329995	Uncertain	0.800	0.329	0.250											-9.329	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	3.57	Destabilizing	0.4	6.24	Destabilizing	4.91	Destabilizing	0.78	Ambiguous	0.839	Likely Pathogenic	-7.58	Deleterious	0.952	Possibly Damaging	0.521	Possibly Damaging	5.67	Benign	0.01	Affected			0.1130	0.4703		-1	-3	4.6	42.08
c.682A>C	T228P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T228P 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 FATHMM, Rosetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is inconclusive, but the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.104810	Structured	0.321733	Uncertain	0.829	0.316	0.125											-8.559	Likely Pathogenic	0.939	Likely Pathogenic	Ambiguous	1.65	Ambiguous	0.6	0.47	Likely Benign	1.06	Ambiguous	0.21	Likely Benign	0.690	Likely Pathogenic	-3.54	Deleterious	0.984	Probably Damaging	0.690	Possibly Damaging	5.64	Benign	0.02	Affected			0.2207	0.6360		0	-1	-0.9	-3.99
c.682A>G	T228A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T228A variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include FoldX, 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 that predict a pathogenic effect are REVEL, SIFT, and AlphaMissense‑Default. Predictions that are inconclusive or uncertain are Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as benign (majority of its constituent predictors are benign), and Foldetta as uncertain. Overall, the balance of evidence favors a benign interpretation; 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	PH	0.104810	Structured	0.321733	Uncertain	0.829	0.316	0.125											-5.190	Likely Benign	0.793	Likely Pathogenic	Ambiguous	0.44	Likely Benign	0.0	0.82	Ambiguous	0.63	Ambiguous	0.58	Ambiguous	0.520	Likely Pathogenic	-2.30	Neutral	0.363	Benign	0.138	Benign	5.63	Benign	0.04	Affected			0.4072	0.5014		1	0	2.5	-30.03
c.683C>A	T228K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T228K is 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, and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give uncertain results (Rosetta and premPS). High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict any existing ClinVar annotation because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.104810	Structured	0.321733	Uncertain	0.829	0.316	0.125											-9.143	Likely Pathogenic	0.975	Likely Pathogenic	Likely Pathogenic	0.03	Likely Benign	0.1	0.87	Ambiguous	0.45	Likely Benign	0.70	Ambiguous	0.676	Likely Pathogenic	-3.00	Deleterious	0.906	Possibly Damaging	0.521	Possibly Damaging	5.60	Benign	0.02	Affected			0.1322	0.3590		0	-1	-3.2	27.07
c.683C>G	T228R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T228R 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, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.104810	Structured	0.321733	Uncertain	0.829	0.316	0.125											-7.218	In-Between	0.965	Likely Pathogenic	Likely Pathogenic	-0.23	Likely Benign	0.1	0.69	Ambiguous	0.23	Likely Benign	0.67	Ambiguous	0.693	Likely Pathogenic	-3.40	Deleterious	0.952	Possibly Damaging	0.694	Possibly Damaging	5.60	Benign	0.01	Affected			0.1108	0.3405		-1	-1	-3.8	55.08
c.685A>C	K229Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K229Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, FATHMM, and Foldetta; pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this assessment does not conflict with ClinVar status, which currently has no entry for K229Q. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.179055	Structured	0.310912	Uncertain	0.843	0.306	0.000											-9.606	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	0.41	Likely Benign	0.0	-0.05	Likely Benign	0.18	Likely Benign	0.55	Ambiguous	0.813	Likely Pathogenic	-3.03	Deleterious	0.998	Probably Damaging	0.987	Probably Damaging	5.84	Benign	0.02	Affected			0.4456	0.1057		1	1	0.4	-0.04
c.686A>C	K229T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K229T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include Rosetta, Foldetta, premPS, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. High‑accuracy methods give a pathogenic result from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and a benign outcome from Foldetta. 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	0.179055	Structured	0.310912	Uncertain	0.843	0.306	0.000											-12.639	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	0.83	Ambiguous	0.0	-0.08	Likely Benign	0.38	Likely Benign	0.00	Likely Benign	0.813	Likely Pathogenic	-4.77	Deleterious	0.998	Probably Damaging	0.987	Probably Damaging	5.86	Benign	0.01	Affected			0.1890	0.3029		0	-1	3.2	-27.07
c.686A>T	K229I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K229I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from FoldX, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed 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 benign. No prediction is inconclusive. Overall, the majority of tools, including the high‑accuracy ones, lean toward pathogenicity, and this 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	0.179055	Structured	0.310912	Uncertain	0.843	0.306	0.000											-15.276	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	-0.03	Likely Benign	0.1	-0.63	Ambiguous	-0.33	Likely Benign	-0.19	Likely Benign	0.833	Likely Pathogenic	-6.52	Deleterious	0.998	Probably Damaging	0.991	Probably Damaging	5.92	Benign	0.00	Affected			0.1202	0.3711		-2	-3	8.4	-15.01
c.687A>C	K229N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K229N 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 limited to 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) return uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. The variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.179055	Structured	0.310912	Uncertain	0.843	0.306	0.000											-13.620	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.82	Ambiguous	0.1	0.64	Ambiguous	0.73	Ambiguous	0.61	Ambiguous	0.590	Likely Pathogenic	-3.79	Deleterious	0.998	Probably Damaging	0.987	Probably Damaging	5.83	Benign	0.01	Affected			0.3682	0.1013		1	0	0.4	-14.07
c.687A>T	K229N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K229N 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 FATHMM, whereas the remaining nine tools—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is uncertain and therefore not considered evidence for or against pathogenicity. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.179055	Structured	0.310912	Uncertain	0.843	0.306	0.000											-13.620	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.82	Ambiguous	0.1	0.64	Ambiguous	0.73	Ambiguous	0.61	Ambiguous	0.588	Likely Pathogenic	-3.79	Deleterious	0.998	Probably Damaging	0.987	Probably Damaging	5.83	Benign	0.01	Affected			0.3682	0.1013		1	0	0.4	-14.07
c.688T>C	C230R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from FoldX and FATHMM, while pathogenic predictions are made by REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a pathogenic effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for C230R, 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	0.268042	Structured	0.308076	Uncertain	0.870	0.308	0.000											-12.478	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	-0.48	Likely Benign	0.0	-1.61	Ambiguous	-1.05	Ambiguous	1.12	Destabilizing	0.905	Likely Pathogenic	-9.88	Deleterious	0.838	Possibly Damaging	0.548	Possibly Damaging	5.91	Benign	0.01	Affected			0.1744	0.1637		-4	-3	-7.0	53.05
c.688T>G	C230G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reached a consensus fall into two groups: benign predictions come from polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain or inconclusive results from FoldX, Rosetta, Foldetta, and premPS are treated as unavailable and do not influence the overall assessment. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also Likely Pathogenic; Foldetta remains uncertain. Based on the aggregate predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.268042	Structured	0.308076	Uncertain	0.870	0.308	0.000											-10.888	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.72	Ambiguous	0.1	0.86	Ambiguous	0.79	Ambiguous	0.81	Ambiguous	0.775	Likely Pathogenic	-9.95	Deleterious	0.001	Benign	0.004	Benign	5.85	Benign	0.03	Affected			0.3313	0.2574		-3	-3	-2.9	-46.09
c.689G>T	C230F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Foldetta and premPS give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that C230F is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.268042	Structured	0.308076	Uncertain	0.870	0.308	0.000											-11.134	Likely Pathogenic	0.988	Likely Pathogenic	Likely Pathogenic	-0.09	Likely Benign	0.1	-2.03	Stabilizing	-1.06	Ambiguous	0.51	Ambiguous	0.840	Likely Pathogenic	-8.73	Deleterious	0.940	Possibly Damaging	0.641	Possibly Damaging	5.96	Benign	0.03	Affected			0.1329	0.4173		-4	-2	0.3	44.04
c.68A>C	D23A 2D AIThe SynGAP1 D23A missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic versus four benign) suggest a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.			0.557691	Disordered	0.440341	Uncertain	0.369	0.892	0.375											-2.732	Likely Benign	0.777	Likely Pathogenic	Likely Benign										0.112	Likely Benign	-2.57	Deleterious	0.909	Possibly Damaging	0.539	Possibly Damaging	3.52	Benign	0.00	Affected			0.4613	0.8203		0	-2	5.3	-44.01
c.68A>G	D23G 2D AIThe SynGAP1 missense variant D23G is listed in ClinVar (ID 3644551.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification but leans toward a benign interpretation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.557691	Disordered	0.440341	Uncertain	0.369	0.892	0.375					Uncertain		1				-2.622	Likely Benign	0.684	Likely Pathogenic	Likely Benign										0.100	Likely Benign	-2.45	Neutral	0.805	Possibly Damaging	0.539	Possibly Damaging	3.50	Benign	0.00	Affected			0.4682	0.7632		1	-1	3.1	-58.04
c.68A>T	D23V 2D AIThe SynGAP1 D23V missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus unavailable; Foldetta predictions are not provided. Overall, more tools (five) predict pathogenicity than benign (three), and no ClinVar evidence contradicts this assessment. Therefore, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.			0.557691	Disordered	0.440341	Uncertain	0.369	0.892	0.375											-3.244	Likely Benign	0.842	Likely Pathogenic	Ambiguous										0.137	Likely Benign	-2.72	Deleterious	0.972	Probably Damaging	0.804	Possibly Damaging	3.48	Benign	0.00	Affected			0.1515	0.8367		-2	-3	7.7	-15.96
c.690C>G	C230W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by FATHMM and FoldX, whereas the majority of other in silico predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic impact for C230W, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.268042	Structured	0.308076	Uncertain	0.870	0.308	0.000											-11.022	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	-0.21	Likely Benign	0.0	-1.87	Ambiguous	-1.04	Ambiguous	0.74	Ambiguous	0.739	Likely Pathogenic	-8.79	Deleterious	0.983	Probably Damaging	0.841	Possibly Damaging	5.84	Benign	0.01	Affected			0.1589	0.3663		-8	-2	-3.4	83.07
c.691T>A	F231I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta’s stability prediction is uncertain and thus not considered evidence. No other tools provide definitive pathogenic or benign conclusions. Based on the preponderance of pathogenic predictions and the lack of contrary evidence, the variant is most likely pathogenic; this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-13.827	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.16	Ambiguous	0.4	1.65	Ambiguous	1.41	Ambiguous	0.94	Ambiguous	0.894	Likely Pathogenic	-5.01	Deleterious	0.759	Possibly Damaging	0.328	Benign	5.76	Benign	0.00	Affected			0.2122	0.2813		1	0	1.7	-34.02
c.691T>C	F231L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact for F231L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-9.482	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.07	Ambiguous	0.3	1.26	Ambiguous	1.17	Ambiguous	0.85	Ambiguous	0.801	Likely Pathogenic	-5.08	Deleterious	0.390	Benign	0.142	Benign	6.04	Benign	0.01	Affected			0.2338	0.3794		2	0	1.0	-34.02
c.691T>G	F231V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates pathogenicity. Taken together, the evidence overwhelmingly points to a pathogenic effect for F231V, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-13.201	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	2.16	Destabilizing	0.3	2.30	Destabilizing	2.23	Destabilizing	1.13	Destabilizing	0.910	Likely Pathogenic	-5.90	Deleterious	0.759	Possibly Damaging	0.328	Benign	5.72	Benign	0.00	Affected			0.2212	0.3030		-1	-1	1.4	-48.04
c.692T>C	F231S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-14.655	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	2.89	Destabilizing	0.4	4.22	Destabilizing	3.56	Destabilizing	2.22	Destabilizing	0.909	Likely Pathogenic	-6.92	Deleterious	0.608	Possibly Damaging	0.205	Benign	5.48	Benign	0.00	Affected			0.4297	0.0544		-3	-2	-3.6	-60.10
c.692T>G	F231C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231C is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-13.315	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	2.26	Destabilizing	0.3	2.82	Destabilizing	2.54	Destabilizing	2.04	Destabilizing	0.937	Likely Pathogenic	-6.89	Deleterious	0.992	Probably Damaging	0.707	Possibly Damaging	5.49	Benign	0.00	Affected			0.2527	0.1612		-4	-2	-0.3	-44.04
c.693T>A	F231L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact for F231L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-9.482	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.07	Ambiguous	0.3	1.26	Ambiguous	1.17	Ambiguous	0.85	Ambiguous	0.662	Likely Pathogenic	-5.08	Deleterious	0.390	Benign	0.142	Benign	6.04	Benign	0.01	Affected			0.2338	0.3794		2	0	1.0	-34.02
c.693T>G	F231L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar and FATHMM, whereas REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized all predict a pathogenic effect. The SGM‑Consensus score is labeled Likely Pathogenic, and the remaining tools (FoldX, Rosetta, Foldetta, premPS) are inconclusive. High‑accuracy methods give a pathogenic verdict from AlphaMissense‑Optimized, a Likely Pathogenic result from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain outcome from Foldetta. Overall, the majority of evidence points to a pathogenic impact for F231L, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.366687	Structured	0.306467	Uncertain	0.895	0.300	0.000											-9.482	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.07	Ambiguous	0.3	1.26	Ambiguous	1.17	Ambiguous	0.85	Ambiguous	0.661	Likely Pathogenic	-5.08	Deleterious	0.390	Benign	0.142	Benign	6.04	Benign	0.01	Affected			0.2338	0.3794		2	0	1.0	-34.02
c.695C>A	A232D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232D is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus. Uncertain or inconclusive results are reported for Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as pathogenic, while Foldetta remains uncertain. Overall, the majority of available predictions support a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.254060	Structured	0.307228	Uncertain	0.878	0.305	0.000											-13.956	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.14	Likely Benign	0.2	1.55	Ambiguous	0.85	Ambiguous	0.77	Ambiguous	0.725	Likely Pathogenic	-2.50	Deleterious	0.845	Possibly Damaging	0.348	Benign	5.78	Benign	0.02	Affected			0.2066	0.2896		0	-2	-5.3	44.01
c.697T>A	C233S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors pathogenicity (3 pathogenic vs 1 benign). Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.306787	Uncertain	0.868	0.322	0.000											-10.862	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.61	Ambiguous	0.1	1.25	Ambiguous	0.93	Ambiguous	1.50	Destabilizing	0.764	Likely Pathogenic	-8.89	Deleterious	0.421	Benign	0.080	Benign	5.79	Benign	0.03	Affected			0.4528	0.2833		0	-1	-3.3	-16.06
c.697T>C	C233R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and gnomAD presence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.306787	Uncertain	0.868	0.322	0.000											-16.789	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.79	Destabilizing	3.4	2.17	Destabilizing	2.98	Destabilizing	1.75	Destabilizing	0.830	Likely Pathogenic	-10.68	Deleterious	0.002	Benign	0.002	Benign	5.71	Benign	0.01	Affected			0.1733	0.2212		-4	-3	-7.0	53.05
c.698G>A	C233Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233Y is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are Rosetta and FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic (3 pathogenic vs. 1 benign); and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.306787	Uncertain	0.868	0.322	0.000											-17.893	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	13.15	Destabilizing	4.6	0.04	Likely Benign	6.60	Destabilizing	0.71	Ambiguous	0.904	Likely Pathogenic	-9.79	Deleterious	0.940	Possibly Damaging	0.459	Possibly Damaging	5.71	Benign	0.00	Affected	4.29	391	0.1324	0.5284		0	-2	-3.8	60.04	248.9	-63.0	0.0	0.3	0.0	0.4	X						X	Potentially Pathogenic	The introduced residue Tyr233 is located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Ala232) and an α helix (residues Ala236-Val250). Although the thiol group of a cysteine side chain is not a strong hydrogen bond acceptor or donor, it facilitates hydrogen bonding between Cys233 and the backbone carbonyl of Ala232 in the WT simulations. In the variant simulations, the bulky phenol ring of the Tyr233 side chain stacks with the indole ring of the Trp242 side chain. This interaction could alter the tertiary assembly of the β sheet and α helix due to the residue swap. Indeed, in the second replica simulation, the protein structure begins to unfold to accommodate the introduced Tyr233 side chain.	10.1016/j.ajhg.2020.11.011
c.698G>C	C233S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of evidence points to a pathogenic impact for C233S, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.306787	Uncertain	0.868	0.322	0.000											-10.862	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.61	Ambiguous	0.1	1.25	Ambiguous	0.93	Ambiguous	1.50	Destabilizing	0.830	Likely Pathogenic	-8.89	Deleterious	0.421	Benign	0.080	Benign	5.79	Benign	0.03	Affected			0.4528	0.2833		0	-1	-3.3	-16.06
c.698G>T	C233F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include Rosetta, premPS, and FATHMM, whereas the remaining tools—REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and Foldetta—predict a pathogenic or likely pathogenic impact. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence supports a pathogenic effect, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.306787	Uncertain	0.868	0.322	0.000											-14.564	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	9.36	Destabilizing	3.0	-0.19	Likely Benign	4.59	Destabilizing	0.37	Likely Benign	0.901	Likely Pathogenic	-9.79	Deleterious	0.940	Possibly Damaging	0.459	Possibly Damaging	5.73	Benign	0.00	Affected			0.1524	0.5231		-4	-2	0.3	44.04
c.699T>G	C233W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233W is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a benign outcome, while Rosetta and premPS are uncertain. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Taken together, the overwhelming majority of evidence indicates that C233W is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.306787	Uncertain	0.868	0.322	0.000											-17.899	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	14.72	Destabilizing	6.6	1.07	Ambiguous	7.90	Destabilizing	0.54	Ambiguous	0.772	Likely Pathogenic	-9.79	Deleterious	0.983	Probably Damaging	0.715	Possibly Damaging	5.71	Benign	0.00	Affected			0.1727	0.5292		-8	-2	-3.4	83.07
c.69T>A	D23E 2D AIThe SynGAP1 D23E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.557691	Disordered	0.440341	Uncertain	0.369	0.892	0.375											-3.329	Likely Benign	0.565	Likely Pathogenic	Likely Benign										0.084	Likely Benign	-1.35	Neutral	0.643	Possibly Damaging	0.417	Benign	3.59	Benign	0.00	Affected	4.32	1	0.2420	0.8363		2	3	0.0	14.03
c.69T>G	D23E 2D AIThe SynGAP1 missense variant D23E is listed in gnomAD (ID 6‑33423478‑T‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence—including the consensus and high‑accuracy tools—points to a benign effect, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.557691	Disordered	0.440341	Uncertain	0.369	0.892	0.375								6-33423478-T-G	15	9.29e-6	-3.329	Likely Benign	0.565	Likely Pathogenic	Likely Benign										0.084	Likely Benign	-1.35	Neutral	0.643	Possibly Damaging	0.417	Benign	3.59	Benign	0.00	Affected	4.32	1	0.2420	0.8363		2	3	0.0	14.03
c.6C>A	S2R 2D AIThe SynGAP1 missense variant S2R is present in gnomAD (ID 6‑33420270‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score all report benign or likely benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.671169	Disordered	0.543646	Binding	0.382	0.922	0.750								6-33420270-C-A	1	6.52e-7	-3.684	Likely Benign	0.426	Ambiguous	Likely Benign										0.070	Likely Benign	-0.44	Neutral	0.117	Benign	0.008	Benign	4.05	Benign	0.00	Affected	4.32	1	0.0996	0.4503		-1	0	-3.7	69.11
c.6C>G	S2R 2D AIThe SynGAP1 missense variant S2R is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the preponderance of evidence from multiple prediction tools and high‑accuracy methods indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.671169	Disordered	0.543646	Binding	0.382	0.922	0.750											-3.684	Likely Benign	0.426	Ambiguous	Likely Benign										0.065	Likely Benign	-0.44	Neutral	0.117	Benign	0.008	Benign	4.05	Benign	0.00	Affected	4.32	1	0.0996	0.4503		-1	0	-3.7	69.11
c.700C>T	R234W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234W missense variant is listed in ClinVar (ID 856396.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33435551‑C‑T). Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) indicate a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain”; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is “Uncertain.” Overall, the preponderance of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertainty rather than a benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.311558	Uncertain	0.804	0.322	0.000					Uncertain		1	6-33435551-C-T	3	1.86e-6	-12.625	Likely Pathogenic	0.947	Likely Pathogenic	Ambiguous	0.96	Ambiguous	0.3	0.69	Ambiguous	0.83	Ambiguous	0.13	Likely Benign	0.805	Likely Pathogenic	-5.52	Deleterious	0.997	Probably Damaging	0.803	Possibly Damaging	5.76	Benign	0.01	Affected	3.40	14	0.1302	0.4035		2	-3	3.6	30.03	262.8	39.6	-0.1	0.0	-0.2	0.2		X						Potentially Pathogenic	The guanidinium group of Arg234, located in a β-α loop between an anti-parallel β sheet strand (residues Gly227-Phe231) and an α helix (res. Ala236-Val250), forms a salt bridge with the carboxylate group of Glu238 in the α helix. Occasionally, it also bonds with the GAP domain residues Ser678 and Glu680. Thus, the positively charged Arg234 could contribute to the tertiary structure assembly between the PH and GAP domains. In contrast, the indole side chain of Trp234 in the variant is located on the protein surface in the variant simulations and is unable to form any interactions.
c.701G>C	R234P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R234P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of evaluated algorithms (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.239899	Structured	0.311558	Uncertain	0.804	0.322	0.000											-10.126	Likely Pathogenic	0.972	Likely Pathogenic	Likely Pathogenic	1.33	Ambiguous	0.6	1.36	Ambiguous	1.35	Ambiguous	0.13	Likely Benign	0.826	Likely Pathogenic	-4.43	Deleterious	0.929	Possibly Damaging	0.519	Possibly Damaging	5.93	Benign	0.04	Affected			0.1972	0.4336		0	-2	2.9	-59.07
c.703T>C	S235P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235P is listed in ClinVar as Pathogenic (ClinVar ID 1067856.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. No predictions or stability results are missing or inconclusive. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.250310	Structured	0.319150	Uncertain	0.743	0.331	0.000					Likely Pathogenic		1				-14.857	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	4.02	Destabilizing	0.1	6.91	Destabilizing	5.47	Destabilizing	1.23	Destabilizing	0.870	Likely Pathogenic	-4.24	Deleterious	0.917	Possibly Damaging	0.446	Benign	5.47	Benign	0.01	Affected	3.40	14	0.2432	0.5307		1	-1	-0.8	10.04	201.5	17.0	0.1	0.0	-0.6	0.0		X						Potentially Pathogenic	In the WT, the hydroxyl group of Ser235, located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Phe231) and an α helix (residues Ala236-Val250), forms hydrogen bonds with the GAP domain loop residue Glu680 and with the backbone amide groups of Ala237 and Glu238 from the α helix. In the variant simulations, the pyrrolidine ring of Pro235 cannot stabilize the α helix end or maintain tertiary bonding interactions between the PH and GAP domains via hydrogen bonding as effectively as serine.
c.703T>G	S235A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235A has no ClinVar entry and is not present in gnomAD. Prediction tools that indicate benign effects include Rosetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic; Foldetta remains uncertain. Overall, the balance of evidence leans toward a benign interpretation, but the SGM Consensus introduces a pathogenic signal, resulting in a conflicting prediction profile. This assessment does not contradict ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.250310	Structured	0.319150	Uncertain	0.743	0.331	0.000											-10.861	Likely Pathogenic	0.707	Likely Pathogenic	Likely Benign	1.92	Ambiguous	0.1	0.19	Likely Benign	1.06	Ambiguous	0.48	Likely Benign	0.646	Likely Pathogenic	-2.52	Deleterious	0.002	Benign	0.004	Benign	5.49	Benign	0.01	Affected			0.5168	0.4563	Weaken	1	1	2.6	-16.00
c.704C>A	S235Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FATHMM and Rosetta, whereas the majority of other in silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. Two tools give inconclusive results: Foldetta (protein‑folding stability) and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for S235Y, and this conclusion is not contradicted by any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.250310	Structured	0.319150	Uncertain	0.743	0.331	0.000											-15.842	Likely Pathogenic	0.977	Likely Pathogenic	Likely Pathogenic	3.53	Destabilizing	1.8	0.43	Likely Benign	1.98	Ambiguous	0.66	Ambiguous	0.887	Likely Pathogenic	-5.14	Deleterious	0.971	Probably Damaging	0.641	Possibly Damaging	5.45	Benign	0.00	Affected			0.0733	0.5269		-3	-2	-0.5	76.10
c.704C>G	S235C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FATHMM and Rosetta, whereas a majority of tools (REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Results from high‑accuracy methods are mixed: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta is uncertain. Because the uncertain predictions are treated as unavailable, the overall evidence still favors pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.250310	Structured	0.319150	Uncertain	0.743	0.331	0.000											-11.350	Likely Pathogenic	0.800	Likely Pathogenic	Ambiguous	1.74	Ambiguous	0.1	0.42	Likely Benign	1.08	Ambiguous	0.76	Ambiguous	0.878	Likely Pathogenic	-4.24	Deleterious	0.977	Probably Damaging	0.620	Possibly Damaging	5.45	Benign	0.00	Affected			0.1284	0.6015		0	-1	3.3	16.06
c.704C>T	S235F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235F is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FATHMM and Rosetta, whereas the majority of other in silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. Two tools give inconclusive results: Foldetta (protein‑folding stability) and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.250310	Structured	0.319150	Uncertain	0.743	0.331	0.000											-14.456	Likely Pathogenic	0.988	Likely Pathogenic	Likely Pathogenic	3.03	Destabilizing	1.7	0.46	Likely Benign	1.75	Ambiguous	0.56	Ambiguous	0.919	Likely Pathogenic	-5.14	Deleterious	0.917	Possibly Damaging	0.548	Possibly Damaging	5.45	Benign	0.00	Affected			0.0617	0.5393		-3	-2	3.6	60.10
c.706G>A	A236T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A236T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and thus unavailable. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, six tools favor pathogenicity versus three favor benign, and no high‑confidence consensus tool contradicts this trend. Therefore, the variant is most likely pathogenic, and this assessment does not conflict with any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.185198	Structured	0.329926	Uncertain	0.775	0.330	0.000											-8.319	Likely Pathogenic	0.240	Likely Benign	Likely Benign	0.73	Ambiguous	0.2	1.58	Ambiguous	1.16	Ambiguous	0.83	Ambiguous	0.811	Likely Pathogenic	-3.35	Deleterious	0.982	Probably Damaging	0.747	Possibly Damaging	5.79	Benign	0.03	Affected			0.1342	0.6926		1	0	-2.5	30.03
c.707C>A	A236E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A236E is not reported in ClinVar and is present in gnomAD (ID 6‑33435558‑C‑A). Functional prediction tools show a split assessment: benign calls come from FATHMM, Rosetta, and the protein‑folding stability method Foldetta; pathogenic calls come from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. When grouped by agreement, the benign‑predicting tools (FATHMM, Rosetta, Foldetta) represent one consensus, while the pathogenic‑predicting tools (REVEL, premPS, PROVEAN, polyPhen‑2, SIFT, ESM1b, AlphaMissense‑Default, SGM‑Consensus) form the opposing consensus. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain; SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely pathogenic; Foldetta, combining FoldX‑MD and Rosetta outputs, is benign. Overall, the majority of predictions lean toward pathogenicity, and this does not contradict the ClinVar status, which has no reported classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.185198	Structured	0.329926	Uncertain	0.775	0.330	0.000								6-33435558-C-A	1	6.20e-7	-10.844	Likely Pathogenic	0.835	Likely Pathogenic	Ambiguous	-0.75	Ambiguous	0.2	0.28	Likely Benign	-0.24	Likely Benign	1.08	Destabilizing	0.844	Likely Pathogenic	-4.24	Deleterious	0.998	Probably Damaging	0.900	Possibly Damaging	6.06	Benign	0.02	Affected	3.40	14	0.1075	0.1970		-1	0	-5.3	58.04
c.707C>T	A236V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A236V is listed in ClinVar as Benign (ID 469162.0) and is present in gnomAD (6‑33435558‑C‑T). Prediction tools that report benign include polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, and ESM1b. Four tools give uncertain or inconclusive results: FoldX, Rosetta, Foldetta, and premPS. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because the votes are evenly split. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as uncertain, and the SGM Consensus as unavailable. Consequently, the overall prediction profile is mixed, but the most reliable high‑accuracy evidence points toward a benign effect. Therefore, the variant is most likely benign, which aligns with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.185198	Structured	0.329926	Uncertain	0.775	0.330	0.000					Benign/Likely benign		2	6-33435558-C-T	6	3.72e-6	-8.752	Likely Pathogenic	0.267	Likely Benign	Likely Benign	0.61	Ambiguous	0.2	1.08	Ambiguous	0.85	Ambiguous	0.64	Ambiguous	0.777	Likely Pathogenic	-3.55	Deleterious	0.981	Probably Damaging	0.446	Benign	5.79	Benign	0.03	Affected	3.40	14	0.0913	0.5859		0	0	2.4	28.05	213.8	-44.7	0.0	0.0	-0.2	0.2						X		Potentially Benign	The methyl side chain of Ala236, located on an α helix (residues Ala236-Val250) facing an anti-parallel β sheet strand (residues Ile205-Val209), interacts hydrophobically with nearby residues such as Arg239 and Phe218. In the variant simulations, the isopropyl branched hydrocarbon side chain of Val236 maintains similar hydrophobic interactions as alanine in the WT, with an overall arrangement remarkably similar to Ala236. The residue swap does not affect the protein structure based on the simulations.
c.709G>C	A237P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, Rosetta, and Foldetta. High‑accuracy assessments further support pathogenicity: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, Foldetta is pathogenic, and AlphaMissense‑Optimized is uncertain (treated as unavailable). Overall, the preponderance of evidence indicates that A237P is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar status is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.200174	Structured	0.334699	Uncertain	0.719	0.352	0.000											-9.119	Likely Pathogenic	0.827	Likely Pathogenic	Ambiguous	0.10	Likely Benign	0.5	4.20	Destabilizing	2.15	Destabilizing	1.04	Destabilizing	0.752	Likely Pathogenic	-3.68	Deleterious	0.995	Probably Damaging	0.832	Possibly Damaging	5.77	Benign	0.03	Affected			0.1593	0.3724		1	-1	-3.4	26.04
c.70G>A	V24I 2D AIThe SynGAP1 missense variant V24I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33423479-G-A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, the overwhelming majority of computational evidence supports a benign impact for V24I, and this conclusion does not contradict the ClinVar designation, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438970	Uncertain	0.382	0.890	0.500					Uncertain		1	6-33423479-G-A	9	5.58e-6	-3.701	Likely Benign	0.137	Likely Benign	Likely Benign										0.069	Likely Benign	-0.25	Neutral	0.043	Benign	0.031	Benign	3.96	Benign	0.00	Affected	4.32	1	0.0844	0.4564		3	4	0.3	14.03
c.70G>C	V24L 2D AIThe SynGAP1 missense variant V24L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for V24L, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438970	Uncertain	0.382	0.890	0.500											-2.590	Likely Benign	0.320	Likely Benign	Likely Benign										0.053	Likely Benign	-0.62	Neutral	0.043	Benign	0.011	Benign	3.94	Benign	0.00	Affected			0.1102	0.5226		2	1	-0.4	14.03
c.70G>T	V24L 2D AIThe SynGAP1 missense variant V24L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for V24L, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438970	Uncertain	0.382	0.890	0.500											-2.590	Likely Benign	0.320	Likely Benign	Likely Benign										0.053	Likely Benign	-0.62	Neutral	0.043	Benign	0.011	Benign	3.94	Benign	0.00	Affected			0.1102	0.5226		2	1	-0.4	14.03
c.710C>A	A237D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237D is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining tools—SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict pathogenicity. Two tools, FoldX and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support a deleterious impact: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenicity, AlphaMissense‑Optimized is uncertain, and Foldetta predicts a destabilizing, pathogenic effect. Overall, the evidence overwhelmingly indicates that the variant is pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.200174	Structured	0.334699	Uncertain	0.719	0.352	0.000											-8.880	Likely Pathogenic	0.921	Likely Pathogenic	Ambiguous	1.23	Ambiguous	0.4	3.49	Destabilizing	2.36	Destabilizing	1.20	Destabilizing	0.769	Likely Pathogenic	-3.97	Deleterious	0.969	Probably Damaging	0.704	Possibly Damaging	5.88	Benign	0.05	Affected			0.1419	0.2302		0	-2	-5.3	44.01
c.710C>G	A237G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237G is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Given the balance of evidence, the majority of high‑confidence predictions lean toward a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.200174	Structured	0.334699	Uncertain	0.719	0.352	0.000											-6.647	Likely Benign	0.316	Likely Benign	Likely Benign	1.00	Ambiguous	0.0	2.01	Destabilizing	1.51	Ambiguous	1.14	Destabilizing	0.538	Likely Pathogenic	-2.91	Deleterious	0.900	Possibly Damaging	0.430	Benign	5.81	Benign	0.05	Affected			0.1809	0.2910		1	0	-2.2	-14.03
c.712G>A	E238K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238K missense change is not reported in ClinVar and is absent from gnomAD. In silico predictors cluster into two groups: a single benign call from FATHMM, and a consensus of pathogenic predictions from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are not considered evidence. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, while Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E238K. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.194234	Structured	0.332638	Uncertain	0.796	0.326	0.000											-13.475	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.56	Ambiguous	0.4	1.83	Ambiguous	1.20	Ambiguous	0.83	Ambiguous	0.858	Likely Pathogenic	-3.63	Deleterious	0.995	Probably Damaging	0.695	Possibly Damaging	5.46	Benign	0.01	Affected	4.29	391	0.2812	0.5524		0	1	-0.4	-0.94	209.0	55.9	0.0	0.0	-0.1	0.0		X						Potentially Pathogenic	The negatively charged residue Glu238, located in an α helix (res. Ala236-Val250), is replaced by the positively charged residue Lys238. This charge reversal removes the periodically formed salt bridge between the carboxylate group of Glu238 and the guanidinium group of Arg234 observed in the WT simulations. In the variant simulations, both Lys238 and Arg234 form alternative salt bridges with the carboxylate group of Glu680 in the GAP domain loop. Although not visible in the simulations, the absence of the Glu238-Arg234 salt bridge could weaken the integrity of the α helix (residues Ala236-Val250) and potentially affect the tertiary assembly between the PH and GAP domains.
c.713A>C	E238A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E238A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: FATHMM predicts benign, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. Four methods (FoldX, Rosetta, Foldetta, premPS) return uncertain results and are treated as unavailable. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta is uncertain. Overall, the preponderance of evidence indicates that E238A is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.194234	Structured	0.332638	Uncertain	0.796	0.326	0.000											-13.252	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	0.91	Ambiguous	0.3	1.89	Ambiguous	1.40	Ambiguous	0.57	Ambiguous	0.879	Likely Pathogenic	-5.44	Deleterious	0.970	Probably Damaging	0.681	Possibly Damaging	5.44	Benign	0.04	Affected			0.4164	0.5610		0	-1	5.3	-58.04
c.713A>G	E238G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E238G is reported in gnomAD (variant ID 6‑33435564‑A‑G) but has no entry in ClinVar. Functional prediction tools largely agree on a deleterious effect: the benign‑predicting tool FATHMM is the only one that classifies it as benign, whereas the pathogenic‑predicting tools (REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Pathogenic” call) all predict a harmful impact. Predictions of uncertain status (FoldX, premPS) are treated as unavailable. High‑accuracy assessments reinforce the pathogenic view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among high‑confidence tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.194234	Structured	0.332638	Uncertain	0.796	0.326	0.000								6-33435564-A-G	1	6.19e-7	-12.582	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	1.09	Ambiguous	0.2	3.42	Destabilizing	2.26	Destabilizing	0.87	Ambiguous	0.889	Likely Pathogenic	-6.35	Deleterious	0.970	Probably Damaging	0.607	Possibly Damaging	5.39	Benign	0.00	Affected	3.40	14	0.3137	0.4833		-2	0	3.1	-72.06
c.713A>T	E238V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E238V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E238V. This conclusion is not contradicted by ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.194234	Structured	0.332638	Uncertain	0.796	0.326	0.000											-14.329	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.88	Ambiguous	0.4	0.75	Ambiguous	0.82	Ambiguous	0.45	Likely Benign	0.890	Likely Pathogenic	-6.35	Deleterious	0.997	Probably Damaging	0.879	Possibly Damaging	5.42	Benign	0.00	Affected			0.0848	0.6093		-2	-2	7.7	-29.98
c.714A>C	E238D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; the remaining methods (FoldX, Rosetta, Foldetta, premPS, ESM1b) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. The variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.194234	Structured	0.332638	Uncertain	0.796	0.326	0.000											-7.861	In-Between	0.995	Likely Pathogenic	Likely Pathogenic	1.25	Ambiguous	0.4	1.72	Ambiguous	1.49	Ambiguous	0.78	Ambiguous	0.691	Likely Pathogenic	-2.72	Deleterious	0.868	Possibly Damaging	0.504	Possibly Damaging	5.57	Benign	0.05	Affected			0.1975	0.3619		3	2	0.0	-14.03
c.714A>T	E238D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; the remaining methods (FoldX, Rosetta, Foldetta, premPS, ESM1b) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. The variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.194234	Structured	0.332638	Uncertain	0.796	0.326	0.000											-7.861	In-Between	0.995	Likely Pathogenic	Likely Pathogenic	1.25	Ambiguous	0.4	1.72	Ambiguous	1.49	Ambiguous	0.78	Ambiguous	0.691	Likely Pathogenic	-2.72	Deleterious	0.868	Possibly Damaging	0.504	Possibly Damaging	5.57	Benign	0.05	Affected			0.1975	0.3619		3	2	0.0	-14.03
c.715A>G	R239G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239G missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining twelve tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.170161	Structured	0.336504	Uncertain	0.854	0.319	0.000											-12.133	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	4.05	Destabilizing	0.1	3.41	Destabilizing	3.73	Destabilizing	1.33	Destabilizing	0.912	Likely Pathogenic	-6.26	Deleterious	0.982	Probably Damaging	0.533	Possibly Damaging	5.62	Benign	0.02	Affected			0.3415	0.3154		-3	-2	4.1	-99.14
c.716G>A	R239K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239K missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM, while the majority of other in silico predictors (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default) indicate a pathogenic impact. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Because uncertain or unavailable results are not taken as evidence for or against pathogenicity, the overall evidence still leans toward a deleterious effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.170161	Structured	0.336504	Uncertain	0.854	0.319	0.000											-12.492	Likely Pathogenic	0.897	Likely Pathogenic	Ambiguous	1.93	Ambiguous	0.2	1.62	Ambiguous	1.78	Ambiguous	1.41	Destabilizing	0.719	Likely Pathogenic	-2.52	Deleterious	0.882	Possibly Damaging	0.428	Benign	5.78	Benign	0.03	Affected			0.5222	0.4000	Weaken	3	2	0.6	-28.01
c.716G>C	R239T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R239T is recorded in gnomAD (ID 6‑33435567‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions arise from REVEL, Rosetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX reports an uncertain effect and is therefore not considered. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Consequently, the variant is most likely pathogenic according to the available computational evidence, and this assessment does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.170161	Structured	0.336504	Uncertain	0.854	0.319	0.000								6-33435567-G-C	1	6.19e-7	-14.792	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.96	Ambiguous	0.3	2.44	Destabilizing	2.20	Destabilizing	1.21	Destabilizing	0.869	Likely Pathogenic	-5.35	Deleterious	0.259	Benign	0.064	Benign	5.66	Benign	0.01	Affected	3.40	14	0.1805	0.4414		-1	-1	3.8	-55.08
c.716G>T	R239I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R239I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.170161	Structured	0.336504	Uncertain	0.854	0.319	0.000											-19.414	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.32	Destabilizing	0.5	2.53	Destabilizing	3.43	Destabilizing	0.83	Ambiguous	0.890	Likely Pathogenic	-7.16	Deleterious	0.985	Probably Damaging	0.724	Possibly Damaging	5.69	Benign	0.00	Affected			0.1480	0.3985		-2	-3	9.0	-43.03
c.717A>C	R239S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.170161	Structured	0.336504	Uncertain	0.854	0.319	0.000											-13.418	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.67	Destabilizing	0.1	2.94	Destabilizing	3.31	Destabilizing	1.26	Destabilizing	0.813	Likely Pathogenic	-5.31	Deleterious	0.900	Possibly Damaging	0.376	Benign	5.64	Benign	0.02	Affected			0.3160	0.3788		0	-1	3.7	-69.11
c.717A>T	R239S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.170161	Structured	0.336504	Uncertain	0.854	0.319	0.000											-13.418	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.67	Destabilizing	0.1	2.94	Destabilizing	3.31	Destabilizing	1.26	Destabilizing	0.813	Likely Pathogenic	-5.31	Deleterious	0.900	Possibly Damaging	0.376	Benign	5.64	Benign	0.02	Affected			0.3160	0.3788		0	-1	3.7	-69.11
c.718G>A	D240N 2D AIThe SynGAP1 missense variant D240N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Benign predictions are provided by FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. High‑accuracy methods give a split: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts pathogenic, and Foldetta predicts benign. Overall, the majority of tools favor a benign effect, and this consensus does not contradict the ClinVar uncertain status. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.343480	Uncertain	0.822	0.333	0.000					Uncertain		1				-12.942	Likely Pathogenic	0.755	Likely Pathogenic	Likely Benign	0.22	Likely Benign	0.9	0.47	Likely Benign	0.35	Likely Benign	0.37	Likely Benign	0.701	Likely Pathogenic	-4.37	Deleterious	0.993	Probably Damaging	0.984	Probably Damaging	5.88	Benign	0.01	Affected			0.0993	0.4973		2	1	0.0	-0.98
c.718G>C	D240H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240H missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy methods give a pathogenic verdict: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the consensus of the available predictions indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.343480	Uncertain	0.822	0.333	0.000											-14.551	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	1.14	Ambiguous	0.0	0.61	Ambiguous	0.88	Ambiguous	0.19	Likely Benign	0.865	Likely Pathogenic	-6.12	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	5.78	Benign	0.00	Affected			0.1223	0.5398		1	-1	0.3	22.05
c.718G>T	D240Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240Y missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, premPS, and FATHMM; pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore not considered evidence. Taken together, the overwhelming majority of reliable predictors indicate a pathogenic effect for D240Y. This conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.343480	Uncertain	0.822	0.333	0.000											-16.890	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	0.29	Likely Benign	0.3	1.07	Ambiguous	0.68	Ambiguous	-0.01	Likely Benign	0.899	Likely Pathogenic	-7.90	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	5.77	Benign	0.00	Affected			0.0439	0.4932		-4	-3	2.2	48.09
c.719A>C	D240A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are premPS and FATHMM, while the remaining pathogenic‑predicting tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently flag the variant as deleterious. Tools with uncertain outcomes (FoldX, Rosetta, Foldetta) provide no definitive guidance. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.343480	Uncertain	0.822	0.333	0.000											-12.935	Likely Pathogenic	0.980	Likely Pathogenic	Likely Pathogenic	0.75	Ambiguous	0.1	0.99	Ambiguous	0.87	Ambiguous	0.22	Likely Benign	0.872	Likely Pathogenic	-7.03	Deleterious	0.998	Probably Damaging	0.991	Probably Damaging	5.80	Benign	0.05	Affected			0.3317	0.4992		0	-2	5.3	-44.01
c.719A>G	D240G 2D AIThe SynGAP1 missense variant D240G is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Benign predictions are provided by premPS and FATHMM, whereas pathogenic predictions are made by REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. FoldX‑MD is inconclusive, and AlphaMissense‑Optimized is uncertain. High‑accuracy methods show that AlphaMissense‑Optimized is inconclusive, SGM Consensus predicts pathogenic, and Foldetta predicts pathogenic. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.343480	Uncertain	0.822	0.333	0.000					Uncertain		1				-12.825	Likely Pathogenic	0.951	Likely Pathogenic	Ambiguous	1.85	Ambiguous	0.1	2.72	Destabilizing	2.29	Destabilizing	0.24	Likely Benign	0.912	Likely Pathogenic	-6.19	Deleterious	0.993	Probably Damaging	0.984	Probably Damaging	5.79	Benign	0.01	Affected			0.3474	0.4989		1	-1	3.1	-58.04
c.719A>T	D240V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, FATHMM, and premPS, whereas the majority of algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score—classify the change as pathogenic or likely pathogenic. FoldX and Foldetta return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for D240V. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.127496	Structured	0.343480	Uncertain	0.822	0.333	0.000											-15.095	Likely Pathogenic	0.986	Likely Pathogenic	Likely Pathogenic	1.32	Ambiguous	0.1	0.28	Likely Benign	0.80	Ambiguous	0.11	Likely Benign	0.894	Likely Pathogenic	-7.94	Deleterious	0.998	Probably Damaging	0.994	Probably Damaging	5.82	Benign	0.00	Affected			0.0610	0.4949		-2	-3	7.7	-15.96
c.71T>A	V24E 2D AIThe SynGAP1 missense variant V24E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, the SGM‑Consensus also indicates Likely Benign, and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438970	Uncertain	0.382	0.890	0.500											-3.397	Likely Benign	0.517	Ambiguous	Likely Benign										0.171	Likely Benign	-1.73	Neutral	0.198	Benign	0.074	Benign	3.77	Benign	0.00	Affected			0.1133	0.2415		-2	-2	-7.7	29.98
c.71T>C	V24A 2D AIThe SynGAP1 missense variant V24A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only SIFT predicts pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign impact for V24A. This prediction is consistent with the lack of ClinVar evidence and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438970	Uncertain	0.382	0.890	0.500											-2.980	Likely Benign	0.299	Likely Benign	Likely Benign										0.074	Likely Benign	-1.09	Neutral	0.000	Benign	0.001	Benign	3.83	Benign	0.00	Affected			0.3117	0.3350		0	0	-2.4	-28.05
c.71T>G	V24G 2D AIThe SynGAP1 missense variant V24G is not reported in ClinVar (ClinVar status: not present) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.			0.541878	Disordered	0.438970	Uncertain	0.382	0.890	0.500											-2.673	Likely Benign	0.256	Likely Benign	Likely Benign										0.178	Likely Benign	-1.67	Neutral	0.026	Benign	0.049	Benign	3.77	Benign	0.00	Affected			0.2081	0.3105		-1	-3	-4.6	-42.08
c.721A>C	K241Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K241Q missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, FATHMM, and Foldetta, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, nine tools predict pathogenicity versus four predicting benign, with no ClinVar evidence to contradict these findings. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.196879	Structured	0.349250	Uncertain	0.797	0.347	0.000											-10.593	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	0.33	Likely Benign	0.0	0.46	Likely Benign	0.40	Likely Benign	0.63	Ambiguous	0.767	Likely Pathogenic	-3.33	Deleterious	0.995	Probably Damaging	0.914	Probably Damaging	5.83	Benign	0.04	Affected			0.4225	0.1527		1	1	0.4	-0.04
c.722A>C	K241T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are reported by Rosetta and FATHMM. Two tools (Foldetta and premPS) give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta remains uncertain. Overall, the consensus of the majority of evidence points to a pathogenic effect for K241T, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.196879	Structured	0.349250	Uncertain	0.797	0.347	0.000											-10.911	Likely Pathogenic	0.987	Likely Pathogenic	Likely Pathogenic	2.00	Destabilizing	0.4	0.06	Likely Benign	1.03	Ambiguous	0.60	Ambiguous	0.853	Likely Pathogenic	-5.14	Deleterious	0.995	Probably Damaging	0.747	Possibly Damaging	5.74	Benign	0.03	Affected			0.2021	0.3951		0	-1	3.2	-27.07
c.722A>T	K241I 2D 3DClick to see structure in 3D Viewer AISynGAP1 K241I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta, premPS, and FATHMM. Those that predict a damaging effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX and Foldetta return uncertain results. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized reports pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta remains inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.196879	Structured	0.349250	Uncertain	0.797	0.347	0.000											-14.370	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	1.31	Ambiguous	0.5	0.28	Likely Benign	0.80	Ambiguous	0.41	Likely Benign	0.852	Likely Pathogenic	-6.96	Deleterious	0.985	Probably Damaging	0.704	Possibly Damaging	5.71	Benign	0.01	Affected			0.1176	0.3868		-2	-3	8.4	-15.01
c.723A>C	K241N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.196879	Structured	0.349250	Uncertain	0.797	0.347	0.000											-10.198	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.92	Ambiguous	0.1	1.13	Ambiguous	1.03	Ambiguous	0.89	Ambiguous	0.663	Likely Pathogenic	-4.23	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	5.81	Benign	0.03	Affected			0.3426	0.1872		1	0	0.4	-14.07
c.723A>T	K241N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported for FoldX, Rosetta, Foldetta, and premPS and are not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.196879	Structured	0.349250	Uncertain	0.797	0.347	0.000											-10.198	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.92	Ambiguous	0.1	1.13	Ambiguous	1.03	Ambiguous	0.89	Ambiguous	0.663	Likely Pathogenic	-4.23	Deleterious	0.995	Probably Damaging	0.829	Possibly Damaging	5.81	Benign	0.03	Affected			0.3426	0.1872		1	0	0.4	-14.07
c.724T>A	W242R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant W242R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess evolutionary conservation and protein function uniformly indicate a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Consequently, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.328603	Structured	0.352582	Uncertain	0.847	0.341	0.000											-11.948	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.85	Ambiguous	0.5	1.15	Ambiguous	1.00	Ambiguous	1.34	Destabilizing	0.859	Likely Pathogenic	-12.71	Deleterious	0.995	Probably Damaging	0.854	Possibly Damaging	1.52	Pathogenic	0.00	Affected	3.40	14	0.4206	0.0771		-3	2	-3.6	-30.03
c.724T>C	W242R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242R is reported in gnomAD (ID 6‑33435575‑T‑C) but has no ClinVar entry. Across the evaluated predictors, every tool that provides a definitive call classifies the substitution as pathogenic: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No predictor reports a benign effect. FoldX, Rosetta, and Foldetta return uncertain results and are treated as unavailable evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta remains inconclusive. Consequently, the variant is most likely pathogenic based on the consensus of pathogenic predictions, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.328603	Structured	0.352582	Uncertain	0.847	0.341	0.000								6-33435575-T-C	2	1.24e-6	-11.948	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.85	Ambiguous	0.5	1.15	Ambiguous	1.00	Ambiguous	1.34	Destabilizing	0.858	Likely Pathogenic	-12.71	Deleterious	0.995	Probably Damaging	0.854	Possibly Damaging	1.52	Pathogenic	0.00	Affected	3.40	14	0.4206	0.0771		-3	2	-3.6	-30.03
c.724T>G	W242G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD, so no population frequency data are available. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the single uncertain call from premPS is treated as unavailable. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.328603	Structured	0.352582	Uncertain	0.847	0.341	0.000											-14.319	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	2.70	Destabilizing	0.3	2.48	Destabilizing	2.59	Destabilizing	0.83	Ambiguous	0.883	Likely Pathogenic	-11.80	Deleterious	0.900	Possibly Damaging	0.452	Possibly Damaging	1.52	Pathogenic	0.00	Affected			0.4378	0.1851		-7	-2	0.5	-129.16
c.725G>C	W242S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242S, located in the PH domain, is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy assessments further support a harmful impact: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic,” while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the consensus of available predictions indicates that W242S is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.328603	Structured	0.352582	Uncertain	0.847	0.341	0.000											-14.674	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.96	Ambiguous	0.2	1.97	Ambiguous	1.97	Ambiguous	0.83	Ambiguous	0.797	Likely Pathogenic	-12.71	Deleterious	0.900	Possibly Damaging	0.535	Possibly Damaging	1.52	Pathogenic	0.00	Affected			0.4424	0.1418		-2	-3	0.1	-99.14
c.725G>T	W242L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (FoldX, Rosetta, Foldetta, premPS) and pathogenic predictions (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Pathogenic). High‑accuracy assessments further support this dichotomy: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. Overall, the majority of evidence points toward a pathogenic impact for W242L. This conclusion is consistent with the absence of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.328603	Structured	0.352582	Uncertain	0.847	0.341	0.000											-12.297	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	-0.29	Likely Benign	0.3	0.12	Likely Benign	-0.09	Likely Benign	0.44	Likely Benign	0.799	Likely Pathogenic	-11.80	Deleterious	0.948	Possibly Damaging	0.533	Possibly Damaging	1.52	Pathogenic	0.01	Affected			0.2370	0.2986		-2	-2	4.7	-73.05
c.726G>C	W242C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 W242C missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS, and no tools predict a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the collective predictions, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as ClinVar has not yet classified the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.328603	Structured	0.352582	Uncertain	0.847	0.341	0.000											-13.117	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.77	Ambiguous	0.4	1.62	Ambiguous	1.70	Ambiguous	0.63	Ambiguous	0.889	Likely Pathogenic	-11.80	Deleterious	0.999	Probably Damaging	0.887	Possibly Damaging	1.52	Pathogenic	0.00	Affected			0.3626	0.1617		-8	-2	3.4	-83.07
c.726G>T	W242C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS, and no tools predict a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the collective predictions, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as ClinVar has not yet classified the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.328603	Structured	0.352582	Uncertain	0.847	0.341	0.000											-13.117	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.77	Ambiguous	0.4	1.62	Ambiguous	1.70	Ambiguous	0.63	Ambiguous	0.889	Likely Pathogenic	-11.80	Deleterious	0.999	Probably Damaging	0.887	Possibly Damaging	1.52	Pathogenic	0.00	Affected			0.3626	0.1617		-8	-2	3.4	-83.07
c.727A>T	I243F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I243F missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give inconclusive results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus unavailable; Foldetta is uncertain. Overall, the majority of available predictions (7 pathogenic vs. 3 benign) indicate a likely pathogenic impact. This assessment does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.363090	Structured	0.344471	Uncertain	0.842	0.347	0.000											-12.559	Likely Pathogenic	0.934	Likely Pathogenic	Ambiguous	2.92	Destabilizing	2.5	0.53	Ambiguous	1.73	Ambiguous	0.42	Likely Benign	0.793	Likely Pathogenic	-2.21	Neutral	0.985	Probably Damaging	0.724	Possibly Damaging	5.53	Benign	0.02	Affected			0.0409	0.2205		1	0	-1.7	34.02
c.728T>A	I243N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant I243N is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into three groups: benign (FATHMM), pathogenic (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized), and uncertain (FoldX, Rosetta, Foldetta). High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.363090	Structured	0.344471	Uncertain	0.842	0.347	0.000											-14.784	Likely Pathogenic	0.988	Likely Pathogenic	Likely Pathogenic	1.90	Ambiguous	0.2	1.43	Ambiguous	1.67	Ambiguous	1.76	Destabilizing	0.811	Likely Pathogenic	-4.46	Deleterious	0.995	Probably Damaging	0.854	Possibly Damaging	5.49	Benign	0.00	Affected			0.0899	0.0212		-2	-3	-8.0	0.94
c.728T>C	I243T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all classify the variant as pathogenic. Only FATHMM predicts a benign outcome, while Foldetta, AlphaMissense‑Optimized, and Rosetta return uncertain results, which are treated as unavailable evidence. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that I243T is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.363090	Structured	0.344471	Uncertain	0.842	0.347	0.000											-9.102	Likely Pathogenic	0.922	Likely Pathogenic	Ambiguous	2.15	Destabilizing	0.2	1.52	Ambiguous	1.84	Ambiguous	1.72	Destabilizing	0.816	Likely Pathogenic	-3.06	Deleterious	0.982	Probably Damaging	0.702	Possibly Damaging	5.55	Benign	0.01	Affected			0.1027	0.0541		0	-1	-5.2	-12.05
c.728T>G	I243S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.363090	Structured	0.344471	Uncertain	0.842	0.347	0.000											-14.097	Likely Pathogenic	0.975	Likely Pathogenic	Likely Pathogenic	2.52	Destabilizing	0.2	2.22	Destabilizing	2.37	Destabilizing	1.71	Destabilizing	0.802	Likely Pathogenic	-3.55	Deleterious	0.995	Probably Damaging	0.795	Possibly Damaging	5.52	Benign	0.00	Affected			0.2658	0.0600		-1	-2	-5.3	-26.08
c.730G>C	E244Q 2D AIThe SynGAP1 E244Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, six tools predict pathogenicity versus five predicting benignity, with no ClinVar evidence to contradict these findings. Thus, the variant is most likely pathogenic based on the current predictive landscape. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.450668	Structured	0.329406	Uncertain	0.778	0.360	0.000											-10.245	Likely Pathogenic	0.928	Likely Pathogenic	Ambiguous	0.23	Likely Benign	0.9	-0.77	Ambiguous	-0.27	Likely Benign	0.40	Likely Benign	0.695	Likely Pathogenic	-2.49	Neutral	0.990	Probably Damaging	0.815	Possibly Damaging	5.78	Benign	0.05	Affected			0.1016	0.5610		2	2	0.0	-0.98
c.731A>C	E244A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244A missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, and FATHMM, while pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign stability. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.450668	Structured	0.329406	Uncertain	0.778	0.360	0.000											-11.227	Likely Pathogenic	0.969	Likely Pathogenic	Likely Pathogenic	0.39	Likely Benign	0.1	-0.45	Likely Benign	-0.03	Likely Benign	0.82	Ambiguous	0.865	Likely Pathogenic	-4.99	Deleterious	0.970	Probably Damaging	0.584	Possibly Damaging	5.74	Benign	0.01	Affected			0.2672	0.4926		0	-1	5.3	-58.04
c.731A>G	E244G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of computational evidence points to the variant being most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.450668	Structured	0.329406	Uncertain	0.778	0.360	0.000											-10.452	Likely Pathogenic	0.958	Likely Pathogenic	Likely Pathogenic	1.28	Ambiguous	0.0	0.74	Ambiguous	1.01	Ambiguous	1.01	Destabilizing	0.900	Likely Pathogenic	-5.67	Deleterious	0.990	Probably Damaging	0.815	Possibly Damaging	5.73	Benign	0.01	Affected			0.2266	0.5252		0	-2	3.1	-72.06
c.731A>T	E244V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244V missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.450668	Structured	0.329406	Uncertain	0.778	0.360	0.000											-12.118	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	1.04	Ambiguous	0.1	1.02	Ambiguous	1.03	Ambiguous	0.56	Ambiguous	0.925	Likely Pathogenic	-5.90	Deleterious	0.997	Probably Damaging	0.879	Possibly Damaging	5.68	Benign	0.00	Affected			0.0636	0.6073		-2	-2	7.7	-29.98
c.732G>C	E244D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic classification for E244D, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.450668	Structured	0.329406	Uncertain	0.778	0.360	0.000											-7.839	In-Between	0.979	Likely Pathogenic	Likely Pathogenic	0.46	Likely Benign	0.1	1.61	Ambiguous	1.04	Ambiguous	0.93	Ambiguous	0.730	Likely Pathogenic	-2.53	Deleterious	0.976	Probably Damaging	0.675	Possibly Damaging	5.78	Benign	0.03	Affected			0.1740	0.3783		3	2	0.0	-14.03
c.732G>T	E244D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results come from Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence points to a likely pathogenic effect for E244D, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.450668	Structured	0.329406	Uncertain	0.778	0.360	0.000											-7.839	In-Between	0.979	Likely Pathogenic	Likely Pathogenic	0.46	Likely Benign	0.1	1.61	Ambiguous	1.04	Ambiguous	0.93	Ambiguous	0.730	Likely Pathogenic	-2.53	Deleterious	0.976	Probably Damaging	0.675	Possibly Damaging	5.78	Benign	0.03	Affected			0.1740	0.3783		3	2	0.0	-14.03
c.733A>C	N245H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245H is not reported in ClinVar and is absent from gnomAD. Among in‑silico predictors, benign calls come from FoldX, Rosetta, and FATHMM, whereas pathogenic calls are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. The overall pattern of predictions leans toward pathogenicity, with a majority of tools indicating a deleterious effect. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.454136	Structured	0.315864	Uncertain	0.831	0.351	0.000											-11.536	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.23	Likely Benign	0.1	-0.20	Likely Benign	0.02	Likely Benign	0.55	Ambiguous	0.825	Likely Pathogenic	-4.15	Deleterious	0.995	Probably Damaging	0.880	Possibly Damaging	5.84	Benign	0.01	Affected			0.1437	0.7271		2	1	0.3	23.04
c.733A>T	N245Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N245Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, and FATHMM, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a pathogenic majority (3/4). AlphaMissense‑Optimized independently predicts pathogenicity, while Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. premPS remains uncertain. Overall, the majority of evidence points toward a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Thus, the variant is most likely pathogenic, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.454136	Structured	0.315864	Uncertain	0.831	0.351	0.000											-12.476	Likely Pathogenic	0.982	Likely Pathogenic	Likely Pathogenic	-0.36	Likely Benign	0.1	0.11	Likely Benign	-0.13	Likely Benign	0.59	Ambiguous	0.855	Likely Pathogenic	-6.68	Deleterious	0.995	Probably Damaging	0.880	Possibly Damaging	5.86	Benign	0.00	Affected			0.0706	0.6771		-2	-2	2.2	49.07
c.734A>C	N245T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include FATHMM, Rosetta, and Foldetta, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support this dichotomy: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic, while Foldetta predicts a benign effect. No predictions are missing or inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for the variant, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.454136	Structured	0.315864	Uncertain	0.831	0.351	0.000											-11.955	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	0.52	Ambiguous	0.1	0.04	Likely Benign	0.28	Likely Benign	0.76	Ambiguous	0.794	Likely Pathogenic	-4.79	Deleterious	0.948	Possibly Damaging	0.588	Possibly Damaging	5.87	Benign	0.01	Affected			0.1397	0.7734		0	0	2.8	-13.00
c.734A>T	N245I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245I is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include Rosetta, Foldetta, and FATHMM, while those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.454136	Structured	0.315864	Uncertain	0.831	0.351	0.000											-14.527	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	-0.56	Ambiguous	0.1	0.04	Likely Benign	-0.26	Likely Benign	0.60	Ambiguous	0.831	Likely Pathogenic	-7.46	Deleterious	0.995	Probably Damaging	0.832	Possibly Damaging	5.88	Benign	0.00	Affected			0.0672	0.6999		-2	-3	8.0	-0.94
c.735T>A	N245K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM, aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and yields a majority pathogenic verdict. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, classifies the variant as benign. Overall, the majority of individual predictors and the SGM consensus favor a pathogenic effect, while Foldetta and a subset of benign tools suggest stability preservation. Given the predominance of pathogenic predictions and the absence of ClinVar annotation, the variant is most likely pathogenic and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.454136	Structured	0.315864	Uncertain	0.831	0.351	0.000											-12.110	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	-0.32	Likely Benign	0.1	0.01	Likely Benign	-0.16	Likely Benign	0.83	Ambiguous	0.474	Likely Benign	-4.86	Deleterious	0.948	Possibly Damaging	0.588	Possibly Damaging	5.88	Benign	0.01	Affected			0.2271	0.5645		1	0	-0.4	14.07
c.735T>G	N245K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a Benign effect. Overall, the preponderance of evidence—including the high‑accuracy tools—points to a pathogenic impact for N245K, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.454136	Structured	0.315864	Uncertain	0.831	0.351	0.000											-12.110	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	-0.32	Likely Benign	0.1	0.01	Likely Benign	-0.16	Likely Benign	0.83	Ambiguous	0.474	Likely Benign	-4.86	Deleterious	0.948	Possibly Damaging	0.588	Possibly Damaging	5.88	Benign	0.01	Affected			0.2271	0.5645		1	0	-0.4	14.07
c.736C>A	L246M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L246M has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN and FATHMM, while a majority (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are uncertain. High‑accuracy methods are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Thus no high‑accuracy tool provides a definitive verdict. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any ClinVar status because no ClinVar record exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.472492	Structured	0.302312	Uncertain	0.859	0.364	0.000											-11.386	Likely Pathogenic	0.922	Likely Pathogenic	Ambiguous	0.65	Ambiguous	0.2	0.76	Ambiguous	0.71	Ambiguous	0.87	Ambiguous	0.661	Likely Pathogenic	-1.79	Neutral	0.997	Probably Damaging	0.916	Probably Damaging	4.72	Benign	0.01	Affected			0.0710	0.3511		4	2	-1.9	18.03
c.736C>G	L246V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L246V is reported in gnomAD (variant ID 6‑33435587‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Only FATHMM predicts a benign outcome. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. The overwhelming majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.472492	Structured	0.302312	Uncertain	0.859	0.364	0.000								6-33435587-C-G	1	6.20e-7	-12.092	Likely Pathogenic	0.935	Likely Pathogenic	Ambiguous	2.09	Destabilizing	0.1	1.52	Ambiguous	1.81	Ambiguous	1.13	Destabilizing	0.736	Likely Pathogenic	-2.60	Deleterious	0.930	Possibly Damaging	0.504	Possibly Damaging	4.71	Benign	0.01	Affected	3.41	14	0.1434	0.3607		1	2	0.4	-14.03
c.737T>A	L246Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L246Q missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; Rosetta is uncertain and is not grouped. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the overwhelming majority of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.472492	Structured	0.302312	Uncertain	0.859	0.364	0.000											-15.420	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	2.82	Destabilizing	0.3	1.79	Ambiguous	2.31	Destabilizing	1.69	Destabilizing	0.921	Likely Pathogenic	-5.43	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	4.67	Benign	0.00	Affected			0.1092	0.0758		-2	-2	-7.3	14.97
c.737T>C	L246P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L246P is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from FATHMM, while all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.472492	Structured	0.302312	Uncertain	0.859	0.364	0.000											-16.581	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	6.42	Destabilizing	0.3	8.72	Destabilizing	7.57	Destabilizing	1.79	Destabilizing	0.944	Likely Pathogenic	-6.30	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	4.67	Benign	0.00	Affected			0.3731	0.1582		-3	-3	-5.4	-16.04
c.737T>G	L246R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L246R missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.472492	Structured	0.302312	Uncertain	0.859	0.364	0.000											-13.849	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	3.94	Destabilizing	0.8	2.77	Destabilizing	3.36	Destabilizing	1.72	Destabilizing	0.925	Likely Pathogenic	-5.43	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	4.67	Benign	0.00	Affected			0.1266	0.0600		-3	-2	-8.3	43.03
c.739C>G	Q247E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Tools that predict a pathogenic effect are premPS, SIFT, and ESM1b. AlphaMissense‑Default is uncertain, while AlphaMissense‑Optimized predicts benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign consensus (2 benign vs. 1 pathogenic, with the uncertain result treated as unavailable). High‑accuracy assessments confirm benignity: AlphaMissense‑Optimized is benign, Foldetta (combining FoldX‑MD and Rosetta outputs) is benign, and the SGM Consensus is benign. Overall, the collective evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.490133	Structured	0.283012	Uncertain	0.822	0.339	0.250											-13.564	Likely Pathogenic	0.373	Ambiguous	Likely Benign	0.42	Likely Benign	0.1	-0.26	Likely Benign	0.08	Likely Benign	1.04	Destabilizing	0.474	Likely Benign	-1.46	Neutral	0.128	Benign	0.039	Benign	5.80	Benign	0.03	Affected			0.1055	0.1476		2	2	0.0	0.98
c.73C>G	R25G 2D AIThe SynGAP1 missense variant R25G is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. When high‑accuracy tools are considered separately, AlphaMissense‑Optimized predicts a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome, and Foldetta data are unavailable. Overall, the majority of robust predictors lean toward a benign interpretation. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.461924	Structured	0.438941	Uncertain	0.373	0.890	0.375											-3.533	Likely Benign	0.373	Ambiguous	Likely Benign										0.122	Likely Benign	-1.69	Neutral	0.686	Possibly Damaging	0.630	Possibly Damaging	3.95	Benign	0.00	Affected			0.3621	0.3572		-3	-2	4.1	-99.14
c.73C>T	R25W 2D AIThe SynGAP1 missense variant R25W is listed in ClinVar with an “Uncertain” status (ClinVar ID 2993054.0) and is present in gnomAD (ID 6‑33423482‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.461924	Structured	0.438941	Uncertain	0.373	0.890	0.375					Uncertain		2	6-33423482-C-T	6	3.72e-6	-5.133	Likely Benign	0.549	Ambiguous	Likely Benign										0.158	Likely Benign	-1.60	Neutral	0.994	Probably Damaging	0.919	Probably Damaging	3.92	Benign	0.00	Affected	4.32	1	0.1224	0.3938		-3	2	3.6	30.03
c.740A>C	Q247P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact; premPS is uncertain and therefore treated as unavailable. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.490133	Structured	0.283012	Uncertain	0.822	0.339	0.250											-14.361	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	3.43	Destabilizing	0.2	7.83	Destabilizing	5.63	Destabilizing	0.81	Ambiguous	0.770	Likely Pathogenic	-3.56	Deleterious	0.995	Probably Damaging	0.795	Possibly Damaging	5.69	Benign	0.02	Affected			0.1768	0.3631		0	-1	1.9	-31.01
c.740A>T	Q247L 2D AIThe SynGAP1 missense variant Q247L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence (seven pathogenic versus three benign predictions) points to a pathogenic impact, and this conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.490133	Structured	0.283012	Uncertain	0.822	0.339	0.250											-10.554	Likely Pathogenic	0.352	Ambiguous	Likely Benign	-0.86	Ambiguous	0.5	-1.14	Ambiguous	-1.00	Ambiguous	0.38	Likely Benign	0.687	Likely Pathogenic	-3.89	Deleterious	0.982	Probably Damaging	0.628	Possibly Damaging	5.70	Benign	0.02	Affected			0.0573	0.4129		-2	-2	7.3	-14.97
c.741G>C	Q247H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247H is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include SGM‑Consensus, FoldX, Rosetta, Foldetta, ESM1b, FATHMM, AlphaMissense‑Optimized, and PROVEAN. Tools that predict a pathogenic outcome are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No predictions are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.490133	Structured	0.283012	Uncertain	0.822	0.339	0.250											-6.239	Likely Benign	0.583	Likely Pathogenic	Likely Benign	0.37	Likely Benign	0.2	0.02	Likely Benign	0.20	Likely Benign	0.58	Ambiguous	0.579	Likely Pathogenic	-2.10	Neutral	0.995	Probably Damaging	0.854	Possibly Damaging	5.71	Benign	0.02	Affected			0.0932	0.2558		3	0	0.3	9.01
c.741G>T	Q247H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, ESM1b, FATHMM, AlphaMissense‑Optimized, and PROVEAN. Those that predict a pathogenic impact are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default, while premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as benign. No prediction or folding stability result is missing or inconclusive. Based on the overall balance of evidence—seven benign versus five pathogenic predictions, and all high‑accuracy tools indicating benign—the variant is most likely benign. This conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	PH	0.490133	Structured	0.283012	Uncertain	0.822	0.339	0.250											-6.239	Likely Benign	0.583	Likely Pathogenic	Likely Benign	0.37	Likely Benign	0.2	0.02	Likely Benign	0.20	Likely Benign	0.58	Ambiguous	0.579	Likely Pathogenic	-2.10	Neutral	0.995	Probably Damaging	0.854	Possibly Damaging	5.71	Benign	0.02	Affected			0.0932	0.2558		3	0	0.3	9.01
c.742C>G	R248G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R248G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.267126	Uncertain	0.781	0.346	0.250											-13.413	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	2.23	Destabilizing	0.7	2.67	Destabilizing	2.45	Destabilizing	1.33	Destabilizing	0.770	Likely Pathogenic	-6.07	Deleterious	0.958	Probably Damaging	0.502	Possibly Damaging	5.70	Benign	0.00	Affected			0.3011	0.3385		-3	-2	4.1	-99.14
c.742C>T	R248W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248W is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Rosetta, Foldetta, and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results from FoldX and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.267126	Uncertain	0.781	0.346	0.250					Uncertain		1				-11.647	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	1.17	Ambiguous	0.3	-0.20	Likely Benign	0.49	Likely Benign	0.89	Ambiguous	0.699	Likely Pathogenic	-6.98	Deleterious	1.000	Probably Damaging	0.948	Probably Damaging	5.62	Benign	0.00	Affected	3.41	14	0.1124	0.4037		2	-3	3.6	30.03	266.4	42.3	0.0	0.0	0.3	0.1		X						Potentially Pathogenic	The guanidinium group of Arg248, located on an α helix (res. Ala236-Val250), forms two very stable salt bridges with Asp255 (from a short α helical section, res. Lys254-Asn256) and Glu244 (from a nearby loop) in the WT simulations. In the variant simulations, the indole group of Trp248 cannot form any salt bridges, which could negatively affect the tertiary structure assembly of the PH domain. Instead, in the variant simulations, the indole ring of Trp248 stacks against Pro252, which makes a turn after the α helix.
c.743G>A	R248Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248Q is catalogued in gnomAD (ID 6‑33435594‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: benign predictions come from FoldX and FATHMM, whereas pathogenic predictions are made by REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R248Q, and this conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.267126	Uncertain	0.781	0.346	0.250								6-33435594-G-A	2	1.24e-6	-10.573	Likely Pathogenic	0.979	Likely Pathogenic	Likely Pathogenic	0.45	Likely Benign	0.2	1.67	Ambiguous	1.06	Ambiguous	1.05	Destabilizing	0.739	Likely Pathogenic	-3.34	Deleterious	0.999	Probably Damaging	0.715	Possibly Damaging	5.74	Benign	0.01	Affected	3.41	14	0.2572	0.2549		1	1	1.0	-28.06
c.743G>C	R248P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R248P is listed in ClinVar as Pathogenic (ClinVar ID 1065478.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the overwhelming consensus of pathogenic predictions and the high‑accuracy tool results, the variant is most likely pathogenic, which aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.267126	Uncertain	0.781	0.346	0.250					Likely Pathogenic		1				-10.751	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.09	Destabilizing	0.6	8.87	Destabilizing	5.98	Destabilizing	1.21	Destabilizing	0.848	Likely Pathogenic	-5.97	Deleterious	0.998	Probably Damaging	0.878	Possibly Damaging	5.64	Benign	0.00	Affected	3.41	14	0.1943	0.4528		0	-2	2.9	-59.07	223.8	126.6	0.0	0.0	-0.2	0.1	X	X						Potentially Pathogenic	The guanidinium group of Arg248, located on an α helix (residues Ala236-Val250), forms two very stable salt bridges with Asp255 (from a short α helical section, res. Lys254-Asn256) and Glu244 (from a nearby loop) in the WT simulations. In the variant simulations, the pyrrolidine side chain of Pro248 cannot form any salt bridges, which could negatively affect the tertiary structure assembly of the PH domain. Additionally, Pro248 lacks a free amide group needed for hydrogen bonding with the backbone carbonyl group of Asn245, disrupting the continuity of the α helix.
c.743G>T	R248L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta and FATHMM, whereas the majority of algorithms predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions labeled uncertain are FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the consensus of the available evidence points to a pathogenic effect for R248L, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.267126	Uncertain	0.781	0.346	0.250											-12.110	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	1.13	Ambiguous	0.5	0.01	Likely Benign	0.57	Ambiguous	0.67	Ambiguous	0.825	Likely Pathogenic	-6.06	Deleterious	0.979	Probably Damaging	0.680	Possibly Damaging	5.66	Benign	0.03	Affected			0.1616	0.4741		-3	-2	8.3	-43.03
c.745G>C	A249P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is therefore pathogenic (3 pathogenic vs. 1 benign). High‑accuracy assessments are consistent: AlphaMissense‑Optimized indicates pathogenicity; the SGM‑Consensus (majority vote) is pathogenic; and Foldetta, integrating FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.505461	Disordered	0.255452	Uncertain	0.810	0.336	0.125											-10.727	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	2.76	Destabilizing	0.4	8.40	Destabilizing	5.58	Destabilizing	1.04	Destabilizing	0.756	Likely Pathogenic	-3.32	Deleterious	0.176	Benign	0.039	Benign	5.57	Benign	0.03	Affected			0.1429	0.3537		1	-1	-3.4	26.04
c.746C>G	A249G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A249G is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Only FATHMM predicts a benign outcome. Uncertain results are reported by FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show SGM‑Consensus as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta remain inconclusive. Overall, the preponderance of evidence supports a pathogenic classification for A249G, and this conclusion does not conflict with ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.505461	Disordered	0.255452	Uncertain	0.810	0.336	0.125											-9.678	Likely Pathogenic	0.947	Likely Pathogenic	Ambiguous	1.04	Ambiguous	0.2	2.02	Destabilizing	1.53	Ambiguous	1.19	Destabilizing	0.607	Likely Pathogenic	-2.97	Deleterious	0.990	Probably Damaging	0.760	Possibly Damaging	5.59	Benign	0.04	Affected			0.1667	0.2675		1	0	-2.2	-14.03
c.746C>T	A249V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A249V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, no high‑accuracy tool provides a definitive pathogenic or benign verdict. Overall, the majority of available predictions (seven pathogenic vs. three benign) lean toward a pathogenic interpretation. This assessment does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.505461	Disordered	0.255452	Uncertain	0.810	0.336	0.125											-9.417	Likely Pathogenic	0.856	Likely Pathogenic	Ambiguous	1.48	Ambiguous	0.6	0.51	Ambiguous	1.00	Ambiguous	0.41	Likely Benign	0.652	Likely Pathogenic	-2.47	Neutral	0.990	Probably Damaging	0.760	Possibly Damaging	5.76	Benign	0.03	Affected			0.0737	0.4677		0	0	2.4	28.05
c.748G>C	V250L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250L variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict pathogenicity are REVEL, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—Foldetta and premPS—are noted as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is ambiguous (two pathogenic vs. two benign votes), and Foldetta remains uncertain. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.447574	Structured	0.244075	Uncertain	0.778	0.324	0.125											-11.649	Likely Pathogenic	0.587	Likely Pathogenic	Likely Benign	-0.23	Likely Benign	0.1	2.47	Destabilizing	1.12	Ambiguous	0.66	Ambiguous	0.690	Likely Pathogenic	-2.47	Neutral	0.767	Possibly Damaging	0.344	Benign	5.81	Benign	0.04	Affected			0.0698	0.4229		2	1	-0.4	14.03
c.748G>T	V250L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250L variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict pathogenicity are REVEL, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—Foldetta and premPS—are noted as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is ambiguous (two pathogenic vs. two benign votes), and Foldetta remains uncertain. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.447574	Structured	0.244075	Uncertain	0.778	0.324	0.125											-11.649	Likely Pathogenic	0.587	Likely Pathogenic	Likely Benign	-0.23	Likely Benign	0.1	2.47	Destabilizing	1.12	Ambiguous	0.66	Ambiguous	0.690	Likely Pathogenic	-2.47	Neutral	0.767	Possibly Damaging	0.344	Benign	5.81	Benign	0.04	Affected			0.0698	0.4229		2	1	-0.4	14.03
c.749T>A	V250E 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V250E is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, whereas the remaining 12 tools (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the change as pathogenic. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. No prediction or stability result is inconclusive. Consequently, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.447574	Structured	0.244075	Uncertain	0.778	0.324	0.125											-15.723	Likely Pathogenic	0.983	Likely Pathogenic	Likely Pathogenic	1.85	Ambiguous	0.1	3.34	Destabilizing	2.60	Destabilizing	2.01	Destabilizing	0.906	Likely Pathogenic	-5.13	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	5.74	Benign	0.00	Affected			0.0787	0.1564		-2	-2	-7.7	29.98
c.749T>C	V250A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250A missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a pathogenic effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all indicate pathogenicity, whereas ESM1b and FATHMM predict a benign outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) and AlphaMissense‑Optimized return uncertain results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is balanced and therefore unavailable, and Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for V250A, and this assessment does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.447574	Structured	0.244075	Uncertain	0.778	0.324	0.125											-6.385	Likely Benign	0.852	Likely Pathogenic	Ambiguous	0.82	Ambiguous	0.1	1.22	Ambiguous	1.02	Ambiguous	1.48	Destabilizing	0.818	Likely Pathogenic	-3.11	Deleterious	0.930	Possibly Damaging	0.584	Possibly Damaging	5.82	Benign	0.02	Affected			0.2491	0.2151		0	0	-2.4	-28.05
c.749T>G	V250G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default, while only FATHMM predicts a benign outcome. Uncertain results are reported by FoldX and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, AlphaMissense‑Optimized remains uncertain, and Foldetta is pathogenic. Taken together, the overwhelming majority of evidence indicates a pathogenic effect. This conclusion is consistent with the absence of a ClinVar classification; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.447574	Structured	0.244075	Uncertain	0.778	0.324	0.125											-11.255	Likely Pathogenic	0.917	Likely Pathogenic	Ambiguous	1.65	Ambiguous	0.3	3.18	Destabilizing	2.42	Destabilizing	2.08	Destabilizing	0.900	Likely Pathogenic	-5.90	Deleterious	0.879	Possibly Damaging	0.997	Probably Damaging	5.75	Benign	0.00	Affected			0.1884	0.1996		-1	-3	-4.6	-42.08
c.74G>A	R25Q 2D AIThe SynGAP1 missense variant R25Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33423483‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.461924	Structured	0.438941	Uncertain	0.373	0.890	0.375					Uncertain		1	6-33423483-G-A	15	9.29e-6	-4.126	Likely Benign	0.212	Likely Benign	Likely Benign										0.038	Likely Benign	-0.70	Neutral	0.829	Possibly Damaging	0.614	Possibly Damaging	4.01	Benign	0.00	Affected	4.32	1	0.3447	0.2566		1	1	1.0	-28.06
c.74G>C	R25P 2D AIThe SynGAP1 missense variant R25P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.461924	Structured	0.438941	Uncertain	0.373	0.890	0.375											-3.394	Likely Benign	0.424	Ambiguous	Likely Benign										0.155	Likely Benign	-1.56	Neutral	0.841	Possibly Damaging	0.809	Possibly Damaging	3.94	Benign	0.00	Affected			0.2217	0.4571		0	-2	2.9	-59.07
c.74G>T	R25L 2D AIThe SynGAP1 missense variant R25L is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic impact. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools specifically highlight a benign prediction: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta data are missing. Taken together, the majority of robust predictors and the consensus analysis support a benign classification for R25L. This conclusion is consistent with the lack of ClinVar evidence and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.461924	Structured	0.438941	Uncertain	0.373	0.890	0.375											-3.443	Likely Benign	0.484	Ambiguous	Likely Benign										0.121	Likely Benign	-1.59	Neutral	0.686	Possibly Damaging	0.630	Possibly Damaging	3.97	Benign	0.00	Affected			0.2045	0.4792		-3	-2	8.3	-43.03
c.752A>T	K251M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K251M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, premPS, PROVEAN, and FATHMM. Those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a benign effect. Overall, the evidence is evenly split between benign and pathogenic predictions, with the most reliable high‑accuracy tools leaning toward a benign outcome. Thus, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		PH	0.447574	Structured	0.226632	Uncertain	0.758	0.312	0.125											-10.678	Likely Pathogenic	0.796	Likely Pathogenic	Ambiguous	0.14	Likely Benign	0.1	0.10	Likely Benign	0.12	Likely Benign	0.05	Likely Benign	0.751	Likely Pathogenic	-2.36	Neutral	0.999	Probably Damaging	0.970	Probably Damaging	5.73	Benign	0.05	Affected			0.1271	0.3475		0	-1	5.8	3.02
c.754C>A	P252T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P252T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized and the SGM‑Consensus score (Likely Pathogenic). Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are treated as unavailable. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; Foldetta’s stability assessment is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.461924	Structured	0.211606	Uncertain	0.753	0.304	0.250											-11.824	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	1.24	Ambiguous	0.1	1.89	Ambiguous	1.57	Ambiguous	0.71	Ambiguous	0.828	Likely Pathogenic	-7.35	Deleterious	0.384	Benign	0.177	Benign	5.78	Benign	0.01	Affected			0.1514	0.4842		0	-1	0.9	3.99
c.754C>G	P252A 2D 3DClick to see structure in 3D Viewer AISynGAP1 P252A is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: a single benign call from FATHMM, and a majority of pathogenic calls from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for P252A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.461924	Structured	0.211606	Uncertain	0.753	0.304	0.250											-10.587	Likely Pathogenic	0.977	Likely Pathogenic	Likely Pathogenic	0.97	Ambiguous	0.1	1.74	Ambiguous	1.36	Ambiguous	0.69	Ambiguous	0.831	Likely Pathogenic	-7.35	Deleterious	0.941	Possibly Damaging	0.607	Possibly Damaging	5.87	Benign	0.03	Affected			0.3490	0.4161		1	-1	3.4	-26.04
c.754C>T	P252S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P252S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. Predictions that are uncertain (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the evidence strongly favors a pathogenic effect for P252S, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.461924	Structured	0.211606	Uncertain	0.753	0.304	0.250											-10.926	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.76	Ambiguous	0.1	1.81	Ambiguous	1.29	Ambiguous	0.79	Ambiguous	0.840	Likely Pathogenic	-7.35	Deleterious	0.941	Possibly Damaging	0.531	Possibly Damaging	5.79	Benign	0.05	Affected			0.3508	0.4361		1	-1	0.8	-10.04
c.755C>A	P252H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P252H missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence indicates that P252H is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.461924	Structured	0.211606	Uncertain	0.753	0.304	0.250											-11.991	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	1.06	Ambiguous	0.2	1.96	Ambiguous	1.51	Ambiguous	0.82	Ambiguous	0.845	Likely Pathogenic	-8.27	Deleterious	0.999	Probably Damaging	0.936	Probably Damaging	5.76	Benign	0.00	Affected			0.1592	0.4128		0	-2	-1.6	40.02
c.755C>G	P252R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P252R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Computational predictors that classify the variant as benign are FoldX and FATHMM, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. Predictions that are inconclusive are Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that P252R is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.461924	Structured	0.211606	Uncertain	0.753	0.304	0.250											-14.648	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	0.40	Likely Benign	0.1	1.23	Ambiguous	0.82	Ambiguous	0.81	Ambiguous	0.890	Likely Pathogenic	-8.27	Deleterious	0.997	Probably Damaging	0.916	Probably Damaging	5.80	Benign	0.00	Affected			0.1413	0.2848		0	-2	-2.9	59.07
c.755C>T	P252L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P252L missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign are premPS and FATHMM, while the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic effect. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore do not contribute to the overall assessment. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.461924	Structured	0.211606	Uncertain	0.753	0.304	0.250											-10.181	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.93	Ambiguous	0.0	1.56	Ambiguous	1.25	Ambiguous	0.47	Likely Benign	0.794	Likely Pathogenic	-9.19	Deleterious	0.991	Probably Damaging	0.781	Possibly Damaging	5.81	Benign	0.00	Affected			0.2027	0.6475		-3	-3	5.4	16.04
c.757A>C	N253H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N253H is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include FoldX, FATHMM, and premPS, whereas a larger group predicts pathogenicity: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, while AlphaMissense‑Optimized and Foldetta provide inconclusive results and are treated as unavailable. No contradictory evidence is present in ClinVar. Overall, the preponderance of evidence from multiple in‑silico predictors points to a pathogenic effect for the variant, and this conclusion does not conflict with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.201744	Uncertain	0.771	0.298	0.250											-12.199	Likely Pathogenic	0.899	Likely Pathogenic	Ambiguous	0.31	Likely Benign	0.1	0.76	Ambiguous	0.54	Ambiguous	-0.06	Likely Benign	0.832	Likely Pathogenic	-4.39	Deleterious	0.998	Probably Damaging	0.991	Probably Damaging	5.51	Benign	0.01	Affected			0.1936	0.8033		2	1	0.3	23.04
c.757A>T	N253Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253Y is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX, FATHMM, and premPS, whereas a larger set—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Because the majority of evidence points to a deleterious impact, the variant is most likely pathogenic; this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.201744	Uncertain	0.771	0.298	0.250											-14.749	Likely Pathogenic	0.920	Likely Pathogenic	Ambiguous	0.27	Likely Benign	0.1	1.13	Ambiguous	0.70	Ambiguous	0.29	Likely Benign	0.896	Likely Pathogenic	-7.01	Deleterious	0.998	Probably Damaging	0.994	Probably Damaging	5.55	Benign	0.01	Affected			0.0642	0.7055		-2	-2	2.2	49.07
c.758A>T	N253I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253I is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (ID 6‑33435609‑A‑T). Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are limited to premPS and FATHMM. High‑accuracy assessments reinforce the pathogenic view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.201744	Uncertain	0.771	0.298	0.250								6-33435609-A-T	1	6.20e-7	-15.241	Likely Pathogenic	0.970	Likely Pathogenic	Likely Pathogenic	2.95	Destabilizing	0.1	5.56	Destabilizing	4.26	Destabilizing	0.25	Likely Benign	0.836	Likely Pathogenic	-7.83	Deleterious	0.998	Probably Damaging	0.991	Probably Damaging	5.57	Benign	0.01	Affected	3.39	15	0.0803	0.7553		-3	-2	8.0	-0.94
c.759C>A	N253K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253K resides in the PH domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Functional prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, and FATHMM. In contrast, the majority of predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—label it pathogenic or likely pathogenic. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus also indicates likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect. This assessment is not contradicted by ClinVar, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.201744	Uncertain	0.771	0.298	0.250											-15.834	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.05	Likely Benign	0.0	0.90	Ambiguous	0.48	Likely Benign	0.17	Likely Benign	0.663	Likely Pathogenic	-5.21	Deleterious	0.993	Probably Damaging	0.979	Probably Damaging	5.53	Benign	0.03	Affected			0.2640	0.6592		1	0	-0.4	14.07
c.759C>G	N253K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools fall into two groups: benign predictions come from FoldX, FATHMM, premPS, and Foldetta, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Benign. Overall, the majority of tools predict pathogenicity, and the two most reliable predictors also lean pathogenic, whereas only one high‑accuracy tool suggests benign. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.201744	Uncertain	0.771	0.298	0.250											-15.834	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.05	Likely Benign	0.0	0.90	Ambiguous	0.48	Likely Benign	0.17	Likely Benign	0.663	Likely Pathogenic	-5.21	Deleterious	0.993	Probably Damaging	0.979	Probably Damaging	5.53	Benign	0.03	Affected			0.2640	0.6592		1	0	-0.4	14.07
c.760A>G	K254E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: FATHMM is the sole benign predictor, while the remaining 13 tools (REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus) predict pathogenicity; FoldX and Foldetta are uncertain. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized indicates pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the preponderance of evidence supports a pathogenic classification for K254E, and this conclusion does not conflict with ClinVar, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.207751	Uncertain	0.799	0.285	0.375											-14.745	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.72	Ambiguous	0.1	2.34	Destabilizing	1.53	Ambiguous	1.17	Destabilizing	0.860	Likely Pathogenic	-3.27	Deleterious	0.970	Probably Damaging	0.584	Possibly Damaging	5.87	Benign	0.05	Affected			0.3224	0.1352		0	1	0.4	0.94
c.761A>T	K254M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show discordant results: benign predictions come from FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are reported by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight the conflict: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No prediction or stability result is missing or inconclusive. Overall, the majority of tools and the high‑accuracy consensus lean toward a pathogenic effect, and this assessment does not contradict ClinVar status, which currently has no entry for it. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.207751	Uncertain	0.799	0.285	0.375											-12.832	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	-0.35	Likely Benign	0.5	0.48	Likely Benign	0.07	Likely Benign	0.23	Likely Benign	0.864	Likely Pathogenic	-5.08	Deleterious	0.999	Probably Damaging	0.970	Probably Damaging	5.78	Benign	0.00	Affected			0.1073	0.3562		0	-1	5.8	3.02
c.762G>C	K254N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The majority of other in silico predictors—REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—indicate a pathogenic effect. Stability‑based methods FoldX, Rosetta, and Foldetta returned uncertain results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as unavailable. Overall, the preponderance of evidence supports a pathogenic classification, which contradicts the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.207751	Uncertain	0.799	0.285	0.375					Uncertain		1				-13.306	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.73	Ambiguous	0.2	1.87	Ambiguous	1.30	Ambiguous	1.19	Destabilizing	0.757	Likely Pathogenic	-4.23	Deleterious	0.384	Benign	0.070	Benign	5.93	Benign	0.01	Affected	3.39	15	0.3200	0.1488		1	0	0.4	-14.07	215.3	-21.0	-1.0	1.7	0.2	0.3		X						Potentially Pathogenic	The amino group of Lys254, located in an α-β loop connecting the PH and C2 domains (res. Lys251-Arg258), forms salt bridges with the carboxylate groups of Glu244 and Asp684. Since the neutral carboxamide group of the Asn254 side chain cannot form salt bridges with acidic residues, the residue swap potentially weakens the tertiary structure assembly and/or influences the loop positioning. Regardless, in both the variant and WT simulations, all hydrogen bonds formed by the residue’s side chain were broken, and the residue rotated outwards. The partially α helical conformation of the loop, which extends to a nearby α helix (res. Met414-Asn426), is dynamic, making it unclear if the mutation affects it.
c.762G>T	K254N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K254N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic” (3 pathogenic vs. 1 benign). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Based on the overall pattern of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not currently catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	PH	0.513880	Disordered	0.207751	Uncertain	0.799	0.285	0.375											-13.306	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.73	Ambiguous	0.2	1.87	Ambiguous	1.30	Ambiguous	1.19	Destabilizing	0.757	Likely Pathogenic	-4.23	Deleterious	0.384	Benign	0.070	Benign	5.93	Benign	0.01	Affected	3.39	15	0.3200	0.1488		1	0	0.4	-14.07	215.3	-21.0	-1.0	1.7	0.2	0.3		X						Potentially Pathogenic	The amino group of Lys254, located in an α-β loop connecting the PH and C2 domains (res. Lys251-Arg258), forms salt bridges with the carboxylate groups of Glu244 and Asp684. Since the neutral carboxamide group of the Asn254 side chain cannot form salt bridges with acidic residues, the residue swap potentially weakens the tertiary structure assembly and/or influences the loop positioning. Regardless, in both the variant and WT simulations, all hydrogen bonds formed by the residue’s side chain were broken, and the residue rotated outwards. The partially α helical conformation of the loop, which extends to a nearby α helix (res. Met414-Asn426), is dynamic, making it unclear if the mutation affects it.
c.763G>A	D255N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. FoldX, Rosetta, and Foldetta provide uncertain results. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta remains inconclusive. Overall, the consensus of the available predictions points to a pathogenic effect for D255N, and this conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.501700	Disordered	0.219132	Uncertain	0.801	0.273	0.250											-12.251	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.86	Ambiguous	0.1	1.48	Ambiguous	1.17	Ambiguous	0.38	Likely Benign	0.682	Likely Pathogenic	-4.30	Deleterious	0.997	Probably Damaging	0.989	Probably Damaging	5.84	Benign	0.01	Affected			0.1117	0.4774		2	1	0.0	-0.98
c.763G>C	D255H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, while pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce the pathogenic interpretation: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains Uncertain. Overall, the consensus of the available predictions points to a pathogenic effect for D255H, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.501700	Disordered	0.219132	Uncertain	0.801	0.273	0.250											-14.645	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.72	Ambiguous	0.2	1.17	Ambiguous	1.45	Ambiguous	0.44	Likely Benign	0.808	Likely Pathogenic	-5.93	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	5.76	Benign	0.00	Affected			0.1447	0.5211		1	-1	0.3	22.05
c.763G>T	D255Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include premPS and FATHMM, while the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.501700	Disordered	0.219132	Uncertain	0.801	0.273	0.250											-13.180	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	1.25	Ambiguous	0.2	0.96	Ambiguous	1.11	Ambiguous	0.13	Likely Benign	0.832	Likely Pathogenic	-7.77	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	5.73	Benign	0.00	Affected			0.0464	0.5178		-4	-3	2.2	48.09
c.764A>C	D255A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D255A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Pathogenic” vote) predict a pathogenic impact. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore do not contribute evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.501700	Disordered	0.219132	Uncertain	0.801	0.273	0.250											-11.789	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.48	Ambiguous	0.2	1.04	Ambiguous	1.26	Ambiguous	0.35	Likely Benign	0.829	Likely Pathogenic	-6.85	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	5.80	Benign	0.01	Affected			0.3363	0.4805		0	-2	5.3	-44.01
c.764A>G	D255G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D255G missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include premPS and FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are therefore not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.501700	Disordered	0.219132	Uncertain	0.801	0.273	0.250											-12.652	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	1.72	Ambiguous	0.1	1.34	Ambiguous	1.53	Ambiguous	0.31	Likely Benign	0.885	Likely Pathogenic	-6.13	Deleterious	0.997	Probably Damaging	0.989	Probably Damaging	5.86	Benign	0.01	Affected			0.3211	0.5185		1	-1	3.1	-58.04
c.764A>T	D255V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, while pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce the pathogenic interpretation: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains Uncertain. Overall, the consensus of available predictions points to a pathogenic effect for D255V, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic		0.501700	Disordered	0.219132	Uncertain	0.801	0.273	0.250											-13.575	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.76	Ambiguous	0.2	1.07	Ambiguous	1.42	Ambiguous	0.16	Likely Benign	0.895	Likely Pathogenic	-7.77	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	5.75	Benign	0.00	Affected			0.0684	0.5162		-2	-3	7.7	-15.96
c.766A>C	N256H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256H is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta, Foldetta, premPS, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250											-8.090	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	0.56	Ambiguous	0.3	0.26	Likely Benign	0.41	Likely Benign	0.08	Likely Benign	0.698	Likely Pathogenic	-4.06	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	5.82	Benign	0.05	Affected			0.1233	0.5646		2	1	0.3	23.04
c.766A>G	N256D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N256D is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, Foldetta, premPS, and FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX is uncertain and therefore not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Taken together, the overall consensus leans toward a pathogenic effect, with 10 tools supporting pathogenicity versus 4 supporting benignity. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250											-12.478	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	0.69	Ambiguous	0.3	0.21	Likely Benign	0.45	Likely Benign	0.44	Likely Benign	0.701	Likely Pathogenic	-4.36	Deleterious	0.997	Probably Damaging	0.980	Probably Damaging	5.81	Benign	0.03	Affected			0.1890	0.3514		2	1	0.0	0.98
c.766A>T	N256Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, and FATHMM, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—label it pathogenic. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the preponderance of evidence from standard predictors and the two high‑accuracy pathogenic calls suggests that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250											-10.881	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	0.17	Likely Benign	0.2	-0.80	Ambiguous	-0.32	Likely Benign	0.30	Likely Benign	0.868	Likely Pathogenic	-6.85	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	5.83	Benign	0.00	Affected			0.0493	0.5881		-2	-2	2.2	49.07
c.767A>C	N256T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). The high‑accuracy AlphaMissense‑Optimized model classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while the Foldetta stability assessment reports a benign effect. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250											-12.212	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.88	Ambiguous	0.1	-0.18	Likely Benign	0.35	Likely Benign	0.49	Likely Benign	0.819	Likely Pathogenic	-5.25	Deleterious	0.997	Probably Damaging	0.980	Probably Damaging	5.85	Benign	0.01	Affected			0.1249	0.5848		0	0	2.8	-13.00
c.767A>G	N256S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256S is listed in ClinVar as Pathogenic (ClinVar ID 2584352.0) and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic calls come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy subset gives AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of predictions support a pathogenic effect, aligning with the ClinVar classification. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250					Likely Pathogenic		1				-10.640	Likely Pathogenic	0.950	Likely Pathogenic	Ambiguous	0.31	Likely Benign	0.2	0.36	Likely Benign	0.34	Likely Benign	0.48	Likely Benign	0.707	Likely Pathogenic	-4.33	Deleterious	0.997	Probably Damaging	0.970	Probably Damaging	5.87	Benign	0.02	Affected	3.39	15	0.3024	0.5864		1	1	2.7	-27.03
c.767A>T	N256I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, premPS, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give a pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250											-14.050	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	0.64	Ambiguous	0.4	0.45	Likely Benign	0.55	Ambiguous	0.31	Likely Benign	0.849	Likely Pathogenic	-7.91	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	5.87	Benign	0.00	Affected			0.0596	0.6260		-2	-3	8.0	-0.94
c.768C>A	N256K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and FATHMM. Those that predict pathogenicity comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools favor a pathogenic effect, whereas a minority suggest benign. Thus, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250											-13.814	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.22	Likely Benign	0.3	-0.10	Likely Benign	0.06	Likely Benign	0.55	Ambiguous	0.569	Likely Pathogenic	-5.02	Deleterious	0.997	Probably Damaging	0.986	Probably Damaging	5.90	Benign	0.01	Affected			0.1702	0.5240		1	0	-0.4	14.07
c.768C>G	N256K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and FATHMM. Those that predict pathogenicity comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools support a pathogenic effect, whereas a minority suggest benign. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.414856	Structured	0.234105	Uncertain	0.826	0.271	0.250											-13.814	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	0.22	Likely Benign	0.3	-0.10	Likely Benign	0.06	Likely Benign	0.55	Ambiguous	0.569	Likely Pathogenic	-5.02	Deleterious	0.997	Probably Damaging	0.986	Probably Damaging	5.90	Benign	0.01	Affected			0.1702	0.5240		1	0	-0.4	14.07
c.76G>A	G26R 2D AIThe SynGAP1 missense variant G26R is listed in ClinVar as a benign alteration (ClinVar ID 1521495.0) and is present in the gnomAD database (gnomAD ID 6‑33423485‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence supports a benign impact, aligning with the ClinVar designation and indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.486429	Structured	0.438291	Uncertain	0.351	0.878	0.375					Benign		1	6-33423485-G-A	3	1.86e-6	-2.946	Likely Benign	0.678	Likely Pathogenic	Likely Benign										0.189	Likely Benign	-2.22	Neutral	0.994	Probably Damaging	0.990	Probably Damaging	3.87	Benign	0.00	Affected	4.32	1	0.1097	0.4407		-3	-2	-4.1	99.14
c.76G>C	G26R 2D AIThe SynGAP1 missense variant G26R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of the four high‑accuracy tools) also yields benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy consensus—indicates that G26R is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.486429	Structured	0.438291	Uncertain	0.351	0.878	0.375											-2.946	Likely Benign	0.678	Likely Pathogenic	Likely Benign										0.189	Likely Benign	-2.22	Neutral	0.994	Probably Damaging	0.990	Probably Damaging	3.87	Benign	0.00	Affected	4.32	1	0.1097	0.4407		-3	-2	-4.1	99.14
c.772C>A	R258S 2D AIThe SynGAP1 missense variant R258S is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect are limited to FATHMM, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect for R258S, and this conclusion is consistent with the absence of ClinVar annotation or gnomAD frequency data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.295083	Structured	0.293667	Uncertain	0.894	0.260	0.250											-14.336	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	2.11	Destabilizing	0.8	1.29	Ambiguous	1.70	Ambiguous	1.14	Destabilizing	0.796	Likely Pathogenic	-4.92	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	5.89	Benign	0.01	Affected			0.3057	0.3881		0	-1	3.7	-69.11
c.772C>G	R258G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R258G is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining twelve tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the variant as pathogenic; premPS remains uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No prediction is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.295083	Structured	0.293667	Uncertain	0.894	0.260	0.250											-14.239	Likely Pathogenic	0.980	Likely Pathogenic	Likely Pathogenic	2.42	Destabilizing	0.5	2.33	Destabilizing	2.38	Destabilizing	0.94	Ambiguous	0.788	Likely Pathogenic	-5.83	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	5.78	Benign	0.04	Affected			0.3166	0.3447		-3	-2	4.1	-99.14
c.772C>T	R258C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R258C missense variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33437677‑C‑T). Prediction tools that agree on a benign effect include only FATHMM. All other evaluated predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—indicate a pathogenic or likely pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.295083	Structured	0.293667	Uncertain	0.894	0.260	0.250					Uncertain		1	6-33437677-C-T	1	6.20e-7	-10.285	Likely Pathogenic	0.790	Likely Pathogenic	Ambiguous	1.17	Ambiguous	0.4	1.76	Ambiguous	1.47	Ambiguous	0.87	Ambiguous	0.771	Likely Pathogenic	-6.79	Deleterious	1.000	Probably Damaging	0.993	Probably Damaging	5.77	Benign	0.00	Affected	3.39	15	0.3307	0.3411		-3	-4	7.0	-53.05
c.773G>A	R258H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R258H is listed as Benign in ClinVar (ID 949697.0) and is present in gnomAD (6‑33437678‑G‑A). Prediction tools that agree on a benign effect include FATHMM and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain calls come from FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. The high‑accuracy consensus (SGM) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic verdict. AlphaMissense‑Optimized remains benign, while Foldetta is inconclusive. Overall, the majority of evidence points to a pathogenic impact, which contradicts the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.295083	Structured	0.293667	Uncertain	0.894	0.260	0.250					Benign/Likely benign		3	6-33437678-G-A	10	6.20e-6	-10.533	Likely Pathogenic	0.525	Ambiguous	Likely Benign	1.60	Ambiguous	0.6	1.00	Ambiguous	1.30	Ambiguous	1.47	Destabilizing	0.830	Likely Pathogenic	-4.06	Deleterious	1.000	Probably Damaging	0.991	Probably Damaging	5.77	Benign	0.01	Affected	3.39	15	0.2925	0.1980		2	0	1.3	-19.05	212.5	81.8	0.1	0.0	-0.5	0.2		X						Potentially Pathogenic	The guanidinium group of Arg258, located at the end of an α-β loop connecting the PH domain to the C2 domain (res. Lys251-Arg258), forms hydrogen bonds with the carboxamide groups of Asn727 and Asn729 side chains, as well as with the backbone carbonyl groups of Ala724, Leu725, and Asn727 in the WT simulations. Although the imidazole group of His258 can act as a hydrogen bond donor/acceptor, the swapped residue is unable to maintain an equally well-coordinated hydrogen bond network for linking the C2 and GAP domains in the variant simulations.
c.773G>C	R258P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R258P is not reported in ClinVar and has no entries in gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only FATHMM predicts a benign outcome. Predictions of uncertain status come from FoldX, Rosetta, and Foldetta. High‑accuracy tools reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta remains inconclusive. Overall, the preponderance of evidence supports a pathogenic classification for R258P, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.295083	Structured	0.293667	Uncertain	0.894	0.260	0.250											-14.293	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	1.26	Ambiguous	0.4	0.92	Ambiguous	1.09	Ambiguous	1.00	Destabilizing	0.924	Likely Pathogenic	-5.83	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	5.79	Benign	0.01	Affected			0.2148	0.4557		0	-2	2.9	-59.07
c.773G>T	R258L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R258L is not reported in ClinVar and is present in gnomAD (ID 6‑33437678‑G‑T). Prediction tools that agree on a benign effect include FoldX, Rosetta, FATHMM, and the combined Foldetta stability method. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Two tools give inconclusive results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.295083	Structured	0.293667	Uncertain	0.894	0.260	0.250								6-33437678-G-T	1	6.20e-7	-13.302	Likely Pathogenic	0.905	Likely Pathogenic	Ambiguous	0.14	Likely Benign	0.2	0.10	Likely Benign	0.12	Likely Benign	0.52	Ambiguous	0.908	Likely Pathogenic	-5.90	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	5.84	Benign	0.01	Affected	3.39	15	0.1606	0.4602		-2	-3	8.3	-43.03
c.775C>G	R259G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas the remaining 13 tools—including SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The high‑accuracy subset reinforces this assessment: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. Rosetta alone is uncertain and is treated as unavailable. Overall, the consensus of available predictions indicates that R259G is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.338208	Uncertain	0.885	0.255	0.250											-15.389	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	3.17	Destabilizing	0.6	1.53	Ambiguous	2.35	Destabilizing	1.14	Destabilizing	0.762	Likely Pathogenic	-6.43	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	5.78	Benign	0.00	Affected			0.3342	0.4139		-3	-2	4.1	-99.14
c.775C>T	R259W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R259W is listed in ClinVar with an uncertain significance (ClinVar ID 2014570.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, remains inconclusive. Overall, the preponderance of evidence indicates that R259W is most likely pathogenic, a conclusion that does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.338208	Uncertain	0.885	0.255	0.250					Uncertain		1				-12.186	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	1.95	Ambiguous	0.8	0.51	Ambiguous	1.23	Ambiguous	0.51	Ambiguous	0.691	Likely Pathogenic	-7.35	Deleterious	1.000	Probably Damaging	0.993	Probably Damaging	5.76	Benign	0.00	Affected	3.39	15	0.1221	0.4269		2	-3	3.6	30.03	254.0	40.0	0.2	0.2	0.2	0.4	X	X					X	Potentially Pathogenic	The guanidinium group of Arg259, located at the beginning of an anti-parallel β sheet strand (res. Arg259-Arg272), forms salt bridges with the carboxylate groups of Asp684 at the end of an α helix (res. Ile683-Gln702, GAP domain) and Asp261 on the same β strand. The Arg259 side chain also frequently forms hydrogen bonds with the backbone carbonyl groups of Ser257, Asn256, and Asp255. In the variant simulations, the indole ring of the Trp259 side chain cannot form salt bridges or maintain hydrogen bonding with the carboxylate group of Asp684 or other nearby residues. Notably, the amino group of the Lys254 side chain maintains a salt bridge with Asp684 and Glu244 throughout the variant simulations, while it forms a cation-π bond with the indole ring of Trp259 in the variant. This salt bridge is not maintained in the WT simulations. Additionally, the partially or loosely α helical conformation of a lysine-containing loop (res. Lys251-Ser257), which extends to a nearby α helix (res. Met414-Asn426), could be stabilized due to the residue swap. Moreover, the bulky size of the Trp259 side chain requires nearby residues to adjust their positioning to accommodate the introduced residue, weakening the tertiary structure assembly between the C2, PH, and GAP domains. The residue swap potentially causes more severe effects during protein folding or for the SynGAP-membrane interaction than the solvent-only simulations imply.
c.776G>A	R259Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259Q is catalogued in gnomAD (6‑33437681‑G‑A) but has no entry in ClinVar. In silico assessment shows a consensus of pathogenicity: 9 of 11 evaluated tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a deleterious effect, while only FATHMM indicates a benign outcome. Predictions of protein‑stability change are inconclusive, with FoldX, Rosetta and the combined Foldetta method returning uncertain results. High‑accuracy predictors reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies the variant as likely pathogenic; Foldetta remains uncertain. Overall, the computational evidence strongly favors a pathogenic interpretation, and this is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.338208	Uncertain	0.885	0.255	0.250								6-33437681-G-A	1	6.20e-7	-12.598	Likely Pathogenic	0.966	Likely Pathogenic	Likely Pathogenic	1.19	Ambiguous	0.3	1.30	Ambiguous	1.25	Ambiguous	1.40	Destabilizing	0.851	Likely Pathogenic	-3.68	Deleterious	0.999	Probably Damaging	0.978	Probably Damaging	5.81	Benign	0.01	Affected	3.39	15	0.3329	0.2703		1	1	1.0	-28.06	258.7	52.8	0.1	0.1	-0.3	0.4	X	X						Potentially Pathogenic	The guanidinium group of Arg259, located at the beginning of an anti-parallel β sheet strand (res. Arg259-Arg272), forms salt bridges with the carboxylate groups of Asp684 at the end of an α helix (res. Ile683-Gln702, GAP domain) and Asp261 on the same β strand. The Arg259 side chain also frequently forms hydrogen bonds with the backbone carbonyl groups of Ser257, Asn256, and Asp255. In the variant simulations, the carboxamide group of the Gln259 side chain cannot form salt bridges or maintain hydrogen bonding with the carboxylate group of Asp684, which could affect the tertiary structure assembly between the C2 and GAP domains. Notably, the amino group of the Lys254 side chain maintains a salt bridge with Asp684 and Glu244 throughout the variant simulations, but this interaction is not maintained in the WT simulations. Thus, the partially or loosely α helical conformation of a lysine-containing loop (res. Lys251-Ser257), which extends to a nearby α helix (res. Met414-Asn426), could be stabilized due to the residue swap.
c.776G>C	R259P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods further support this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.338208	Uncertain	0.885	0.255	0.250											-14.876	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	6.34	Destabilizing	1.6	3.78	Destabilizing	5.06	Destabilizing	1.16	Destabilizing	0.902	Likely Pathogenic	-6.43	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	5.84	Benign	0.00	Affected			0.2051	0.5249		0	-2	2.9	-59.07
c.776G>T	R259L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259L is not reported in ClinVar and is absent from gnomAD. Among the available in‑silico predictors, the benign‑predicted tools are Rosetta and FATHMM, while the pathogenic‑predicted tools include SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Foldetta and premPS are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of predictions support a pathogenic effect, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.338208	Uncertain	0.885	0.255	0.250											-14.185	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	2.84	Destabilizing	1.1	0.16	Likely Benign	1.50	Ambiguous	0.64	Ambiguous	0.894	Likely Pathogenic	-6.43	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	5.87	Benign	0.00	Affected			0.1934	0.5499		-3	-2	8.3	-43.03
c.779T>G	V260G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V260G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FATHMM and AlphaMissense‑Optimized, while the majority of tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. FoldX, Rosetta, and Foldetta are uncertain and therefore not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (3 pathogenic vs. 1 benign). Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for V260G, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.254060	Structured	0.382651	Uncertain	0.888	0.259	0.250											-9.300	Likely Pathogenic	0.644	Likely Pathogenic	Likely Benign	1.00	Ambiguous	0.3	1.86	Ambiguous	1.43	Ambiguous	1.40	Destabilizing	0.817	Likely Pathogenic	-4.20	Deleterious	0.991	Probably Damaging	0.999	Probably Damaging	5.76	Benign	0.00	Affected			0.1844	0.1949		-1	-3	-4.6	-42.08
c.77G>A	G26E 2D AIThe SynGAP1 missense variant G26E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.486429	Structured	0.438291	Uncertain	0.351	0.878	0.375											-3.966	Likely Benign	0.481	Ambiguous	Likely Benign										0.199	Likely Benign	-2.08	Neutral	0.994	Probably Damaging	0.986	Probably Damaging	3.90	Benign	0.00	Affected			0.1623	0.4238		0	-2	-3.1	72.06
c.77G>C	G26A 2D AIThe SynGAP1 missense variant G26A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G26A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.486429	Structured	0.438291	Uncertain	0.351	0.878	0.375											-3.308	Likely Benign	0.135	Likely Benign	Likely Benign										0.062	Likely Benign	-1.25	Neutral	0.953	Possibly Damaging	0.952	Probably Damaging	4.02	Benign	0.00	Affected			0.4093	0.5251		1	0	2.2	14.03
c.77G>T	G26V 2D AIThe SynGAP1 missense variant G26V is reported in gnomAD (variant ID 6‑33423486‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: the benign‑predicted set includes REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the pathogenic‑predicted set contains polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” No Foldetta stability result is available, so it does not influence the conclusion. Overall, the majority of evidence points to a benign effect for G26V, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.486429	Structured	0.438291	Uncertain	0.351	0.878	0.375								6-33423486-G-T	1	6.20e-7	-3.499	Likely Benign	0.165	Likely Benign	Likely Benign										0.197	Likely Benign	-2.34	Neutral	0.994	Probably Damaging	0.990	Probably Damaging	3.89	Benign	0.00	Affected	4.32	1	0.1344	0.4333		-3	-1	4.6	42.08
c.781G>A	D261N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261N is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include premPS, FATHMM, and AlphaMissense‑Optimized, while the majority of tools predict a pathogenic outcome: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.422514	Uncertain	0.883	0.264	0.125											-11.804	Likely Pathogenic	0.746	Likely Pathogenic	Likely Benign	1.58	Ambiguous	0.7	1.28	Ambiguous	1.43	Ambiguous	0.23	Likely Benign	0.579	Likely Pathogenic	-2.94	Deleterious	0.997	Probably Damaging	0.989	Probably Damaging	5.82	Benign	0.02	Affected			0.0767	0.4745		2	1	0.0	-0.98
c.781G>C	D261H 2D AIThe SynGAP1 missense variant D261H is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are premPS and FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; Rosetta is uncertain and is treated as unavailable. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic (3 pathogenic vs. 1 benign); and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.422514	Uncertain	0.883	0.264	0.125											-13.688	Likely Pathogenic	0.961	Likely Pathogenic	Likely Pathogenic	4.33	Destabilizing	3.2	0.93	Ambiguous	2.63	Destabilizing	0.33	Likely Benign	0.780	Likely Pathogenic	-3.67	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	6.04	Benign	0.01	Affected			0.0937	0.5465		1	-1	0.3	22.05
c.781G>T	D261Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D261Y missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are premPS and FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect; and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No prediction or folding stability result is missing or inconclusive beyond the stated uncertainties. Overall, the preponderance of evidence points to a pathogenic effect for D261Y, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.422514	Uncertain	0.883	0.264	0.125											-14.961	Likely Pathogenic	0.955	Likely Pathogenic	Ambiguous	2.93	Destabilizing	2.1	0.81	Ambiguous	1.87	Ambiguous	-0.12	Likely Benign	0.886	Likely Pathogenic	-5.50	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	5.73	Benign	0.01	Affected			0.0474	0.5476		-4	-3	2.2	48.09
c.782A>C	D261A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D261A missense variant is not reported in ClinVar (status: None) and has no entries in gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, while the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Given the preponderance of pathogenic predictions and the lack of conflicting evidence, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.422514	Uncertain	0.883	0.264	0.125											-11.426	Likely Pathogenic	0.913	Likely Pathogenic	Ambiguous	1.70	Ambiguous	0.3	1.46	Ambiguous	1.58	Ambiguous	0.04	Likely Benign	0.839	Likely Pathogenic	-4.59	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	5.80	Benign	0.04	Affected			0.2785	0.4577		0	-2	5.3	-44.01
c.782A>G	D261G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261G is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include premPS and FATHMM, while the remaining tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Based on the aggregate predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.422514	Uncertain	0.883	0.264	0.125											-10.847	Likely Pathogenic	0.945	Likely Pathogenic	Ambiguous	2.81	Destabilizing	0.5	2.96	Destabilizing	2.89	Destabilizing	0.21	Likely Benign	0.850	Likely Pathogenic	-4.77	Deleterious	0.997	Probably Damaging	0.989	Probably Damaging	5.81	Benign	0.02	Affected			0.2924	0.4562		1	-1	3.1	-58.04
c.784A>G	N262D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N262D is reported in gnomAD (ID 6‑33437689‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from FoldX, Rosetta, Foldetta, and FATHMM; pathogenic predictions from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is Uncertain, SGM‑Consensus remains Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.399879	Uncertain	0.912	0.240	0.000								6-33437689-A-G	1	6.20e-7	-13.363	Likely Pathogenic	0.848	Likely Pathogenic	Ambiguous	0.27	Likely Benign	0.1	0.36	Likely Benign	0.32	Likely Benign	1.16	Destabilizing	0.820	Likely Pathogenic	-4.31	Deleterious	0.997	Probably Damaging	0.980	Probably Damaging	5.85	Benign	0.05	Affected	3.40	14	0.1696	0.2586		1	2	0.0	0.98
c.784A>T	N262Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (seven pathogenic vs. three benign) lean toward a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.284882	Structured	0.399879	Uncertain	0.912	0.240	0.000											-12.177	Likely Pathogenic	0.490	Ambiguous	Likely Benign	1.86	Ambiguous	0.5	0.52	Ambiguous	1.19	Ambiguous	0.36	Likely Benign	0.858	Likely Pathogenic	-6.48	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	5.85	Benign	0.01	Affected			0.0445	0.3877		-2	-2	2.2	49.07
c.785A>T	N262I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262I is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include premPS and FATHMM, whereas the majority of tools predict a pathogenic outcome: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are uncertain and therefore treated as unavailable. High‑accuracy methods give an uncertain result for AlphaMissense‑Optimized, a pathogenic consensus from SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain result for Foldetta. Overall, the evidence points to a pathogenic effect for the variant, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.399879	Uncertain	0.912	0.240	0.000											-15.203	Likely Pathogenic	0.868	Likely Pathogenic	Ambiguous	1.21	Ambiguous	0.4	0.54	Ambiguous	0.88	Ambiguous	0.09	Likely Benign	0.777	Likely Pathogenic	-7.79	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	5.88	Benign	0.01	Affected			0.0449	0.4638		-2	-3	8.0	-0.94
c.786T>A	N262K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262K has no ClinVar entry and is not present in gnomAD. Prediction tools that indicate a benign effect include FoldX, premPS, and FATHMM. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic impact for N262K. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.399879	Uncertain	0.912	0.240	0.000											-12.512	Likely Pathogenic	0.962	Likely Pathogenic	Likely Pathogenic	0.47	Likely Benign	0.2	1.00	Ambiguous	0.74	Ambiguous	0.33	Likely Benign	0.531	Likely Pathogenic	-5.13	Deleterious	0.997	Probably Damaging	0.986	Probably Damaging	5.84	Benign	0.02	Affected			0.1799	0.3413		1	0	-0.4	14.07
c.786T>G	N262K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262K has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely disagree: benign predictions come from FoldX, premPS, and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and Foldetta. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Taken together, the majority of evidence points to a pathogenic effect for N262K. This conclusion is consistent with the absence of a ClinVar classification, as there is no existing report to contradict the prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.284882	Structured	0.399879	Uncertain	0.912	0.240	0.000											-12.512	Likely Pathogenic	0.962	Likely Pathogenic	Likely Pathogenic	0.47	Likely Benign	0.2	1.00	Ambiguous	0.74	Ambiguous	0.33	Likely Benign	0.532	Likely Pathogenic	-5.13	Deleterious	0.997	Probably Damaging	0.986	Probably Damaging	5.84	Benign	0.02	Affected			0.1799	0.3413		1	0	-0.4	14.07
c.787G>A	V263M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Benign. No conflicting evidence is present. Based on the aggregate predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.268042	Structured	0.356141	Uncertain	0.918	0.257	0.000											-5.956	Likely Benign	0.218	Likely Benign	Likely Benign	0.20	Likely Benign	0.1	-0.24	Likely Benign	-0.02	Likely Benign	0.43	Likely Benign	0.444	Likely Benign	-0.95	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	5.84	Benign	0.03	Affected			0.0665	0.3545		2	1	-2.3	32.06
c.788T>A	V263E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V263E missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools largely agree on a deleterious effect: FATHMM predicts the variant as benign, while the remaining twelve tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—classify it as pathogenic. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized remains uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Overall, the preponderance of evidence points to a pathogenic impact for V263E, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.268042	Structured	0.356141	Uncertain	0.918	0.257	0.000											-13.498	Likely Pathogenic	0.809	Likely Pathogenic	Ambiguous	2.04	Destabilizing	0.3	2.18	Destabilizing	2.11	Destabilizing	1.99	Destabilizing	0.862	Likely Pathogenic	-3.84	Deleterious	0.999	Probably Damaging	0.991	Probably Damaging	5.96	Benign	0.01	Affected			0.0886	0.1436		-2	-2	-7.7	29.98
c.788T>C	V263A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Rosetta, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), and SIFT. Predictions marked “Uncertain” include FoldX, Foldetta, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of evidence points to a benign effect. Thus, the variant is most likely benign based on current predictions, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.268042	Structured	0.356141	Uncertain	0.918	0.257	0.000											-6.877	Likely Benign	0.530	Ambiguous	Likely Benign	1.40	Ambiguous	0.1	0.00	Likely Benign	0.70	Ambiguous	1.26	Destabilizing	0.622	Likely Pathogenic	-2.17	Neutral	0.994	Probably Damaging	0.970	Probably Damaging	5.97	Benign	0.04	Affected			0.2565	0.1822		0	0	-2.4	-28.05
c.788T>G	V263G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V263G missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized; those that agree on a pathogenic effect are REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta’s stability prediction is uncertain. Overall, the preponderance of evidence points to a pathogenic impact for V263G, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.268042	Structured	0.356141	Uncertain	0.918	0.257	0.000											-10.388	Likely Pathogenic	0.669	Likely Pathogenic	Likely Benign	2.27	Destabilizing	0.2	1.63	Ambiguous	1.95	Ambiguous	1.88	Destabilizing	0.820	Likely Pathogenic	-4.59	Deleterious	0.991	Probably Damaging	0.999	Probably Damaging	6.07	Benign	0.01	Affected			0.1790	0.1868		-1	-3	-4.6	-42.08
c.790C>A	L264I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L264I is not reported in ClinVar and is present in gnomAD (ID 6‑33437695‑C‑A). Prediction tools that indicate a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the balance of evidence—six pathogenic versus three benign predictions, a pathogenic SGM Consensus, and an uncertain Foldetta—suggests that the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.185198	Structured	0.323473	Uncertain	0.939	0.264	0.000								6-33437695-C-A	1	6.20e-7	-10.945	Likely Pathogenic	0.638	Likely Pathogenic	Likely Benign	1.90	Ambiguous	0.5	0.84	Ambiguous	1.37	Ambiguous	0.95	Ambiguous	0.418	Likely Benign	-1.84	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	0.66	Pathogenic	0.02	Affected	3.38	18	0.0764	0.2630		2	2	0.7	0.00
c.790C>G	L264V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and AlphaMissense‑Optimized; all other evaluated algorithms (SGM‑Consensus, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic or likely pathogenic outcome, while Rosetta remains uncertain. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies the variant as Pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for L264V, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.185198	Structured	0.323473	Uncertain	0.939	0.264	0.000											-10.621	Likely Pathogenic	0.630	Likely Pathogenic	Likely Benign	2.55	Destabilizing	0.1	1.62	Ambiguous	2.09	Destabilizing	1.24	Destabilizing	0.444	Likely Benign	-2.76	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	0.73	Pathogenic	0.01	Affected			0.1280	0.2289		2	1	0.4	-14.03
c.791T>A	L264Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264Q is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.185198	Structured	0.323473	Uncertain	0.939	0.264	0.000					Uncertain		1				-15.729	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	3.43	Destabilizing	0.1	2.41	Destabilizing	2.92	Destabilizing	2.48	Destabilizing	0.678	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.49	Pathogenic	0.00	Affected	3.38	18	0.0942	0.0558		-2	-2	-7.3	14.97	254.7	-7.6	0.0	0.0	0.0	0.3	X		X				X	Potentially Pathogenic	The iso-butyl branched hydrocarbon side chain of Leu264, located at the end of an anti-parallel β sheet strand (res. Arg259-Arg272), packs against multiple hydrophobic residues such as Leu266, Phe314, Leu317, and Leu323 in the WT simulations. In the variant simulations, the hydrophilic carboxamide group of the Gln264 side chain is not suitable for the hydrophobic niche, causing the hydrophobic residues to make room for the swapped residue. Additionally, the carboxamide group of Gln264 forms hydrogen bonds with the backbone amide groups of Arg405 and Lys256 in the β sheet and the carbonyl group of Val350 in an α helical section of a nearby loop (res. Pro359-Phe358). The residue swap disrupts the packing of the C2 domain, which could adversely affect the C2 domain structure during folding. This disruption could potentially weaken the stability of the SynGAP-membrane association.
c.791T>C	L264P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset reports a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.185198	Structured	0.323473	Uncertain	0.939	0.264	0.000					Uncertain		1				-12.285	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	5.73	Destabilizing	0.3	6.57	Destabilizing	6.15	Destabilizing	2.65	Destabilizing	0.767	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.49	Pathogenic	0.00	Affected			0.3239	0.1053		-3	-3	-5.4	-16.04
c.791T>G	L264R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264R is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.185198	Structured	0.323473	Uncertain	0.939	0.264	0.000											-16.976	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.25	Destabilizing	0.3	3.37	Destabilizing	3.81	Destabilizing	2.28	Destabilizing	0.742	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.49	Pathogenic	0.00	Affected			0.1132	0.0558		-3	-2	-8.3	43.03
c.793A>C	K265Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K265Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Among standard in‑silico predictors, five tools (REVEL, FoldX, PROVEAN, AlphaMissense‑Optimized, Foldetta) predict a benign effect, while five (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM) predict pathogenicity. Three tools (premPS, AlphaMissense‑Default, Rosetta) are inconclusive. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a pathogenic consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and a benign outcome from Foldetta. Overall, the predictions are mixed; the balance of evidence, including the two high‑confidence benign calls, suggests the variant is more likely benign, and this does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.209395	Structured	0.309758	Uncertain	0.936	0.275	0.000											-8.533	Likely Pathogenic	0.505	Ambiguous	Likely Benign	0.35	Likely Benign	0.1	-1.15	Ambiguous	-0.40	Likely Benign	0.80	Ambiguous	0.386	Likely Benign	-2.46	Neutral	1.000	Probably Damaging	0.998	Probably Damaging	1.85	Pathogenic	0.05	Affected			0.4401	0.1062		1	1	0.4	-0.04
c.793A>G	K265E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265E missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and Foldetta. Those that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are AlphaMissense‑Optimized, FoldX, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evaluated tools (eight pathogenic vs. three benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.209395	Structured	0.309758	Uncertain	0.936	0.275	0.000											-12.163	Likely Pathogenic	0.952	Likely Pathogenic	Ambiguous	0.63	Ambiguous	0.2	0.00	Likely Benign	0.32	Likely Benign	0.95	Ambiguous	0.461	Likely Benign	-2.79	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.94	Pathogenic	0.05	Affected			0.3801	0.0882		0	1	0.4	0.94
c.794A>T	K265M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265M missense variant is not reported in ClinVar and has no entries in gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify it as damaging. Benign predictions are limited to FoldX, Foldetta, and premPS. Uncertain results come from Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this view: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, while Foldetta predicts a benign folding‑stability change. Overall, the preponderance of evidence supports a pathogenic classification for K265M, and this conclusion is not contradicted by the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.209395	Structured	0.309758	Uncertain	0.936	0.275	0.000											-10.885	Likely Pathogenic	0.904	Likely Pathogenic	Ambiguous	-0.22	Likely Benign	0.2	-0.63	Ambiguous	-0.43	Likely Benign	0.19	Likely Benign	0.516	Likely Pathogenic	-3.78	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.79	Pathogenic	0.01	Affected			0.1005	0.3695		0	-1	5.8	3.02
c.795G>C	K265N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and Rosetta, whereas the majority of algorithms predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.209395	Structured	0.309758	Uncertain	0.936	0.275	0.000											-8.759	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	0.98	Ambiguous	0.1	0.16	Likely Benign	0.57	Ambiguous	0.85	Ambiguous	0.350	Likely Benign	-3.26	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.86	Pathogenic	0.03	Affected			0.3691	0.1158		1	0	0.4	-14.07
c.795G>T	K265N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and Rosetta, while the majority of algorithms predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain or inconclusive results are reported only for FoldX, Foldetta, and premPS, and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.209395	Structured	0.309758	Uncertain	0.936	0.275	0.000											-8.759	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	0.98	Ambiguous	0.1	0.16	Likely Benign	0.57	Ambiguous	0.85	Ambiguous	0.351	Likely Benign	-3.26	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.86	Pathogenic	0.03	Affected			0.3691	0.1158		1	0	0.4	-14.07
c.797T>A	L266Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L266Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect: none. Tools that agree on a pathogenic effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The only tool with an uncertain outcome is Rosetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.232838	Structured	0.297157	Uncertain	0.948	0.264	0.000											-16.672	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	2.92	Destabilizing	0.1	1.49	Ambiguous	2.21	Destabilizing	2.21	Destabilizing	0.563	Likely Pathogenic	-5.25	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.53	Pathogenic	0.00	Affected			0.0815	0.0558		-2	-2	-7.3	14.97
c.797T>C	L266P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No conflicting benign evidence is present. Therefore, the variant is most likely pathogenic, and this conclusion is consistent with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.232838	Structured	0.297157	Uncertain	0.948	0.264	0.000											-15.752	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	7.08	Destabilizing	0.1	4.02	Destabilizing	5.55	Destabilizing	2.31	Destabilizing	0.654	Likely Pathogenic	-6.06	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.53	Pathogenic	0.00	Affected			0.3158	0.1021		-3	-3	-5.4	-16.04
c.797T>G	L266R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect, so the benign‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.232838	Structured	0.297157	Uncertain	0.948	0.264	0.000											-17.131	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	3.97	Destabilizing	0.2	2.76	Destabilizing	3.37	Destabilizing	2.04	Destabilizing	0.574	Likely Pathogenic	-5.32	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.53	Pathogenic	0.00	Affected			0.1059	0.0558		-3	-2	-8.3	43.03
c.799T>A	W267R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267R has no ClinVar entry and is not reported in gnomAD. Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic or likely pathogenic scores. Tools that are inconclusive (FoldX and premPS) are noted as uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No benign predictions are present. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.298060	Uncertain	0.943	0.274	0.000											-13.868	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.94	Ambiguous	0.1	2.47	Destabilizing	2.21	Destabilizing	0.51	Ambiguous	0.672	Likely Pathogenic	-12.87	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.00	Pathogenic	0.01	Affected			0.3763	0.0571		2	-3	-3.6	-30.03
c.799T>C	W267R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267R is not reported in ClinVar (ClinVar status: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tools predict a benign outcome. Uncertain predictions are provided by FoldX and premPS. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts Likely Pathogenic; and Foldetta predicts Pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.298060	Uncertain	0.943	0.274	0.000											-13.868	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.94	Ambiguous	0.1	2.47	Destabilizing	2.21	Destabilizing	0.51	Ambiguous	0.672	Likely Pathogenic	-12.87	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.00	Pathogenic	0.01	Affected			0.3763	0.0571		2	-3	-3.6	-30.03
c.799T>G	W267G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy methods corroborate this: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic, with no contradiction to its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.298060	Uncertain	0.943	0.274	0.000											-15.020	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	4.40	Destabilizing	0.2	3.99	Destabilizing	4.20	Destabilizing	1.20	Destabilizing	0.678	Likely Pathogenic	-11.95	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.96	Pathogenic	0.03	Affected			0.4049	0.1481		-7	-2	0.5	-129.16
c.79C>A	P27T 2D AIThe SynGAP1 missense variant P27T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including high‑accuracy tools, points to a benign effect for P27T, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.517562	Disordered	0.437871	Uncertain	0.430	0.881	0.375											-3.612	Likely Benign	0.103	Likely Benign	Likely Benign										0.106	Likely Benign	-2.07	Neutral	0.909	Possibly Damaging	0.901	Possibly Damaging	3.85	Benign	0.00	Affected			0.2430	0.5923		0	-1	0.9	3.99
c.79C>G	P27A 2D AIThe SynGAP1 missense variant P27A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including high‑accuracy tools, points to a benign effect for P27A, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.517562	Disordered	0.437871	Uncertain	0.430	0.881	0.375											-3.409	Likely Benign	0.079	Likely Benign	Likely Benign										0.077	Likely Benign	-1.98	Neutral	0.805	Possibly Damaging	0.857	Possibly Damaging	3.90	Benign	0.00	Affected			0.4041	0.5219		1	-1	3.4	-26.04
c.79C>T	P27S 2D AIThe SynGAP1 missense variant P27S is reported in gnomAD (ID 6‑33423488‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign, and the SGM‑Consensus (derived from the majority of these high‑accuracy predictors) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign. Foldetta stability analysis is unavailable. Overall, the preponderance of evidence indicates that P27S is most likely benign, and this assessment does not contradict any ClinVar classification, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.517562	Disordered	0.437871	Uncertain	0.430	0.881	0.375								6-33423488-C-T	1	6.20e-7	-2.891	Likely Benign	0.098	Likely Benign	Likely Benign										0.063	Likely Benign	-2.01	Neutral	0.909	Possibly Damaging	0.901	Possibly Damaging	3.91	Benign	0.00	Affected	4.32	1	0.3916	0.5443		-1	1	0.8	-10.04
c.7A>G	R3G 2D AIThe SynGAP1 missense variant R3G is reported in gnomAD (ID 6‑33420271‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign; Foldetta results are unavailable. Taken together, the preponderance of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.550331	Binding	0.358	0.920	0.875								6-33420271-A-G			-3.093	Likely Benign	0.160	Likely Benign	Likely Benign										0.099	Likely Benign	-0.20	Neutral	0.115	Benign	0.018	Benign	3.99	Benign	0.00	Affected	4.32	1	0.3559	0.4114		-2	-3	4.1	-99.14
c.7A>T	R3W 2D AIThe SynGAP1 missense variant R3W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R3W, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.550331	Binding	0.358	0.920	0.875											-5.023	Likely Benign	0.591	Likely Pathogenic	Likely Benign										0.122	Likely Benign	0.08	Neutral	0.962	Probably Damaging	0.363	Benign	3.94	Benign	0.00	Affected			0.1407	0.4634		2	-3	3.6	30.03
c.800G>T	W267L 2D AIThe SynGAP1 missense variant W267L is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign effect. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS, which are treated as unavailable evidence. High‑accuracy assessments further support a damaging effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” while Foldetta’s stability prediction is uncertain. Overall, the evidence strongly indicates that W267L is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.298060	Uncertain	0.943	0.274	0.000											-13.670	Likely Pathogenic	0.990	Likely Pathogenic	Likely Pathogenic	1.19	Ambiguous	0.7	1.31	Ambiguous	1.25	Ambiguous	0.75	Ambiguous	0.628	Likely Pathogenic	-11.95	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.93	Pathogenic	0.01	Affected			0.2122	0.2843		-2	-2	4.7	-73.05
c.801G>C	W267C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267C is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic based on the consensus of all predictions, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.298060	Uncertain	0.943	0.274	0.000											-12.351	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	2.81	Destabilizing	0.2	2.20	Destabilizing	2.51	Destabilizing	1.00	Destabilizing	0.705	Likely Pathogenic	-11.95	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.90	Pathogenic	0.01	Affected			0.3573	0.1700		-8	-2	3.4	-83.07
c.801G>T	W267C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267C is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic based on the consensus of all predictions, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.298060	Uncertain	0.943	0.274	0.000											-12.351	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	2.81	Destabilizing	0.2	2.20	Destabilizing	2.51	Destabilizing	1.00	Destabilizing	0.705	Likely Pathogenic	-11.95	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.90	Pathogenic	0.01	Affected			0.3573	0.1700		-8	-2	3.4	-83.07
c.802A>C	I268L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Two tools give uncertain results: premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta indicates a benign folding‑stability outcome. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.216401	Structured	0.314336	Uncertain	0.951	0.264	0.000											-6.544	Likely Benign	0.402	Ambiguous	Likely Benign	0.37	Likely Benign	0.1	-0.07	Likely Benign	0.15	Likely Benign	0.96	Ambiguous	0.390	Likely Benign	-1.84	Neutral	0.981	Probably Damaging	0.970	Probably Damaging	1.65	Pathogenic	0.03	Affected			0.0635	0.3037		2	2	-0.7	0.00
c.802A>T	I268F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome; only Rosetta and Foldetta are uncertain. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) remains uncertain. Overall, the consensus of available predictions strongly supports a pathogenic classification for I268F, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.314336	Uncertain	0.951	0.264	0.000											-11.426	Likely Pathogenic	0.968	Likely Pathogenic	Likely Pathogenic	2.85	Destabilizing	0.7	0.59	Ambiguous	1.72	Ambiguous	1.00	Destabilizing	0.685	Likely Pathogenic	-3.68	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.53	Pathogenic	0.00	Affected			0.0427	0.2158		1	0	-1.7	34.02
c.803T>A	I268N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.314336	Uncertain	0.951	0.264	0.000											-13.664	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	3.48	Destabilizing	0.1	3.17	Destabilizing	3.33	Destabilizing	2.21	Destabilizing	0.812	Likely Pathogenic	-6.26	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.51	Pathogenic	0.00	Affected			0.0708	0.0142		-2	-3	-8.0	0.94
c.803T>C	I268T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268T is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on pathogenicity include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a destabilizing, pathogenic effect. All available predictions are concordant and point to a deleterious impact. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.314336	Uncertain	0.951	0.264	0.000											-10.753	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	3.44	Destabilizing	0.1	3.19	Destabilizing	3.32	Destabilizing	1.93	Destabilizing	0.828	Likely Pathogenic	-4.24	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.53	Pathogenic	0.00	Affected			0.0882	0.0638		0	-1	-5.2	-12.05
c.803T>G	I268S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.314336	Uncertain	0.951	0.264	0.000											-13.032	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	4.93	Destabilizing	0.1	4.54	Destabilizing	4.74	Destabilizing	2.10	Destabilizing	0.841	Likely Pathogenic	-5.34	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.53	Pathogenic	0.00	Affected			0.2037	0.0530		-1	-2	-5.3	-26.08
c.804C>G	I268M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I268M missense variant is catalogued in gnomAD (ID 6‑33437709‑C‑G) but has no ClinVar entry. Functional prediction tools largely disagree: benign predictions come from FoldX and AlphaMissense‑Optimized, whereas the remaining evaluated algorithms (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all indicate pathogenicity. Rosetta and Foldetta provide inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it as likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the preponderance of evidence from the majority of prediction tools points to a pathogenic effect, which is consistent with the lack of a ClinVar classification but does not contradict any existing ClinVar status (none). Thus, the variant is most likely pathogenic, and this prediction does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.216401	Structured	0.314336	Uncertain	0.951	0.264	0.000								6-33437709-C-G	1	6.20e-7	-9.721	Likely Pathogenic	0.739	Likely Pathogenic	Likely Benign	0.12	Likely Benign	0.2	0.95	Ambiguous	0.54	Ambiguous	1.32	Destabilizing	0.622	Likely Pathogenic	-2.58	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.52	Pathogenic	0.01	Affected	3.38	19	0.0579	0.2145		1	2	-2.6	18.03
c.807A>G	I269M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269M is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include PROVEAN and AlphaMissense‑Optimized, whereas REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default predict it to be pathogenic. Five tools (FoldX, Rosetta, Foldetta, premPS, and ESM1b) give uncertain results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized reports a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta remains uncertain. Overall, the majority of predictions support a pathogenic impact, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.216401	Structured	0.343787	Uncertain	0.937	0.244	0.125											-7.863	In-Between	0.715	Likely Pathogenic	Likely Benign	0.91	Ambiguous	0.1	1.66	Ambiguous	1.29	Ambiguous	0.94	Ambiguous	0.507	Likely Pathogenic	-2.19	Neutral	0.999	Probably Damaging	0.998	Probably Damaging	1.75	Pathogenic	0.05	Affected			0.0580	0.2283		2	1	-2.6	18.03
c.808G>A	E270K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E270K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FoldX, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give uncertain results: Foldetta (a combined FoldX‑MD/Rosetta stability assessment) and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta remains uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, which is consistent with the lack of ClinVar reporting and gnomAD absence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.382573	Uncertain	0.938	0.231	0.125											-14.466	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	-0.06	Likely Benign	0.2	2.26	Destabilizing	1.10	Ambiguous	0.71	Ambiguous	0.530	Likely Pathogenic	-3.68	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.68	Pathogenic	0.01	Affected			0.2296	0.4251		0	1	-0.4	-0.94
c.808G>C	E270Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E270Q missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, and premPS, whereas the majority of tools predict pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates several high‑accuracy predictors, classifies the variant as Likely Pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized is Uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is Uncertain. Rosetta alone is Uncertain, and Foldetta’s uncertainty reflects limited stability change evidence. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.382573	Uncertain	0.938	0.231	0.125											-11.096	Likely Pathogenic	0.886	Likely Pathogenic	Ambiguous	0.00	Likely Benign	0.2	1.00	Ambiguous	0.50	Ambiguous	0.46	Likely Benign	0.418	Likely Benign	-2.76	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.65	Pathogenic	0.03	Affected			0.1044	0.4015		2	2	0.0	-0.98
c.809A>C	E270A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E270A missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools cluster into three groups: benign predictions are made only by premPS; pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; and three tools (FoldX, Rosetta, Foldetta) give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points to a deleterious effect. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.382573	Uncertain	0.938	0.231	0.125											-13.618	Likely Pathogenic	0.956	Likely Pathogenic	Likely Pathogenic	0.64	Ambiguous	0.2	0.77	Ambiguous	0.71	Ambiguous	0.41	Likely Benign	0.547	Likely Pathogenic	-5.52	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.61	Pathogenic	0.01	Affected			0.4122	0.3951		0	-1	5.3	-58.04
c.809A>G	E270G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E270G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic. Rosetta also predicts pathogenicity, while FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. No tool predicts a benign effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.382573	Uncertain	0.938	0.231	0.125											-13.759	Likely Pathogenic	0.968	Likely Pathogenic	Likely Pathogenic	1.23	Ambiguous	0.2	2.37	Destabilizing	1.80	Ambiguous	0.61	Ambiguous	0.576	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	1.63	Pathogenic	0.00	Affected			0.3254	0.3876		0	-2	3.1	-72.06
c.809A>T	E270V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E270V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess sequence conservation and structural impact uniformly classify the substitution as pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic scores. No tool predicts a benign effect. Uncertain results are reported only by FoldX, Rosetta, Foldetta, and premPS, which are not considered evidence for or against pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic”; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is inconclusive. Overall, the consensus of available predictions indicates that E270V is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.382573	Uncertain	0.938	0.231	0.125											-15.969	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	1.38	Ambiguous	0.6	1.88	Ambiguous	1.63	Ambiguous	-0.52	Ambiguous	0.574	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.53	Pathogenic	0.00	Affected			0.0672	0.4498		-2	-2	7.7	-29.98
c.80C>A	P27H 2D AIThe SynGAP1 missense variant P27H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for P27H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.517562	Disordered	0.437871	Uncertain	0.430	0.881	0.375											-4.116	Likely Benign	0.177	Likely Benign	Likely Benign										0.128	Likely Benign	-2.46	Neutral	0.992	Probably Damaging	0.977	Probably Damaging	3.79	Benign	0.00	Affected			0.2384	0.5290		0	-2	-1.6	40.02
c.80C>G	P27R 2D AIThe SynGAP1 missense variant P27R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for P27R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.517562	Disordered	0.437871	Uncertain	0.430	0.881	0.375											-3.260	Likely Benign	0.268	Likely Benign	Likely Benign										0.146	Likely Benign	-2.28	Neutral	0.972	Probably Damaging	0.954	Probably Damaging	3.82	Benign	0.00	Affected			0.1744	0.4203		0	-2	-2.9	59.07
c.80C>T	P27L 2D AIThe SynGAP1 missense variant P27L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The predictions do not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.517562	Disordered	0.437871	Uncertain	0.430	0.881	0.375											-3.297	Likely Benign	0.161	Likely Benign	Likely Benign										0.174	Likely Benign	-2.59	Deleterious	0.909	Possibly Damaging	0.927	Probably Damaging	3.82	Benign	0.00	Affected			0.2684	0.6161		-3	-3	5.4	16.04
c.810G>C	E270D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E270D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. The majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Rosetta. Tools with inconclusive results—FoldX, Foldetta, and premPS—are listed as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.382573	Uncertain	0.938	0.231	0.125											-11.954	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	1.52	Ambiguous	0.1	2.15	Destabilizing	1.84	Ambiguous	0.91	Ambiguous	0.379	Likely Benign	-2.76	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.60	Pathogenic	0.02	Affected			0.1908	0.2540		3	2	0.0	-14.03
c.810G>T	E270D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E270D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. The majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Rosetta, and the SGM‑Consensus (which is “Likely Pathogenic”). Predictions that are inconclusive or uncertain are FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also indicating a likely pathogenic outcome, while Foldetta’s stability analysis is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E270D, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.382573	Uncertain	0.938	0.231	0.125											-11.954	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	1.52	Ambiguous	0.1	2.15	Destabilizing	1.84	Ambiguous	0.91	Ambiguous	0.383	Likely Benign	-2.76	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.60	Pathogenic	0.02	Affected			0.1908	0.2540		3	2	0.0	-14.03
c.811G>A	A271T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining evidence—premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—consistently predict pathogenicity. FoldX, Rosetta, and Foldetta are inconclusive, and AlphaMissense‑Optimized also yields an uncertain result. High‑accuracy assessments show that the SGM‑Consensus (majority vote) predicts pathogenicity, while AlphaMissense‑Optimized and Foldetta remain unavailable. Taken together, the overwhelming majority of reliable predictors classify the variant as pathogenic, and this conclusion does not conflict with the ClinVar status, which currently has no entry for A271T. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.413873	Uncertain	0.939	0.220	0.125											-9.564	Likely Pathogenic	0.934	Likely Pathogenic	Ambiguous	0.59	Ambiguous	0.1	0.54	Ambiguous	0.57	Ambiguous	1.00	Destabilizing	0.498	Likely Benign	-3.68	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	0.66	Pathogenic	0.01	Affected			0.1076	0.4691		1	0	-2.5	30.03
c.811G>C	A271P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (integrating FoldX‑MD and Rosetta outputs) also reports a pathogenic effect. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.413873	Uncertain	0.939	0.220	0.125											-14.699	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.06	Destabilizing	0.2	2.97	Destabilizing	3.52	Destabilizing	1.15	Destabilizing	0.680	Likely Pathogenic	-4.60	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.62	Pathogenic	0.01	Affected			0.1705	0.3267		1	-1	-3.4	26.04
c.811G>T	A271S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A271S 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, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are Foldetta and Rosetta. 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 uncertain. Overall, the majority of evidence points to a pathogenic impact for A271S, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.413873	Uncertain	0.939	0.220	0.125					Uncertain		1				-9.552	Likely Pathogenic	0.629	Likely Pathogenic	Likely Benign	0.19	Likely Benign	0.1	1.47	Ambiguous	0.83	Ambiguous	1.14	Destabilizing	0.453	Likely Benign	-2.76	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	0.64	Pathogenic	0.03	Affected			0.2260	0.3312		1	1	-2.6	16.00
c.812C>A	A271D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271D is listed in ClinVar as Pathogenic (ClinVar ID 2019732.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.413873	Uncertain	0.939	0.220	0.125					Pathogenic		1				-18.590	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.71	Destabilizing	0.4	2.67	Destabilizing	3.69	Destabilizing	1.59	Destabilizing	0.706	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.62	Pathogenic	0.00	Affected	3.38	19	0.1565	0.1541		0	-2	-5.3	44.01	226.2	-63.4	0.0	0.0	0.9	0.1	X		X	X			X	Potentially Pathogenic	The methyl group of Ala271, located near the end of an anti-parallel β sheet strand (res. Arg259-Arg272), packs against multiple hydrophobic residues such as Val400, Val306, and Leu274 in the WT simulations. In the variant simulations, the carboxylate group of Asp271 is not suitable for the hydrophobic niche, causing the hydrophobic residues to make room for the swapped residue. Additionally, the carboxylate group of the Asp271 side chain forms hydrogen bonds with the backbone amide groups of Arg272 and Ala399 in the β sheet, or even forms a salt bridge with the amino group of the Lys394 side chain. This directly affects the integrity of the anti-parallel β sheet at the end. In short, the residue swap disrupts the C2 domain packing during folding, which could weaken the stability of the SynGAP-membrane association.
c.812C>G	A271G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or unavailable stability results and are not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as unavailable. Overall, the balance of evidence (seven pathogenic versus three benign predictions) indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.413873	Uncertain	0.939	0.220	0.125											-9.508	Likely Pathogenic	0.183	Likely Benign	Likely Benign	1.73	Ambiguous	0.1	1.43	Ambiguous	1.58	Ambiguous	1.31	Destabilizing	0.434	Likely Benign	-3.68	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	0.89	Pathogenic	0.01	Affected			0.1869	0.2388		1	0	-2.2	-14.03
c.812C>T	A271V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, and Foldetta, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains inconclusive; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.413873	Uncertain	0.939	0.220	0.125											-8.185	Likely Pathogenic	0.940	Likely Pathogenic	Ambiguous	-0.22	Likely Benign	0.2	0.78	Ambiguous	0.28	Likely Benign	0.37	Likely Benign	0.466	Likely Benign	-3.68	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	0.69	Pathogenic	0.02	Affected			0.0986	0.4409		0	0	2.4	28.05
c.814C>G	R272G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R272G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions are limited to REVEL, whereas pathogenic predictions are made by FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results come from Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this assessment is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.071867	Structured	0.425620	Uncertain	0.925	0.215	0.125											-11.540	Likely Pathogenic	0.831	Likely Pathogenic	Ambiguous	3.40	Destabilizing	0.0	1.94	Ambiguous	2.67	Destabilizing	1.06	Destabilizing	0.479	Likely Benign	-4.57	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.75	Pathogenic	0.01	Affected			0.3082	0.3062		-3	-2	4.1	-99.14
c.814C>T	R272W 2D AISynGAP1 missense variant R272W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a predominance of pathogenic calls: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict deleterious effects, while the consensus SGM tool (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely pathogenic outcome. Benign predictions are limited to REVEL, Rosetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the balance of evidence favors a pathogenic impact for R272W, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.071867	Structured	0.425620	Uncertain	0.925	0.215	0.125											-12.145	Likely Pathogenic	0.863	Likely Pathogenic	Ambiguous	2.98	Destabilizing	1.6	0.12	Likely Benign	1.55	Ambiguous	0.19	Likely Benign	0.461	Likely Benign	-5.49	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.72	Pathogenic	0.00	Affected			0.1460	0.3643		2	-3	3.6	30.03
c.815G>A	R272Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R272Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437720‑G‑A). Prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, AlphaMissense‑Default, AlphaMissense‑Optimized, and PROVEAN. Those that predict pathogenicity are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive; and Foldetta predicts benign. With the majority of high‑accuracy tools supporting a benign effect, the variant is most likely benign, which does not contradict its current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.071867	Structured	0.425620	Uncertain	0.925	0.215	0.125					Uncertain		2	6-33437720-G-A	14	8.67e-6	-9.559	Likely Pathogenic	0.286	Likely Benign	Likely Benign	0.73	Ambiguous	0.1	0.15	Likely Benign	0.44	Likely Benign	1.00	Destabilizing	0.321	Likely Benign	-1.81	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	1.88	Pathogenic	0.03	Affected	3.38	19	0.2966	0.1973		1	1	1.0	-28.06	255.7	52.9	0.0	0.0	-0.2	0.1				X				Uncertain	The guanidinium group of Arg272, located at the end of an anti-parallel β sheet strand (res. Arg259-Arg272), is stably maintained in an upright and outward position via stacking with the indole ring of the Trp362 side chain in another β strand (res. Thr359-Pro364). In the WT simulations, Arg272 forms hydrogen bonds with the glycine-rich Ω loop residues (res. Val365-Pro398, e.g., Gly380) and creates a salt bridge with the carboxylate group of the Asp304 side chain.In the variant simulations, the carboxamide group of the Gln272 side chain does not stack with the indole ring of Trp362 as stably as the guanidinium group of Arg272 in the WT. Consequently, the Gln272 side chain is freer to interact with the loop residues than Arg272, potentially negatively affecting the dynamic SynGAP-membrane association. Additionally, Arg272 faces the RasGTPase interface, so the residue swap could impact the SynGAP-Ras complex formation and GTPase activation.
c.815G>C	R272P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R272P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the single uncertain call (premPS) does not alter the overall consensus. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.071867	Structured	0.425620	Uncertain	0.925	0.215	0.125											-11.812	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	5.64	Destabilizing	0.2	3.99	Destabilizing	4.82	Destabilizing	0.80	Ambiguous	0.561	Likely Pathogenic	-3.95	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.74	Pathogenic	0.01	Affected			0.2057	0.4102		0	-2	2.9	-59.07
c.815G>T	R272L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R272L missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and premPS. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the majority of evaluated tools predict a pathogenic impact. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.071867	Structured	0.425620	Uncertain	0.925	0.215	0.125											-10.796	Likely Pathogenic	0.796	Likely Pathogenic	Ambiguous	1.66	Ambiguous	0.3	-0.46	Likely Benign	0.60	Ambiguous	0.41	Likely Benign	0.470	Likely Benign	-4.57	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.75	Pathogenic	0.01	Affected			0.1691	0.4230		-3	-2	8.3	-43.03
c.817G>C	E273Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E273Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of individual predictors (seven benign vs. five pathogenic) lean toward a benign classification, while the SGM Consensus and AlphaMissense‑Optimized provide conflicting signals. Thus, the variant is most likely benign based on the aggregate predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.071867	Structured	0.398918	Uncertain	0.863	0.196	0.125											-9.865	Likely Pathogenic	0.503	Ambiguous	Likely Benign	-0.29	Likely Benign	0.1	-0.29	Likely Benign	-0.29	Likely Benign	-0.01	Likely Benign	0.168	Likely Benign	-1.84	Neutral	0.946	Possibly Damaging	0.671	Possibly Damaging	1.77	Pathogenic	0.04	Affected			0.1220	0.3130		2	2	0.0	-0.98
c.818A>C	E273A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E273A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, whereas AlphaMissense‑Optimized predicts Benign and Foldetta (combining FoldX‑MD and Rosetta) predicts Benign. Overall, the majority of individual tools are split evenly, but the two high‑accuracy methods favor a benign effect. Thus, the variant is most likely benign based on current computational predictions, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.071867	Structured	0.398918	Uncertain	0.863	0.196	0.125											-8.851	Likely Pathogenic	0.422	Ambiguous	Likely Benign	0.29	Likely Benign	0.2	-0.29	Likely Benign	0.00	Likely Benign	0.16	Likely Benign	0.240	Likely Benign	-3.61	Deleterious	0.896	Possibly Damaging	0.492	Possibly Damaging	1.73	Pathogenic	0.04	Affected			0.3160	0.3615		0	-1	5.3	-58.04
c.818A>T	E273V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E273V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL and premPS. The majority of tools predict a pathogenic impact: Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, SGM‑Consensus (Likely Pathogenic), and Foldetta. Two tools give inconclusive results: AlphaMissense‑Optimized (Uncertain) and FoldX (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as Pathogenic. Overall, the consensus of pathogenic‑predicting tools outweighs the benign predictions, indicating that E273V is most likely pathogenic; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.071867	Structured	0.398918	Uncertain	0.863	0.196	0.125											-11.671	Likely Pathogenic	0.814	Likely Pathogenic	Ambiguous	1.93	Ambiguous	0.3	3.31	Destabilizing	2.62	Destabilizing	0.17	Likely Benign	0.361	Likely Benign	-4.66	Deleterious	0.984	Probably Damaging	0.825	Possibly Damaging	1.70	Pathogenic	0.01	Affected			0.0811	0.3813		-2	-2	7.7	-29.98
c.820C>A	L274M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, PROVEAN, and AlphaMissense‑Optimized, whereas those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Three tools (Rosetta, premPS, and ESM1b) returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting benign. Overall, the majority of predictions (seven pathogenic vs. four benign) and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.066181	Structured	0.377483	Uncertain	0.866	0.195	0.250											-7.386	In-Between	0.658	Likely Pathogenic	Likely Benign	0.24	Likely Benign	0.2	0.74	Ambiguous	0.49	Likely Benign	0.81	Ambiguous	0.512	Likely Pathogenic	-1.77	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	0.04	Pathogenic	0.01	Affected			0.0810	0.2202		4	2	-1.9	18.03
c.820C>G	L274V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while both the SGM‑Consensus and Foldetta (combining FoldX‑MD and Rosetta outputs) predict pathogenicity. No predictions are missing or inconclusive. Overall, the preponderance of evidence from multiple independent tools points to a pathogenic impact for L274V. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.066181	Structured	0.377483	Uncertain	0.866	0.195	0.250											-5.634	Likely Benign	0.593	Likely Pathogenic	Likely Benign	2.13	Destabilizing	0.6	2.22	Destabilizing	2.18	Destabilizing	0.99	Ambiguous	0.378	Likely Benign	-2.56	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	0.10	Pathogenic	0.02	Affected			0.1448	0.1860		2	1	0.4	-14.03
c.821T>A	L274Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274Q is reported in ClinVar with an uncertain significance (ClinVar ID 1810279.0) and is not found in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while Rosetta remains inconclusive. No tool predicts a benign outcome. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.066181	Structured	0.377483	Uncertain	0.866	0.195	0.250					Uncertain		1				-15.518	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	2.54	Destabilizing	0.3	1.74	Ambiguous	2.14	Destabilizing	1.97	Destabilizing	0.774	Likely Pathogenic	-5.42	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.00	Pathogenic	0.00	Affected	3.38	19	0.1128	0.0688		-2	-2	-7.3	14.97	245.9	1.8	0.0	0.0	0.1	0.2	X		X				X	Potentially Pathogenic	The aliphatic side chain of Leu274, located in a β hairpin loop (res. Glu273-Lys278) connecting two anti-parallel β sheet strands, packs against multiple hydrophobic residues facing the β sheet (e.g., Ala271, Leu327, Tyr280, Val306). The hydrophilic carboxamide group of the Gln274 side chain is not suitable for this hydrophobic niche, causing nearby residues to adjust to make room for the hydrophilic glutamine. Additionally, a new hydrogen bond forms with the backbone carboxyl group of Arg272 in another β strand (res. Glu273-Arg259).As a result, the backbone amide group of Ala399 and the carbonyl group of Arg272, which connect two β strands at the β sheet end, form fewer hydrogen bonds in the variant than in the WT simulations. Although no major secondary structure disruption is observed in the variant simulations, the residue swap could profoundly affect the C2 domain folding, as the hydrophobic packing of Leu274 is crucial for maintaining the loop's contact with the rest of the C2 domain. Lastly, because the Leu274-containing loop faces the membrane surface, the residue swap could also negatively impact the SynGAP-membrane association.
c.821T>C	L274P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool in the dataset predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.066181	Structured	0.377483	Uncertain	0.866	0.195	0.250											-14.667	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	5.62	Destabilizing	1.5	4.49	Destabilizing	5.06	Destabilizing	1.66	Destabilizing	0.804	Likely Pathogenic	-6.30	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.00	Pathogenic	0.00	Affected			0.3535	0.0625		-3	-3	-5.4	-16.04
c.821T>G	L274R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274R is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. All available predictions and stability analyses are concordant and indicate a likely pathogenic impact. Thus, based on the current computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.066181	Structured	0.377483	Uncertain	0.866	0.195	0.250											-17.691	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	3.61	Destabilizing	0.8	3.15	Destabilizing	3.38	Destabilizing	1.56	Destabilizing	0.807	Likely Pathogenic	-5.45	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.00	Pathogenic	0.00	Affected			0.1404	0.0488		-3	-2	-8.3	43.03
c.823C>A	P275T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P275T is reported in gnomAD (ID 6‑33437728‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain and therefore not considered evidence. No other tools provide conclusive results. Overall, the majority of predictions, including the SGM‑Consensus, indicate a pathogenic effect, and this assessment does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.059222	Structured	0.353469	Uncertain	0.811	0.208	0.250								6-33437728-C-A	3	1.86e-6	-8.708	Likely Pathogenic	0.309	Likely Benign	Likely Benign	2.44	Destabilizing	0.3	1.15	Ambiguous	1.80	Ambiguous	0.69	Ambiguous	0.425	Likely Benign	-5.38	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.75	Pathogenic	0.01	Affected	3.38	19	0.1808	0.4000		-1	0	0.9	3.99
c.823C>T	P275S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275S is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437728‑C‑T). Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for P275S, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.059222	Structured	0.353469	Uncertain	0.811	0.208	0.250								6-33437728-C-T	1	6.20e-7	-7.886	In-Between	0.312	Likely Benign	Likely Benign	2.11	Destabilizing	0.3	1.28	Ambiguous	1.70	Ambiguous	0.77	Ambiguous	0.388	Likely Benign	-5.24	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.78	Pathogenic	0.03	Affected	3.38	19	0.3489	0.3339		-1	1	0.8	-10.04
c.824C>A	P275H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a deleterious effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default, all of which classify the change as pathogenic. Tools that are inconclusive or uncertain are Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Taken together, the majority of evidence points to a pathogenic impact, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.059222	Structured	0.353469	Uncertain	0.811	0.208	0.250											-13.157	Likely Pathogenic	0.804	Likely Pathogenic	Ambiguous	2.34	Destabilizing	0.8	0.87	Ambiguous	1.61	Ambiguous	0.88	Ambiguous	0.585	Likely Pathogenic	-6.54	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.73	Pathogenic	0.01	Affected			0.2069	0.3074		0	-2	-1.6	40.02
c.824C>G	P275R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments further support this view: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. AlphaMissense‑Optimized remains uncertain, but its result does not counter the overall consensus. Consequently, the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.059222	Structured	0.353469	Uncertain	0.811	0.208	0.250											-13.557	Likely Pathogenic	0.915	Likely Pathogenic	Ambiguous	2.10	Destabilizing	0.6	2.11	Destabilizing	2.11	Destabilizing	0.82	Ambiguous	0.645	Likely Pathogenic	-6.36	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.75	Pathogenic	0.01	Affected			0.1637	0.3039		0	-2	-2.9	59.07
c.824C>T	P275L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275L is not reported in ClinVar and is absent from gnomAD. In silico predictions cluster into two groups: benign predictions come from REVEL, premPS, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Overall, the majority of tools predict pathogenicity, and the high‑accuracy consensus supports a likely pathogenic classification. This prediction does not contradict any ClinVar status, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.059222	Structured	0.353469	Uncertain	0.811	0.208	0.250											-9.785	Likely Pathogenic	0.304	Likely Benign	Likely Benign	1.63	Ambiguous	0.2	1.22	Ambiguous	1.43	Ambiguous	0.29	Likely Benign	0.430	Likely Benign	-6.81	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.83	Pathogenic	0.00	Affected			0.2139	0.5056		-3	-3	5.4	16.04
c.826C>A	P276T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P276T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign, two pathogenic), and Foldetta is uncertain. Overall, the majority of tools (six pathogenic vs. four benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.037156	Structured	0.338937	Uncertain	0.724	0.230	0.250											-5.793	Likely Benign	0.146	Likely Benign	Likely Benign	2.61	Destabilizing	0.1	0.75	Ambiguous	1.68	Ambiguous	0.63	Ambiguous	0.293	Likely Benign	-3.53	Deleterious	0.961	Probably Damaging	0.721	Possibly Damaging	1.87	Pathogenic	0.03	Affected			0.1601	0.4676		0	-1	0.9	3.99
c.826C>T	P276S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P276S missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign calls from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic calls from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Four tools predict benign while five predict pathogenic, and four additional methods (FoldX, Rosetta, Foldetta, premPS) return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive; Foldetta also reports an uncertain stability change. Taken together, the preponderance of evidence leans toward a pathogenic effect, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.037156	Structured	0.338937	Uncertain	0.724	0.230	0.250											-5.946	Likely Benign	0.142	Likely Benign	Likely Benign	1.78	Ambiguous	0.2	0.96	Ambiguous	1.37	Ambiguous	0.65	Ambiguous	0.205	Likely Benign	-3.25	Deleterious	0.835	Possibly Damaging	0.468	Possibly Damaging	1.92	Pathogenic	0.05	Affected			0.3191	0.3736		1	-1	0.8	-10.04
c.827C>A	P276H 2D 3DClick to see structure in 3D Viewer AISynGAP1 P276H is reported in gnomAD (ID 6‑33437732‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the variant as pathogenic, while only AlphaMissense‑Optimized predicts a benign outcome. Uncertain results are provided by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.037156	Structured	0.338937	Uncertain	0.724	0.230	0.250								6-33437732-C-A	1	6.20e-7	-10.469	Likely Pathogenic	0.575	Likely Pathogenic	Likely Benign	1.98	Ambiguous	0.1	1.09	Ambiguous	1.54	Ambiguous	0.85	Ambiguous	0.534	Likely Pathogenic	-4.80	Deleterious	1.000	Probably Damaging	0.961	Probably Damaging	1.84	Pathogenic	0.00	Affected	3.38	19	0.1739	0.3439		-2	0	-1.6	40.02
c.827C>G	P276R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P276R missense variant is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (gnomAD ID 6‑33437732‑C‑G). Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Stability‑based predictors (FoldX, Rosetta, premPS, Foldetta) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.037156	Structured	0.338937	Uncertain	0.724	0.230	0.250								6-33437732-C-G	7	4.34e-6	-10.983	Likely Pathogenic	0.714	Likely Pathogenic	Likely Benign	1.78	Ambiguous	0.2	1.02	Ambiguous	1.40	Ambiguous	0.78	Ambiguous	0.498	Likely Benign	-4.52	Deleterious	0.994	Probably Damaging	0.892	Possibly Damaging	1.89	Pathogenic	0.01	Affected	3.38	19	0.1445	0.2828		-2	0	-2.9	59.07
c.827C>T	P276L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P276L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. FoldX, Rosetta, and Foldetta provide uncertain or unavailable stability results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta remains unavailable. Overall, the predictions are mixed, with an equal split between benign and pathogenic calls, and the high‑accuracy tools do not yield a definitive verdict. Consequently, the variant is most likely benign based on the current evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.037156	Structured	0.338937	Uncertain	0.724	0.230	0.250											-6.687	Likely Benign	0.196	Likely Benign	Likely Benign	1.64	Ambiguous	0.1	0.87	Ambiguous	1.26	Ambiguous	0.33	Likely Benign	0.439	Likely Benign	-4.92	Deleterious	0.961	Probably Damaging	0.655	Possibly Damaging	1.87	Pathogenic	0.01	Affected			0.2179	0.5650		-3	-3	5.4	16.04
c.829A>C	K277Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K277Q is reported in gnomAD (ID 6‑33437734‑A‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from FoldX, Foldetta, and premPS; pathogenic predictions from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic effect, with only a minority of tools indicating benign or uncertain outcomes. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.061840	Structured	0.321811	Uncertain	0.649	0.247	0.250								6-33437734-A-C	1	6.20e-7	-12.547	Likely Pathogenic	0.904	Likely Pathogenic	Ambiguous	0.03	Likely Benign	0.1	0.63	Ambiguous	0.33	Likely Benign	0.42	Likely Benign	0.655	Likely Pathogenic	-3.68	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.83	Pathogenic	0.02	Affected	3.38	19	0.4000	0.0672		1	1	0.4	-0.04
c.829A>G	K277E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K277E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, and Foldetta. Tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No predictions are missing or inconclusive. Overall, the majority of tools (10/13) predict pathogenicity, whereas only three predict benign. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.061840	Structured	0.321811	Uncertain	0.649	0.247	0.250											-14.886	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	-0.14	Likely Benign	0.1	0.18	Likely Benign	0.02	Likely Benign	0.51	Ambiguous	0.694	Likely Pathogenic	-3.68	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.85	Pathogenic	0.01	Affected			0.3462	0.0492		0	1	0.4	0.94
c.82T>C	S28P 2D AIThe SynGAP1 missense variant S28P is listed in ClinVar (ID 1500161.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only SIFT indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta stability analysis is unavailable. Overall, the collective evidence points to a benign classification for S28P, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.545602	Disordered	0.438157	Uncertain	0.354	0.884	0.125					Uncertain		1				-3.309	Likely Benign	0.051	Likely Benign	Likely Benign										0.047	Likely Benign	1.37	Neutral	0.000	Benign	0.000	Benign	4.53	Benign	0.00	Affected	4.32	1	0.2432	0.5499		1	-1	-0.8	10.04
c.830A>C	K277T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K277T missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect are Rosetta and premPS, while the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict pathogenicity. FoldX and Foldetta return uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that K277T is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.061840	Structured	0.321811	Uncertain	0.649	0.247	0.250											-11.688	Likely Pathogenic	0.981	Likely Pathogenic	Likely Pathogenic	1.46	Ambiguous	0.1	0.14	Likely Benign	0.80	Ambiguous	0.17	Likely Benign	0.573	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	2.02	Pathogenic	0.01	Affected			0.1837	0.2220		0	-1	3.2	-27.07
c.830A>T	K277M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K277M missense variant is not reported in ClinVar and has no entries in gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX and premPS, while the majority of tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label the change as pathogenic. High‑accuracy methods reinforce this trend: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.061840	Structured	0.321811	Uncertain	0.649	0.247	0.250											-13.918	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	0.18	Likely Benign	0.0	1.14	Ambiguous	0.66	Ambiguous	0.15	Likely Benign	0.712	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.80	Pathogenic	0.00	Affected			0.0945	0.2584		0	-1	5.8	3.02
c.831G>C	K277N 2D AIThe SynGAP1 missense variant K277N is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and premPS. Tools that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as Benign. No predictions are missing or inconclusive. Overall, the majority of tools (10/14) predict pathogenicity, whereas four tools predict benign. Therefore, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.061840	Structured	0.321811	Uncertain	0.649	0.247	0.250											-9.646	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	-0.07	Likely Benign	0.4	0.08	Likely Benign	0.01	Likely Benign	0.46	Likely Benign	0.572	Likely Pathogenic	-4.60	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.83	Pathogenic	0.03	Affected			0.3265	0.0568		1	0	0.4	-14.07
c.831G>T	K277N 2D AIThe SynGAP1 missense variant K277N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, and premPS. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also likely pathogenic; Foldetta, a protein‑folding stability predictor, reports a benign effect. Overall, the preponderance of evidence (10 pathogenic vs. 4 benign predictions) points to a pathogenic classification. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.061840	Structured	0.321811	Uncertain	0.649	0.247	0.250											-9.646	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	-0.07	Likely Benign	0.4	0.08	Likely Benign	0.01	Likely Benign	0.46	Likely Benign	0.572	Likely Pathogenic	-4.60	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.83	Pathogenic	0.03	Affected			0.3265	0.0568		1	0	0.4	-14.07
c.832A>C	K278Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts a likely pathogenic outcome, whereas Foldetta (combining FoldX‑MD and Rosetta stability outputs) predicts a benign effect, and AlphaMissense‑Optimized remains uncertain. Overall, the majority of evidence points to a pathogenic impact for K278Q, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.120615	Structured	0.310130	Uncertain	0.748	0.253	0.125											-11.107	Likely Pathogenic	0.902	Likely Pathogenic	Ambiguous	0.23	Likely Benign	0.1	0.25	Likely Benign	0.24	Likely Benign	0.73	Ambiguous	0.387	Likely Benign	-3.63	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.71	Pathogenic	0.05	Affected			0.3770	0.0672		1	1	0.4	-0.04
c.833A>C	K278T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278T is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, Rosetta, Foldetta, and premPS. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict any ClinVar annotation because the variant is not yet classified in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.120615	Structured	0.310130	Uncertain	0.748	0.253	0.125											-11.227	Likely Pathogenic	0.978	Likely Pathogenic	Likely Pathogenic	0.85	Ambiguous	0.2	-0.08	Likely Benign	0.39	Likely Benign	0.46	Likely Benign	0.484	Likely Benign	-5.40	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.70	Pathogenic	0.04	Affected			0.1775	0.2220		0	-1	3.2	-27.07
c.833A>T	K278M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278M is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that indicate a benign effect include FoldX, Foldetta, and premPS, whereas the majority of tools predict a pathogenic effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic impact for K278M, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.120615	Structured	0.310130	Uncertain	0.748	0.253	0.125											-12.861	Likely Pathogenic	0.989	Likely Pathogenic	Likely Pathogenic	-0.15	Likely Benign	0.1	-0.59	Ambiguous	-0.37	Likely Benign	0.25	Likely Benign	0.526	Likely Pathogenic	-5.47	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.67	Pathogenic	0.01	Affected			0.0975	0.2584		0	-1	5.8	3.02
c.835C>G	R279G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote) which labels it “Likely Pathogenic.” AlphaMissense‑Optimized is uncertain, providing no definitive evidence. High‑accuracy assessments further support pathogenicity: the SGM‑Consensus remains “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the overwhelming majority of predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.155435	Structured	0.309382	Uncertain	0.887	0.257	0.125											-9.941	Likely Pathogenic	0.920	Likely Pathogenic	Ambiguous	3.10	Destabilizing	0.7	2.85	Destabilizing	2.98	Destabilizing	1.11	Destabilizing	0.442	Likely Benign	-5.37	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.92	Pathogenic	0.02	Affected			0.2961	0.2209		-3	-2	4.1	-99.14
c.835C>T	R279W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279W is listed in ClinVar with an uncertain significance (ClinVar ID 1204186.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining pathogenic‑predicating tools—FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—consistently predict a deleterious impact. Uncertain or inconclusive results come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R279W, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.155435	Structured	0.309382	Uncertain	0.887	0.257	0.125					Uncertain		1				-11.417	Likely Pathogenic	0.942	Likely Pathogenic	Ambiguous	2.00	Destabilizing	0.8	1.47	Ambiguous	1.74	Ambiguous	0.80	Ambiguous	0.485	Likely Benign	-6.29	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.88	Pathogenic	0.00	Affected	3.39	18	0.1200	0.2519		2	-3	3.6	30.03	270.0	38.3	0.1	0.0	0.3	0.0								Uncertain	The guanidinium group of Arg279, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), can form hydrogen bond with the backbone carbonyl groups of nearby loop residues (e.g., Ser296, Ser331, and As332) and form salt bridges with the carboxylate groups of Asp330 and Asp332. In the WT simulations, Arg279 sporadically forms a salt bridge even with the carboxylate group of Glu613, loosely connecting the C2 domain and GAP domain. Meanwhile, the indole ring of the Trp279 side chain is unable to hydrogen bond with the loop residues in the variant simulations. The lack of hydrogen bond or salt bridge formation with the loop residues could be significant, as Arg279 and the loops face the polar head group region of the membrane. Thus, although Trp279 could interact with the membrane surface as a “lipid anchor,” any changes to the wider loop dynamics could still adversely affect the formation of a stable SynGAP-membrane association. However, no definite conclusions on the effect of the residue swap on the SynGAP-membrane association can be drawn from solvent-only simulations.
c.836G>C	R279P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. No tool predicts a benign effect. FoldX reports an uncertain outcome, but Rosetta, Foldetta, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all predict pathogenicity. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus, based on a majority vote of the aforementioned predictors, is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.155435	Structured	0.309382	Uncertain	0.887	0.257	0.125											-14.926	Likely Pathogenic	0.971	Likely Pathogenic	Likely Pathogenic	1.42	Ambiguous	0.9	4.27	Destabilizing	2.85	Destabilizing	1.21	Destabilizing	0.626	Likely Pathogenic	-5.01	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.90	Pathogenic	0.02	Affected			0.2179	0.3281		0	-2	2.9	-59.07
c.836G>T	R279L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R279L is reported in gnomAD (ID 6‑33437741‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a unanimous majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.155435	Structured	0.309382	Uncertain	0.887	0.257	0.125								6-33437741-G-T	1	6.20e-7	-12.390	Likely Pathogenic	0.926	Likely Pathogenic	Ambiguous	0.01	Likely Benign	0.2	0.14	Likely Benign	0.08	Likely Benign	0.39	Likely Benign	0.576	Likely Pathogenic	-5.37	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.91	Pathogenic	0.03	Affected	3.39	18	0.1682	0.3266		-2	-3	8.3	-43.03
c.838T>C	Y280H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280H is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Among the available in‑silico predictors, none indicate a benign effect; all 14 tools that produced a classification predict pathogenicity: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are inconclusive or missing. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.161087	Structured	0.321243	Uncertain	0.917	0.248	0.125											-9.970	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	3.01	Destabilizing	0.3	2.58	Destabilizing	2.80	Destabilizing	1.95	Destabilizing	0.588	Likely Pathogenic	-4.60	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.94	Pathogenic	0.01	Affected			0.2021	0.0212		0	2	-1.9	-26.03
c.838T>G	Y280D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280D is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.161087	Structured	0.321243	Uncertain	0.917	0.248	0.125											-16.885	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	5.91	Destabilizing	0.2	5.89	Destabilizing	5.90	Destabilizing	2.00	Destabilizing	0.580	Likely Pathogenic	-9.19	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.94	Pathogenic	0.02	Affected			0.3593	0.0212		-4	-3	-2.2	-48.09
c.839A>C	Y280S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the substitution as pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (integrating FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is consistent with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.161087	Structured	0.321243	Uncertain	0.917	0.248	0.125											-13.491	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	4.63	Destabilizing	0.3	4.80	Destabilizing	4.72	Destabilizing	2.03	Destabilizing	0.635	Likely Pathogenic	-8.27	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	2.00	Pathogenic	0.05	Affected			0.3993	0.1227		-3	-2	0.5	-76.10
c.839A>G	Y280C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic or likely pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a pathogenic effect on protein stability. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.161087	Structured	0.321243	Uncertain	0.917	0.248	0.125											-10.645	Likely Pathogenic	0.982	Likely Pathogenic	Likely Pathogenic	3.85	Destabilizing	0.2	4.45	Destabilizing	4.15	Destabilizing	1.68	Destabilizing	0.629	Likely Pathogenic	-8.24	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.96	Pathogenic	0.01	Affected			0.2877	0.1296		0	-2	3.8	-60.04
c.839A>T	Y280F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—premPS, ESM1b, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive and therefore unavailable. Overall, the majority of available predictions favor a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.161087	Structured	0.321243	Uncertain	0.917	0.248	0.125											-7.844	In-Between	0.414	Ambiguous	Likely Benign	0.49	Likely Benign	0.2	0.03	Likely Benign	0.26	Likely Benign	0.87	Ambiguous	0.544	Likely Pathogenic	-3.68	Deleterious	0.999	Probably Damaging	0.992	Probably Damaging	1.98	Pathogenic	0.02	Affected			0.2263	0.2398		7	3	4.1	-16.00
c.83C>A	S28Y 2D AIThe SynGAP1 missense variant S28Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. There is no conflict with ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.545602	Disordered	0.438157	Uncertain	0.354	0.884	0.125											-4.521	Likely Benign	0.270	Likely Benign	Likely Benign										0.041	Likely Benign	-0.94	Neutral	0.009	Benign	0.001	Benign	4.13	Benign	0.05	Affected			0.0895	0.5067		-3	-2	-0.5	76.10
c.83C>T	S28F 2D AIThe SynGAP1 missense variant S28F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.545602	Disordered	0.438157	Uncertain	0.354	0.884	0.125											-4.548	Likely Benign	0.255	Likely Benign	Likely Benign										0.045	Likely Benign	-1.13	Neutral	0.009	Benign	0.002	Benign	4.13	Benign	0.05	Affected			0.0748	0.5340		-3	-2	3.6	60.10
c.842A>G	Y281C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized indicates a benign outcome, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. Consequently, the variant is most likely pathogenic based on the overwhelming majority of predictions, and this assessment does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.337647	Uncertain	0.927	0.254	0.000											-8.528	Likely Pathogenic	0.752	Likely Pathogenic	Likely Benign	3.00	Destabilizing	0.1	2.71	Destabilizing	2.86	Destabilizing	1.48	Destabilizing	0.615	Likely Pathogenic	-5.55	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.99	Pathogenic	0.05	Affected			0.2949	0.2176		0	-2	3.8	-60.04
c.844T>A	C282S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, whereas the majority of other in‑silico predictors (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all classify the variant as pathogenic. Stability‑based methods (FoldX, Rosetta, and Foldetta) return uncertain results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.348535	Uncertain	0.942	0.250	0.000					Uncertain		1				-11.846	Likely Pathogenic	0.958	Likely Pathogenic	Likely Pathogenic	1.55	Ambiguous	0.1	1.23	Ambiguous	1.39	Ambiguous	1.62	Destabilizing	0.460	Likely Benign	-9.19	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.64	Pathogenic	0.03	Affected	3.39	18	0.5009	0.1286	Weaken	0	-1	-3.3	-16.06	233.2	14.8	-0.1	0.0	-0.2	0.3						X		Potentially Benign	The thiol-containing side chain of Cys282, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), packs against multiple hydrophobic residues (e.g., Ile268, Leu284, Trp308, Leu327). In the variant simulations, the hydroxyl-containing side chain of Ser282 is more hydrophilic and, hence, not as favorable as Cys282 for this hydrophobic niche. Due to this polarity difference, the residue swap could potentially weaken the hydrophobic packing of the C2 domain during the folding process.Moreover, because the C2 domain interacts with the membrane, there could also be a negative effect on the stability of the SynGAP-membrane association. However, no large-scale structural changes were observed during the variant simulations. The hydroxyl group of Ser282 forms a hydrogen bond with the backbone carbonyl group of His326 in another β strand (res. Ala322-Arg329), which competes directly with the backbone amide group of Glu283 within the secondary structure element.
c.844T>C	C282R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282R is listed in ClinVar as Pathogenic (ClinVar ID 635755.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to REVEL, which scores the variant as benign. All other evaluated algorithms predict a pathogenic outcome: FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Rosetta’s output is uncertain and is therefore not counted as evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) also predicts pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, which aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.348535	Uncertain	0.942	0.250	0.000					Pathogenic		2				-16.378	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	3.13	Destabilizing	0.6	1.58	Ambiguous	2.36	Destabilizing	1.70	Destabilizing	0.466	Likely Benign	-11.03	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.63	Pathogenic	0.00	Affected	3.39	18	0.1696	0.1557		-4	-3	-7.0	53.05	297.4	-98.2	-0.1	0.1	0.5	0.0	X		X				X	Potentially Pathogenic	The thiol-containing side chain of Cys282, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), is packed against multiple hydrophobic residues (e.g., Ile268, Leu284, Trp308, Leu327). In the variant simulations, the bulky side chain of Arg282 with its positively charged guanidinium group is not suitable for this hydrophobic niche. Consequently, the hydrophobic residues must either make room to accommodate Arg282 or it must escape the hydrophobic C2 domain core.As a result, new hydrogen bonds are formed with the backbone carbonyl groups of the surrounding β sheet residues Ala399, Leu325, and His326, which decreases the unity of the secondary structure elements. Notably, it is likely that the residue swap causes major problems during the C2 domain folding that are not visible in the variant simulations. In fact, even increased lability in the C2 domain could adversely affect the establishment of a stable SynGAP-membrane association.
c.844T>G	C282G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The high‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; SGM‑Consensus is pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among pathogenic predictors and the high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.348535	Uncertain	0.942	0.250	0.000											-15.830	Likely Pathogenic	0.837	Likely Pathogenic	Ambiguous	2.60	Destabilizing	0.1	2.83	Destabilizing	2.72	Destabilizing	1.60	Destabilizing	0.482	Likely Benign	-11.03	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.64	Pathogenic	0.04	Affected			0.3229	0.2238		-3	-3	-2.9	-46.09
c.845G>A	C282Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282Y resides in the C2 domain. ClinVar has no entry for this variant, and it is not listed in gnomAD. Prediction tools that indicate a benign effect are REVEL and premPS. All other evaluated algorithms—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.348535	Uncertain	0.942	0.250	0.000											-13.438	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	8.50	Destabilizing	1.1	2.91	Destabilizing	5.71	Destabilizing	0.41	Likely Benign	0.419	Likely Benign	-10.11	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.63	Pathogenic	0.00	Affected			0.1069	0.3089		0	-2	-3.8	60.04
c.845G>C	C282S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions from FoldX, Rosetta, and Foldetta are inconclusive and are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, while Foldetta remains uncertain. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.348535	Uncertain	0.942	0.250	0.000											-11.846	Likely Pathogenic	0.958	Likely Pathogenic	Likely Pathogenic	1.55	Ambiguous	0.1	1.23	Ambiguous	1.39	Ambiguous	1.62	Destabilizing	0.436	Likely Benign	-9.19	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.64	Pathogenic	0.03	Affected	3.39	18	0.5009	0.1286	Weaken	0	-1	-3.3	-16.06	233.2	14.8	-0.1	0.0	-0.2	0.3						X		Potentially Benign	The thiol-containing side chain of Cys282, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), packs against multiple hydrophobic residues (e.g., Ile268, Leu284, Trp308, Leu327). In the variant simulations, the hydroxyl-containing side chain of Ser282 is more hydrophilic and, hence, not as favorable as Cys282 for this hydrophobic niche. Due to this polarity difference, the residue swap could potentially weaken the hydrophobic packing of the C2 domain during the folding process.Moreover, because the C2 domain interacts with the membrane, there could also be a negative effect on the stability of the SynGAP-membrane association. However, no large-scale structural changes were observed during the variant simulations. The hydroxyl group of Ser282 forms a hydrogen bond with the backbone carbonyl group of His326 in another β strand (res. Ala322-Arg329), which competes directly with the backbone amide group of Glu283 within the secondary structure element.
c.845G>T	C282F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282F is not listed in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are provided by REVEL and premPS, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic outcome. Taken together, the overwhelming majority of evidence points to a pathogenic impact for C282F. This conclusion is consistent with the absence of a ClinVar entry, which does not contradict the prediction. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.348535	Uncertain	0.942	0.250	0.000											-13.288	Likely Pathogenic	0.983	Likely Pathogenic	Likely Pathogenic	6.22	Destabilizing	1.4	2.38	Destabilizing	4.30	Destabilizing	0.42	Likely Benign	0.430	Likely Benign	-10.11	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.65	Pathogenic	0.00	Affected			0.1267	0.3607		-4	-2	0.3	44.04
c.846T>G	C282W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change C282W is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to REVEL, which scores the variant as benign. All other evaluated predictors—FoldX, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. Uncertain results come only from premPS and Rosetta, which are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic status; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. Thus, the variant is most likely pathogenic based on the collective predictions, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.348535	Uncertain	0.942	0.250	0.000											-15.392	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	10.69	Destabilizing	1.7	-1.05	Ambiguous	4.82	Destabilizing	0.70	Ambiguous	0.418	Likely Benign	-10.11	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.63	Pathogenic	0.03	Affected			0.1457	0.2978		-8	-2	-3.4	83.07
c.847G>A	E283K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E283K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL and FoldX, whereas the majority of algorithms predict it to be pathogenic: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.358602	Uncertain	0.950	0.249	0.000											-14.350	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.30	Likely Benign	0.1	0.82	Ambiguous	0.56	Ambiguous	0.62	Ambiguous	0.443	Likely Benign	-3.68	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.92	Pathogenic	0.01	Affected			0.2989	0.5714		0	1	-0.4	-0.94
c.847G>C	E283Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E283Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The premPS score is uncertain and does not contribute to the consensus. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of tools (nine pathogenic vs. four benign) predict a pathogenic impact. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.358602	Uncertain	0.950	0.249	0.000											-10.650	Likely Pathogenic	0.978	Likely Pathogenic	Likely Pathogenic	0.48	Likely Benign	0.1	-0.01	Likely Benign	0.24	Likely Benign	0.61	Ambiguous	0.372	Likely Benign	-2.76	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.67	Pathogenic	0.01	Affected			0.1432	0.5389		2	2	0.0	-0.98
c.848A>C	E283A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E283A is reported in gnomAD (ID 6‑33437753‑A‑C) but has no ClinVar entry. Functional prediction tools that agree on a deleterious effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, all labeling the change as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. Predictions that are inconclusive or unavailable—FoldX, Rosetta, Foldetta, and premPS—do not provide evidence for or against pathogenicity. High‑accuracy assessments confirm the deleterious nature: AlphaMissense‑Optimized predicts pathogenic, SGM Consensus indicates Likely Pathogenic, while Foldetta remains uncertain. Taken together, the overwhelming majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.358602	Uncertain	0.950	0.249	0.000								6-33437753-A-C	2	1.24e-6	-12.547	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	1.26	Ambiguous	0.1	1.19	Ambiguous	1.23	Ambiguous	0.53	Ambiguous	0.529	Likely Pathogenic	-5.52	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.67	Pathogenic	0.01	Affected	3.38	19	0.4104	0.5807		-1	0	5.3	-58.04
c.848A>G	E283G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E283G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the single uncertain call from premPS is treated as unavailable. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.358602	Uncertain	0.950	0.249	0.000											-13.937	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	3.13	Destabilizing	0.1	2.74	Destabilizing	2.94	Destabilizing	0.55	Ambiguous	0.559	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	1.63	Pathogenic	0.01	Affected			0.3123	0.4842		0	-2	3.1	-72.06
c.848A>T	E283V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E283V missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are FoldX and premPS, while the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give inconclusive results: Rosetta (Uncertain) and Foldetta (Uncertain). High‑accuracy methods specifically indicate that AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely pathogenic, whereas Foldetta’s stability assessment is uncertain. Taken together, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic effect for E283V. This conclusion is consistent with the absence of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.098513	Structured	0.358602	Uncertain	0.950	0.249	0.000											-13.602	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.44	Likely Benign	0.2	0.56	Ambiguous	0.50	Ambiguous	0.36	Likely Benign	0.558	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.83	Pathogenic	0.00	Affected			0.0874	0.6011		-2	-2	7.7	-29.98
c.850C>G	L284V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L284V missense variant has no ClinVar entry and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Predictions that are uncertain or inconclusive are FoldX, AlphaMissense‑Default, and Foldetta. High‑accuracy methods give a benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta remains uncertain. Overall, the balance of evidence leans toward a pathogenic effect, and this assessment does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.094817	Structured	0.371601	Uncertain	0.950	0.255	0.000											-6.726	Likely Benign	0.347	Ambiguous	Likely Benign	1.65	Ambiguous	0.2	2.08	Destabilizing	1.87	Ambiguous	1.38	Destabilizing	0.248	Likely Benign	-2.32	Neutral	0.999	Probably Damaging	0.994	Probably Damaging	2.18	Pathogenic	0.03	Affected			0.1259	0.2456		2	1	0.4	-14.03
c.850C>T	L284F 2D AIThe SynGAP1 missense variant L284F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Taken together, the overwhelming majority of evidence indicates that the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.094817	Structured	0.371601	Uncertain	0.950	0.255	0.000											-11.656	Likely Pathogenic	0.970	Likely Pathogenic	Likely Pathogenic	2.04	Destabilizing	1.9	1.05	Ambiguous	1.55	Ambiguous	0.62	Ambiguous	0.654	Likely Pathogenic	-3.51	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.69	Pathogenic	0.01	Affected			0.0515	0.2779		2	0	-1.0	34.02
c.851T>A	L284H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L284H is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a pathogenic impact. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.094817	Structured	0.371601	Uncertain	0.950	0.255	0.000											-16.581	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.26	Destabilizing	0.1	3.06	Destabilizing	3.16	Destabilizing	2.57	Destabilizing	0.772	Likely Pathogenic	-6.22	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.65	Pathogenic	0.00	Affected			0.0954	0.0726		-2	-3	-7.0	23.98
c.851T>C	L284P 2D AIThe SynGAP1 missense variant L284P is listed in ClinVar as Pathogenic (ClinVar ID 3344808.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.094817	Structured	0.371601	Uncertain	0.950	0.255	0.000					Likely Pathogenic		1				-15.588	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	5.83	Destabilizing	0.2	5.81	Destabilizing	5.82	Destabilizing	1.89	Destabilizing	0.794	Likely Pathogenic	-6.17	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.64	Pathogenic	0.00	Affected			0.3540	0.1021		-3	-3	-5.4	-16.04
c.851T>G	L284R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L284R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.094817	Structured	0.371601	Uncertain	0.950	0.255	0.000											-17.698	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	5.05	Destabilizing	0.5	4.29	Destabilizing	4.67	Destabilizing	2.14	Destabilizing	0.797	Likely Pathogenic	-5.38	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.65	Pathogenic	0.00	Affected			0.1175	0.0600		-3	-2	-8.3	43.03
c.853T>C	C285R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FoldX, which scores the variant as benign. All other evaluated predictors—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms a likely pathogenic status, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Consequently, the preponderance of evidence points to a pathogenic effect for C285R, and this conclusion does not contradict any existing ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.375400	Uncertain	0.946	0.250	0.000											-9.127	Likely Pathogenic	0.981	Likely Pathogenic	Likely Pathogenic	-0.47	Likely Benign	0.2	-0.63	Ambiguous	-0.55	Ambiguous	1.53	Destabilizing	0.583	Likely Pathogenic	-9.66	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.83	Pathogenic	0.04	Affected			0.1947	0.1453		-4	-3	-7.0	53.05
c.853T>G	C285G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a pathogenic interpretation: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict deleterious effects. Tools that assess protein stability (FoldX, Rosetta, Foldetta) and AlphaMissense‑Optimized return uncertain results, providing no clear evidence for or against pathogenicity. High‑accuracy assessments further support a likely pathogenic verdict: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta remain inconclusive. Overall, the consensus of the majority of predictors indicates that the variant is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.144935	Structured	0.375400	Uncertain	0.946	0.250	0.000											-9.937	Likely Pathogenic	0.859	Likely Pathogenic	Ambiguous	1.26	Ambiguous	0.0	1.57	Ambiguous	1.42	Ambiguous	1.50	Destabilizing	0.564	Likely Pathogenic	-9.86	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.78	Pathogenic	0.04	Affected			0.3509	0.2922		-3	-3	-2.9	-46.09
c.856C>A	L286M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L286M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, PROVEAN, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Two tools (premPS and ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions (seven pathogenic vs. five benign) and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.122885	Structured	0.385647	Uncertain	0.932	0.260	0.000											-7.998	In-Between	0.781	Likely Pathogenic	Likely Benign	-0.06	Likely Benign	0.1	0.17	Likely Benign	0.06	Likely Benign	0.98	Ambiguous	0.663	Likely Pathogenic	-1.84	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.54	Pathogenic	0.02	Affected			0.0789	0.3371		4	2	-1.9	18.03
c.856C>G	L286V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L286V is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—consistently predict a pathogenic impact; AlphaMissense‑Default and Rosetta are uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized indicates benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.122885	Structured	0.385647	Uncertain	0.932	0.260	0.000											-9.986	Likely Pathogenic	0.500	Ambiguous	Likely Benign	2.44	Destabilizing	0.5	1.63	Ambiguous	2.04	Destabilizing	1.26	Destabilizing	0.676	Likely Pathogenic	-2.76	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	1.71	Pathogenic	0.01	Affected			0.1492	0.3007		2	1	0.4	-14.03
c.857T>A	L286Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L286Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect. No tool predicts a benign outcome. Two tools, Rosetta and Foldetta, return uncertain results. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts pathogenic; SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.122885	Structured	0.385647	Uncertain	0.932	0.260	0.000											-13.056	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	2.37	Destabilizing	0.3	1.42	Ambiguous	1.90	Ambiguous	2.06	Destabilizing	0.852	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.48	Pathogenic	0.00	Affected			0.1123	0.0958		-2	-2	-7.3	14.97
c.857T>C	L286P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L286P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.122885	Structured	0.385647	Uncertain	0.932	0.260	0.000											-14.982	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	5.43	Destabilizing	0.9	6.38	Destabilizing	5.91	Destabilizing	2.10	Destabilizing	0.878	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.47	Pathogenic	0.00	Affected			0.3719	0.1182		-3	-3	-5.4	-16.04
c.857T>G	L286R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L286R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while Rosetta remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely pathogenic outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity; the SGM‑Consensus (majority vote) is likely pathogenic; and Foldetta, which integrates FoldX‑MD (pathogenic) and Rosetta (uncertain), reports a pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.122885	Structured	0.385647	Uncertain	0.932	0.260	0.000											-15.563	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	2.90	Destabilizing	0.3	1.80	Ambiguous	2.35	Destabilizing	1.97	Destabilizing	0.868	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.49	Pathogenic	0.00	Affected			0.1370	0.0600		-3	-2	-8.3	43.03
c.859G>C	D287H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D287H missense variant is listed in ClinVar as Pathogenic (ClinVar ID 1700054.0) and is not reported in gnomAD. Functional prediction tools that assess the variant’s effect on protein function largely agree on a deleterious outcome. Benign predictions come from FoldX, Rosetta, and Foldetta, whereas pathogenic predictions are reported by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS remains uncertain. High‑accuracy assessments further support a pathogenic classification: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of evidence points to a pathogenic effect, consistent with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000					Likely Pathogenic		1				-14.518	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.48	Likely Benign	0.3	0.32	Likely Benign	0.40	Likely Benign	0.63	Ambiguous	0.589	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.51	Pathogenic	0.00	Affected	3.38	23	0.1620	0.8487		1	-1	0.3	22.05	235.6	3.8	0.1	1.2	0.1	0.1	X	X						Potentially Pathogenic	The carboxylate group of Asp287, located at the beginning of a β hairpin loop connecting two anti-parallel β sheet strands (res. Arg279-Leu286, res. Met289-Pro298), maintains a salt bridge with the guanidinium group of Arg324 in the β sheet during the WT simulations. In the variant simulations, the imidazole ring of the His287 side chain is unable to form a salt bridge with Arg324 or establish any other stable compensatory interactions, which could weaken the beta sandwich assembly of the C2 domain. This destabilization of the C2 domain could adversely affect the stability of the SynGAP-membrane association.
c.859G>T	D287Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D287Y missense variant is reported in ClinVar as Pathogenic (ClinVar ID 2263930.0) and is not found in gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, and premPS, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. High‑accuracy assessments give a pathogenic verdict from AlphaMissense‑Optimized, a Likely Pathogenic consensus from SGM, and a benign outcome from Foldetta. Overall, the majority of evidence points to a deleterious effect. Therefore, the variant is most likely pathogenic, in agreement with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000					Likely Pathogenic		1				-12.877	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.21	Likely Benign	0.2	0.48	Likely Benign	0.35	Likely Benign	0.27	Likely Benign	0.663	Likely Pathogenic	-8.27	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.51	Pathogenic	0.00	Affected	3.38	23	0.0597	0.7361		-4	-3	2.2	48.09	257.8	-44.4	-0.6	1.6	0.2	0.3	X	X						Potentially Pathogenic	The carboxylate group of Asp287, located at the beginning of a β hairpin loop linking two anti-parallel β sheet strands (res. Arg279-Leu286, res. Met289-Pro298), maintains a salt bridge with the guanidinium group of Arg324 in the β sheet during the WT simulations. In the variant simulations, the phenol group of the Tyr287 side chain is unable to form a salt bridge with the guanidinium group of Arg324, which could weaken the tertiary structure assembly of the C2 domain. However, the phenol group of Tyr287 frequently stacks with the Arg324 guanidinium side chain, which could help maintain the tertiary structure, especially compared to the D287H variant. The destabilization of the C2 domain could adversely affect the stability of the SynGAP-membrane association.
c.85A>C	M29L 2D AIThe SynGAP1 missense variant M29L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250											-1.633	Likely Benign	0.079	Likely Benign	Likely Benign										0.200	Likely Benign	-0.49	Neutral	0.006	Benign	0.039	Benign	4.27	Benign	0.00	Affected			0.1984	0.5336		4	2	1.9	-18.03
c.85A>G	M29V 2D AIThe SynGAP1 missense variant M29V is reported in gnomAD (ID 6‑33423494‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, representing the sole discordant signal. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for M29V, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250								6-33423494-A-G	1	6.20e-7	-1.841	Likely Benign	0.057	Likely Benign	Likely Benign										0.209	Likely Benign	-0.39	Neutral	0.006	Benign	0.091	Benign	4.27	Benign	0.00	Affected	4.32	1	0.4022	0.4433		1	2	2.3	-32.06
c.85A>T	M29L 2D AIThe SynGAP1 missense variant M29L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; there is no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250											-1.633	Likely Benign	0.079	Likely Benign	Likely Benign										0.200	Likely Benign	-0.49	Neutral	0.006	Benign	0.039	Benign	4.27	Benign	0.00	Affected			0.1984	0.5336		4	2	1.9	-18.03
c.860A>C	D287A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D287A is listed in ClinVar with an Uncertain significance status and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, FoldX, Rosetta, Foldetta, and premPS, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta) as benign. The overall tally favors pathogenicity (8 tools vs 5 benign), but the conflicting high‑accuracy results leave uncertainty. Thus, the variant is most likely pathogenic according to the majority of predictions, which does not contradict its ClinVar Uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000					Uncertain		1				-14.686	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	0.30	Likely Benign	0.1	-0.04	Likely Benign	0.13	Likely Benign	0.40	Likely Benign	0.484	Likely Benign	-7.35	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.58	Pathogenic	0.01	Affected	3.38	23	0.4448	0.7431		-2	0	5.3	-44.01
c.860A>G	D287G 2D AIThe SynGAP1 missense variant D287G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Foldetta, premPS, and Rosetta, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict it to be pathogenic; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of predictions indicates a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000											-13.558	Likely Pathogenic	0.967	Likely Pathogenic	Likely Pathogenic	0.61	Ambiguous	1.1	0.31	Likely Benign	0.46	Likely Benign	0.38	Likely Benign	0.521	Likely Pathogenic	-6.43	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.59	Pathogenic	0.01	Affected			0.4688	0.7390		1	-1	3.1	-58.04
c.860A>T	D287V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D287V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS; all other evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, while FoldX is uncertain and thus not counted as evidence. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000											-14.418	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.71	Ambiguous	0.4	3.94	Destabilizing	2.83	Destabilizing	0.25	Likely Benign	0.516	Likely Pathogenic	-8.27	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.57	Pathogenic	0.01	Affected			0.0884	0.7788		-2	-3	7.7	-15.96
c.861T>A	D287E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D287E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, ESM1b, and the protein‑folding stability method Foldetta; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic), also reports it as pathogenic. In contrast, Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect on protein stability. No evidence is available from Rosetta alone. Overall, the majority of predictions, including the high‑accuracy methods, indicate a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000											-5.250	Likely Benign	0.990	Likely Pathogenic	Likely Pathogenic	0.35	Likely Benign	0.2	0.54	Ambiguous	0.45	Likely Benign	0.50	Likely Benign	0.416	Likely Benign	-3.68	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.54	Pathogenic	0.01	Affected			0.1541	0.7833		3	2	0.0	14.03
c.861T>G	D287E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D287E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, ESM1b, and the protein‑folding stability method Foldetta; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic), also reports it as pathogenic. In contrast, Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect on protein stability. No evidence is available from Rosetta alone. Overall, the majority of predictions, including the high‑accuracy methods, indicate a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.102787	Structured	0.389029	Uncertain	0.912	0.268	0.000											-5.250	Likely Benign	0.990	Likely Pathogenic	Likely Pathogenic	0.35	Likely Benign	0.2	0.54	Ambiguous	0.45	Likely Benign	0.50	Likely Benign	0.416	Likely Benign	-3.68	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.54	Pathogenic	0.01	Affected			0.1541	0.7833		3	2	0.0	14.03
c.862G>A	D288N 2D 3DClick to see structure in 3D Viewer AISynGAP1 D288N is listed in ClinVar with an uncertain significance (ClinVar ID 2572204.0) and is present in gnomAD (6‑33437767‑G‑A). Computational predictors are divided: benign calls come from REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic. Because the majority of high‑accuracy tools predict benign and the overall split of predictions is even, the variant is most likely benign, which does not contradict the ClinVar status of uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.395525	Uncertain	0.873	0.261	0.000					Uncertain		1	6-33437767-G-A	2	1.24e-6	-10.535	Likely Pathogenic	0.521	Ambiguous	Likely Benign	-0.39	Likely Benign	0.1	0.01	Likely Benign	-0.19	Likely Benign	-0.03	Likely Benign	0.321	Likely Benign	-3.73	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.78	Pathogenic	0.05	Affected	3.38	23	0.1398	0.5770		1	2	0.0	-0.98
c.862G>C	D288H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D288H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, and premPS. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling the variant as Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect on protein folding stability. Overall, the majority of tools (7/12) predict pathogenicity, and the high‑accuracy consensus leans toward pathogenic, with no conflict with ClinVar status. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.395525	Uncertain	0.873	0.261	0.000											-12.589	Likely Pathogenic	0.953	Likely Pathogenic	Ambiguous	0.08	Likely Benign	0.1	0.36	Likely Benign	0.22	Likely Benign	-0.02	Likely Benign	0.460	Likely Benign	-5.40	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.65	Pathogenic	0.01	Affected			0.1639	0.6254		1	-1	0.3	22.05
c.862G>T	D288Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288Y missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, and premPS; pathogenic predictions from SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from the available tools suggests a benign effect. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.395525	Uncertain	0.873	0.261	0.000											-15.269	Likely Pathogenic	0.979	Likely Pathogenic	Likely Pathogenic	0.11	Likely Benign	0.2	1.10	Ambiguous	0.61	Ambiguous	0.10	Likely Benign	0.472	Likely Benign	-7.11	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.64	Pathogenic	0.00	Affected			0.0635	0.5009		-4	-3	2.2	48.09
c.863A>T	D288V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are provided by REVEL and premPS, whereas the remaining tools—FoldX (uncertain), Rosetta, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—all indicate a pathogenic effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.125101	Structured	0.395525	Uncertain	0.873	0.261	0.000											-15.812	Likely Pathogenic	0.981	Likely Pathogenic	Likely Pathogenic	1.74	Ambiguous	0.5	5.44	Destabilizing	3.59	Destabilizing	0.13	Likely Benign	0.481	Likely Benign	-7.14	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.63	Pathogenic	0.05	Affected			0.0838	0.5545		-2	-3	7.7	-15.96
c.868C>A	L290M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L290M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, and PROVEAN, whereas pathogenic predictions are reported by polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Tools with uncertain outcomes include Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta. High‑accuracy analyses indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence leans toward a pathogenic effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.127496	Structured	0.399723	Uncertain	0.904	0.255	0.000											-8.393	Likely Pathogenic	0.901	Likely Pathogenic	Ambiguous	0.48	Likely Benign	0.2	0.98	Ambiguous	0.73	Ambiguous	0.59	Ambiguous	0.438	Likely Benign	-1.84	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.92	Pathogenic	0.02	Affected			0.0823	0.4167		4	2	-1.9	18.03
c.868C>G	L290V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L290V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and Rosetta, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, premPS, ESM1b, AlphaMissense‑Optimized, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence from multiple pathogenic‑predicting tools and the SGM Consensus suggests that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.127496	Structured	0.399723	Uncertain	0.904	0.255	0.000											-7.392	In-Between	0.834	Likely Pathogenic	Ambiguous	1.17	Ambiguous	0.1	0.35	Likely Benign	0.76	Ambiguous	0.62	Ambiguous	0.366	Likely Benign	-2.76	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	1.98	Pathogenic	0.05	Affected			0.1574	0.4177		2	1	0.4	-14.03
c.869T>C	L290P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L290P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously favor a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenicity. No tool in the dataset predicts a benign outcome; the remaining tools (FoldX, Rosetta, Foldetta, premPS) return uncertain results, which are treated as unavailable evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is inconclusive. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.127496	Structured	0.399723	Uncertain	0.904	0.255	0.000											-11.796	Likely Pathogenic	0.973	Likely Pathogenic	Likely Pathogenic	0.79	Ambiguous	0.1	1.10	Ambiguous	0.95	Ambiguous	0.56	Ambiguous	0.727	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.01	Pathogenic	0.03	Affected			0.3646	0.1703		-3	-3	-5.4	-16.04
c.869T>G	L290R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L290R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions are limited to FoldX, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all classify the variant as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. Overall, the consensus of the majority of evidence points to a pathogenic impact. This conclusion is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.127496	Structured	0.399723	Uncertain	0.904	0.255	0.000											-13.938	Likely Pathogenic	0.988	Likely Pathogenic	Likely Pathogenic	0.48	Likely Benign	0.1	0.88	Ambiguous	0.68	Ambiguous	0.89	Ambiguous	0.705	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.03	Pathogenic	0.01	Affected			0.1215	0.1056		-3	-2	-8.3	43.03
c.86T>A	M29K 2D AIThe SynGAP1 missense variant M29K is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency or clinical annotation. Prediction tools that converge on a benign outcome include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective predictions point to a benign effect, and this conclusion does not contradict the absence of a ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250											-2.514	Likely Benign	0.287	Likely Benign	Likely Benign										0.197	Likely Benign	-0.88	Neutral	0.018	Benign	0.184	Benign	4.27	Benign	0.00	Affected			0.2019	0.1312		0	-1	-5.8	-3.02
c.86T>C	M29T 2D AIThe SynGAP1 missense variant M29T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that M29T is most likely benign, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250					Uncertain		1				-2.167	Likely Benign	0.122	Likely Benign	Likely Benign										0.199	Likely Benign	-0.37	Neutral	0.018	Benign	0.184	Benign	4.33	Benign	0.00	Affected	4.32	1	0.2633	0.2716		-1	-1	-2.6	-30.09
c.86T>G	M29R 2D AIThe SynGAP1 missense variant M29R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250											-1.708	Likely Benign	0.241	Likely Benign	Likely Benign										0.211	Likely Benign	-0.92	Neutral	0.042	Benign	0.184	Benign	4.23	Benign	0.00	Affected			0.2076	0.1293		0	-1	-6.4	24.99
c.871T>A	Y291N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291N is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy methods corroborate this: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic effect. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.383842	Uncertain	0.912	0.251	0.000											-13.599	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	2.82	Destabilizing	0.6	3.37	Destabilizing	3.10	Destabilizing	2.16	Destabilizing	0.533	Likely Pathogenic	-7.43	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.76	Pathogenic	0.01	Affected			0.2255	0.0499		-2	-2	-2.2	-49.07
c.871T>C	Y291H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291H is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from REVEL, while all other evaluated algorithms (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a likely pathogenic verdict; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.383842	Uncertain	0.912	0.251	0.000											-8.749	Likely Pathogenic	0.986	Likely Pathogenic	Likely Pathogenic	2.13	Destabilizing	0.2	2.61	Destabilizing	2.37	Destabilizing	1.56	Destabilizing	0.355	Likely Benign	-4.04	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.77	Pathogenic	0.02	Affected			0.2403	0.0499		0	2	-1.9	-26.03
c.871T>G	Y291D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291D is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.383842	Uncertain	0.912	0.251	0.000											-17.570	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	4.13	Destabilizing	0.6	3.86	Destabilizing	4.00	Destabilizing	1.91	Destabilizing	0.650	Likely Pathogenic	-8.19	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.75	Pathogenic	0.01	Affected			0.4300	0.0331		-4	-3	-2.2	-48.09
c.872A>C	Y291S 2D AIThe SynGAP1 missense variant Y291S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in silico predictors classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.383842	Uncertain	0.912	0.251	0.000											-11.928	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	3.47	Destabilizing	0.8	4.47	Destabilizing	3.97	Destabilizing	2.01	Destabilizing	0.588	Likely Pathogenic	-7.31	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.83	Pathogenic	0.02	Affected			0.4850	0.2079		-3	-2	0.5	-76.10
c.872A>G	Y291C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291C is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.383842	Uncertain	0.912	0.251	0.000					Uncertain		1				-8.997	Likely Pathogenic	0.967	Likely Pathogenic	Likely Pathogenic	2.90	Destabilizing	0.4	3.51	Destabilizing	3.21	Destabilizing	1.35	Destabilizing	0.505	Likely Pathogenic	-7.37	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.76	Pathogenic	0.01	Affected	3.38	23	0.3053	0.2527		0	-2	3.8	-60.04	205.2	66.1	0.1	0.0	-0.4	0.4	X						X	Potentially Pathogenic	The phenol group of the Tyr291 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), packs against hydrophobic residues of the C2 and PH domains (e.g., Leu317, Leu286, Leu284, Pro208, Val209). The phenol ring of Tyr291 also forms favorable Met-aromatic stacking with the methyl group of Met289. In the variant simulation, the thiol group of the Cys291 side chain is not as suitable for the hydrophobic inter-domain space as the phenol ring of Tyr291. Consequently, the structural unity of the PH domain is weakened and ultimately unfolds in the second simulation. Moreover, the residue swap might result in severe detrimental effects on the C2 domain structure and the C2-PH domain tertiary structure assembly during folding.
c.874G>A	A292T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely converge on a deleterious effect: only REVEL classifies it as benign, whereas FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a destabilizing, pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.247041	Structured	0.362042	Uncertain	0.929	0.256	0.000											-11.039	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	2.16	Destabilizing	0.7	3.42	Destabilizing	2.79	Destabilizing	1.08	Destabilizing	0.457	Likely Benign	-3.68	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.68	Pathogenic	0.01	Affected			0.1691	0.7377		1	0	-2.5	30.03
c.874G>C	A292P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely converge on a deleterious effect: only REVEL classifies it as benign, whereas FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a destabilizing, pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.247041	Structured	0.362042	Uncertain	0.929	0.256	0.000											-16.897	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.37	Destabilizing	0.3	9.80	Destabilizing	7.09	Destabilizing	1.23	Destabilizing	0.471	Likely Benign	-4.60	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.67	Pathogenic	0.01	Affected			0.2101	0.5988		1	-1	-3.4	26.04
c.874G>T	A292S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292S is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FoldX, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and PROVEAN. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. No prediction or folding‑stability result is missing; uncertain outcomes are treated as unavailable. Overall, the balance of evidence favors a pathogenic classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.247041	Structured	0.362042	Uncertain	0.929	0.256	0.000											-8.514	Likely Pathogenic	0.804	Likely Pathogenic	Ambiguous	0.40	Likely Benign	0.2	2.13	Destabilizing	1.27	Ambiguous	0.70	Ambiguous	0.364	Likely Benign	-2.76	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.69	Pathogenic	0.03	Affected			0.2850	0.6389		1	1	-2.6	16.00
c.875C>A	A292E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292E is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for A292E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.247041	Structured	0.362042	Uncertain	0.929	0.256	0.000											-14.282	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	6.07	Destabilizing	1.2	3.82	Destabilizing	4.95	Destabilizing	1.54	Destabilizing	0.475	Likely Benign	-4.60	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.69	Pathogenic	0.02	Affected			0.1444	0.2205		0	-1	-5.3	58.04
c.875C>T	A292V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.247041	Structured	0.362042	Uncertain	0.929	0.256	0.000											-11.170	Likely Pathogenic	0.987	Likely Pathogenic	Likely Pathogenic	2.04	Destabilizing	0.5	4.60	Destabilizing	3.32	Destabilizing	0.85	Ambiguous	0.430	Likely Benign	-3.68	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.75	Pathogenic	0.03	Affected			0.1272	0.6253		0	0	2.4	28.05
c.877C>A	R293S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R293S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a deleterious effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that are inconclusive or uncertain are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus indicating a likely pathogenic outcome, while Foldetta’s stability analysis remains uncertain. Taken together, the overwhelming majority of evidence points to a pathogenic impact for R293S. This conclusion is consistent with the lack of ClinVar annotation, as there is no conflicting status to contradict the prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.338192	Uncertain	0.924	0.269	0.125											-14.103	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	2.66	Destabilizing	0.2	1.30	Ambiguous	1.98	Ambiguous	0.71	Ambiguous	0.561	Likely Pathogenic	-5.52	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.51	Pathogenic	0.01	Affected			0.2794	0.5045		0	-1	3.7	-69.11
c.877C>G	R293G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R293G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains uncertain. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic outcome, and Foldetta (integrating FoldX‑MD and Rosetta stability outputs) also indicates pathogenicity. No tool suggests a benign effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.338192	Uncertain	0.924	0.269	0.125											-15.861	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	3.70	Destabilizing	0.2	2.35	Destabilizing	3.03	Destabilizing	0.57	Ambiguous	0.604	Likely Pathogenic	-6.43	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.45	Pathogenic	0.02	Affected			0.3235	0.3738		-3	-2	4.1	-99.14
c.877C>T	R293C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R293C is listed in ClinVar with an uncertain significance (ClinVar ID 2500611.0) and is present in gnomAD (6‑33437782‑C‑T). Prediction tools that classify the variant as benign include premPS, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Consequently, the overwhelming majority of computational evidence indicates a pathogenic impact for R293C. This prediction aligns with the ClinVar designation of uncertain significance, not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.338192	Uncertain	0.924	0.269	0.125					Uncertain		1	6-33437782-C-T	3	1.86e-6	-12.844	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	1.38	Ambiguous	0.1	0.62	Ambiguous	1.00	Ambiguous	0.02	Likely Benign	0.579	Likely Pathogenic	-7.35	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.46	Pathogenic	0.00	Affected	3.38	23	0.3031	0.4363		-4	-3	7.0	-53.05	226.0	96.5	0.0	0.0	0.1	0.1		X		X			X	Potentially Pathogenic	The guanidinium group of the Arg293 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), packs against the phenol ring of the Tyr281 side chain or forms a salt bridge with the carboxylate group of Glu283 on the outer side of the C2 domain. The positively charged guanidinium side chain of arginine is on the outside surface of the hydrophobic C2 domain, resulting in a twist in the β strand. Although this twist is maintained in the variant simulations, replacing the positively charged residue with a more hydrophobic one, such as cysteine, could remove the twist during protein folding.Because Arg293 is positioned at the C2 and PH domain interface, the residue swap could significantly impact the tertiary structure assembly. Notably, Arg293 is located at the SynGAP-Ras interface, and its role in complex formation cannot be fully understood through solvent-only simulations.
c.878G>A	R293H 2D AISynGAP1 missense variant R293H is listed in ClinVar with an uncertain significance (ClinVar ID 3901513.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL and premPS, whereas the remaining 13 tools—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, classifies the variant as pathogenic. Overall, the preponderance of evidence indicates that R293H is most likely pathogenic, a conclusion that does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.338192	Uncertain	0.924	0.269	0.125					Uncertain		1				-13.009	Likely Pathogenic	0.973	Likely Pathogenic	Likely Pathogenic	4.45	Destabilizing	2.3	2.12	Destabilizing	3.29	Destabilizing	0.32	Likely Benign	0.438	Likely Benign	-4.60	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.45	Pathogenic	0.04	Affected			0.3120	0.2573		2	0	1.3	-19.05
c.878G>C	R293P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R293P is listed in ClinVar as Pathogenic (ClinVar ID 571092.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL and premPS, whereas the remaining tools—FoldX, Rosetta, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as Pathogenic; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, classifies it as Pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is concordant with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.338192	Uncertain	0.924	0.269	0.125					Likely Pathogenic		1				-16.275	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	3.62	Destabilizing	0.4	9.06	Destabilizing	6.34	Destabilizing	0.47	Likely Benign	0.497	Likely Benign	-6.43	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.45	Pathogenic	0.01	Affected	3.38	23	0.2162	0.4778		0	-2	2.9	-59.07	202.3	132.0	0.1	0.0	0.1	0.1	X	X		X				Potentially Pathogenic	The guanidinium group of the Arg293 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), packs against the phenol ring of the Tyr281 side chain or forms a salt bridge with the carboxylate group of Glu283 on the outer side of the C2 domain. In the WT simulations, the positively charged side chain of arginine remains outside the hydrophobic C2 domain, resulting in a twist in the β strand. The backbone amide bond of Arg293 potentially maintains this twist by forming a hydrogen bond with the carbonyl group of His210 or the hydroxyl group of Ser211 in the anti-parallel β sheet.Although this twist is also maintained in the variant simulations, replacing the positively charged residue with proline, which lacks the backbone amide group altogether, causes the β strand to unfold. Because Arg293 is positioned at the C2 and PH domain interface, the residue swap could significantly impact the tertiary structure assembly. Notably, Arg293 is located at the SynGAP-Ras interface, and its role in complex formation cannot be fully understood through solvent-only simulations.
c.878G>T	R293L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R293L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by REVEL and premPS, while the remaining evaluated tools (SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict pathogenicity. Uncertain results from FoldX, Rosetta, and Foldetta are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta provides no definitive stability change. Consequently, the variant is most likely pathogenic based on the consensus of predictive tools, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.338192	Uncertain	0.924	0.269	0.125											-15.502	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	1.56	Ambiguous	0.2	0.93	Ambiguous	1.25	Ambiguous	0.08	Likely Benign	0.493	Likely Benign	-6.43	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.46	Pathogenic	0.01	Affected			0.1815	0.4987		-3	-2	8.3	-43.03
c.87G>A	M29I 2D AIThe SynGAP1 missense variant M29I is catalogued in gnomAD (6-33423496‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes, while the single pathogenic signal comes from SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign likelihood. Foldetta stability analysis is unavailable for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250								6-33423496-G-A	6	3.72e-6	-2.425	Likely Benign	0.185	Likely Benign	Likely Benign										0.067	Likely Benign	-0.51	Neutral	0.006	Benign	0.091	Benign	4.26	Benign	0.00	Affected	4.32	1	0.1680	0.4385		1	2	2.6	-18.03
c.87G>C	M29I 2D AIThe SynGAP1 missense variant M29I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250											-2.425	Likely Benign	0.185	Likely Benign	Likely Benign										0.067	Likely Benign	-0.51	Neutral	0.006	Benign	0.091	Benign	4.26	Benign	0.00	Affected	4.32	1	0.1680	0.4385		1	2	2.6	-18.03
c.87G>T	M29I 2D AIThe SynGAP1 missense variant M29I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.541878	Disordered	0.438540	Uncertain	0.341	0.883	0.250											-2.425	Likely Benign	0.185	Likely Benign	Likely Benign										0.067	Likely Benign	-0.51	Neutral	0.006	Benign	0.091	Benign	4.26	Benign	0.00	Affected	4.32	1	0.1680	0.4385		1	2	2.6	-18.03
c.880A>C	T294P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T294P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX (Uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool reports a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.316932	Uncertain	0.919	0.267	0.125											-17.477	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	1.97	Ambiguous	0.3	5.18	Destabilizing	3.58	Destabilizing	1.15	Destabilizing	0.741	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	-0.19	Pathogenic	0.01	Affected			0.1906	0.4479		0	-1	-0.9	-3.99
c.880A>G	T294A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T294A missense variant is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the only tool with an uncertain call is FoldX. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts Likely Pathogenic, and Foldetta predicts Pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.316932	Uncertain	0.919	0.267	0.125											-12.371	Likely Pathogenic	0.971	Likely Pathogenic	Likely Pathogenic	1.87	Ambiguous	0.1	2.27	Destabilizing	2.07	Destabilizing	1.05	Destabilizing	0.719	Likely Pathogenic	-4.60	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	-0.18	Pathogenic	0.03	Affected			0.3687	0.3494		1	0	2.5	-30.03
c.880A>T	T294S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T294S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). In silico predictors that classify the variant as benign are absent; all available tools that provide a definitive call predict a deleterious effect. Pathogenic predictions come from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of pathogenic calls and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which contains no opposing evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.316932	Uncertain	0.919	0.267	0.125											-7.785	In-Between	0.954	Likely Pathogenic	Ambiguous	1.12	Ambiguous	0.2	1.70	Ambiguous	1.41	Ambiguous	1.19	Destabilizing	0.613	Likely Pathogenic	-3.68	Deleterious	0.999	Probably Damaging	0.992	Probably Damaging	0.08	Pathogenic	0.03	Affected			0.2983	0.3396		1	1	-0.1	-14.03
c.881C>A	T294N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T294N is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy methods reinforce this assessment: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status (no report). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.316932	Uncertain	0.919	0.267	0.125											-14.925	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	2.74	Destabilizing	0.2	2.66	Destabilizing	2.70	Destabilizing	1.56	Destabilizing	0.630	Likely Pathogenic	-4.60	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	-0.18	Pathogenic	0.01	Affected			0.1040	0.3239		0	0	-2.8	13.00
c.881C>G	T294S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T294S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). In silico predictors that classify the variant as benign are absent; all available tools that provide a definitive call predict a deleterious effect. Pathogenic predictions come from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of pathogenic calls and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which contains no opposing evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.316932	Uncertain	0.919	0.267	0.125											-7.785	In-Between	0.954	Likely Pathogenic	Ambiguous	1.12	Ambiguous	0.2	1.70	Ambiguous	1.41	Ambiguous	1.19	Destabilizing	0.583	Likely Pathogenic	-3.68	Deleterious	0.999	Probably Damaging	0.992	Probably Damaging	0.08	Pathogenic	0.03	Affected			0.2983	0.3396		1	1	-0.1	-14.03
c.881C>T	T294I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T294I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on pathogenicity include REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results are Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Based on the overwhelming agreement among pathogenic predictions and the high‑accuracy tool results, the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.316932	Uncertain	0.919	0.267	0.125											-15.302	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	4.09	Destabilizing	0.2	1.33	Ambiguous	2.71	Destabilizing	0.54	Ambiguous	0.768	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	-0.19	Pathogenic	0.01	Affected			0.0808	0.5485		0	-1	5.2	12.05
c.883A>C	T295P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX and AlphaMissense‑Optimized, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome. High‑accuracy assessments further show that AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it as likely pathogenic, and Foldetta reports an uncertain stability change. With the majority of evidence pointing to deleterious effects, the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.401658	Structured	0.295548	Uncertain	0.881	0.288	0.125											-9.941	Likely Pathogenic	0.688	Likely Pathogenic	Likely Benign	0.26	Likely Benign	0.2	3.30	Destabilizing	1.78	Ambiguous	0.60	Ambiguous	0.531	Likely Pathogenic	-4.65	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.90	Pathogenic	0.02	Affected			0.2442	0.5327		0	-1	-0.9	-3.99
c.884C>A	T295N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T295N missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, ESM1b, and Foldetta, while those that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, seven tools predict pathogenicity versus four predicting benign, with no ClinVar evidence to contradict this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.401658	Structured	0.295548	Uncertain	0.881	0.288	0.125											-6.588	Likely Benign	0.793	Likely Pathogenic	Ambiguous	0.24	Likely Benign	0.1	0.66	Ambiguous	0.45	Likely Benign	0.89	Ambiguous	0.438	Likely Benign	-3.51	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.93	Pathogenic	0.03	Affected			0.1522	0.4457		0	0	-2.8	13.00
c.884C>T	T295I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T295I is reported in gnomAD (ID 6‑33437789‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two consensus groups: benign predictions come from FoldX and Foldetta, while pathogenic predictions are supported by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by AlphaMissense‑Optimized, Rosetta, and premPS and are treated as inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic effect, with only a minority of tools indicating benign or uncertain outcomes. This prediction does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.401658	Structured	0.295548	Uncertain	0.881	0.288	0.125								6-33437789-C-T	4	2.48e-6	-9.330	Likely Pathogenic	0.892	Likely Pathogenic	Ambiguous	0.21	Likely Benign	0.2	0.55	Ambiguous	0.38	Likely Benign	0.58	Ambiguous	0.607	Likely Pathogenic	-4.87	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.88	Pathogenic	0.04	Affected	3.38	23	0.1025	0.5599		-1	0	5.2	12.05
c.887C>A	S296Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and premPS, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. The variant is most likely pathogenic based on predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.444081	Structured	0.282669	Uncertain	0.887	0.284	0.250											-12.148	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	1.46	Ambiguous	0.2	0.48	Likely Benign	0.97	Ambiguous	0.15	Likely Benign	0.486	Likely Benign	-4.34	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.93	Pathogenic	0.05	Affected			0.0800	0.5610		-3	-2	-0.5	76.10
c.887C>G	S296C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as benign. No predictions or stability results are missing or inconclusive. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.444081	Structured	0.282669	Uncertain	0.887	0.284	0.250											-7.842	In-Between	0.286	Likely Benign	Likely Benign	0.46	Likely Benign	0.1	-0.11	Likely Benign	0.18	Likely Benign	0.09	Likely Benign	0.361	Likely Benign	-1.46	Neutral	1.000	Probably Damaging	0.998	Probably Damaging	1.91	Pathogenic	0.05	Affected			0.1052	0.6052		0	-1	3.3	16.06
c.887C>T	S296F 2D AIThe SynGAP1 missense variant S296F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, and premPS. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive and therefore unavailable as evidence. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.444081	Structured	0.282669	Uncertain	0.887	0.284	0.250											-11.721	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	1.29	Ambiguous	1.6	0.24	Likely Benign	0.77	Ambiguous	0.29	Likely Benign	0.494	Likely Benign	-4.34	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.94	Pathogenic	0.04	Affected			0.0720	0.5905		-3	-2	3.6	60.10
c.889A>C	K297Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K297Q missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, Rosetta, and Foldetta. In contrast, the majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX is uncertain and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as benign. Overall, the preponderance of evidence points to a pathogenic effect for K297Q. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.422041	Structured	0.272593	Uncertain	0.880	0.285	0.375											-8.393	Likely Pathogenic	0.970	Likely Pathogenic	Likely Pathogenic	0.66	Ambiguous	0.3	0.14	Likely Benign	0.40	Likely Benign	1.06	Destabilizing	0.450	Likely Benign	-3.48	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.65	Pathogenic	0.01	Affected			0.4768	0.1738		1	1	0.4	-0.04
c.889A>G	K297E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome; the only inconclusive result is FoldX, which is listed as “Uncertain” and is treated as unavailable. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective predictions, K297E is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.422041	Structured	0.272593	Uncertain	0.880	0.285	0.375											-10.143	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	1.99	Ambiguous	0.4	2.43	Destabilizing	2.21	Destabilizing	1.16	Destabilizing	0.507	Likely Pathogenic	-3.54	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.61	Pathogenic	0.02	Affected			0.4073	0.1547		0	1	0.4	0.94
c.88C>A	H30N 2D AIThe SynGAP1 missense variant H30N is not reported in ClinVar and is absent from gnomAD. Consensus among most in silico predictors is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect, while only SIFT predicts pathogenicity. Grouping the tools, the benign‑predicting set (nine tools) overwhelmingly outweighs the single pathogenic prediction. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250											-3.096	Likely Benign	0.108	Likely Benign	Likely Benign										0.052	Likely Benign	-1.91	Neutral	0.273	Benign	0.380	Benign	3.92	Benign	0.00	Affected			0.2699	0.3818		2	1	-0.3	-23.04
c.88C>G	H30D 2D AIThe SynGAP1 missense variant H30D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for H30D, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250											-2.838	Likely Benign	0.318	Likely Benign	Likely Benign										0.150	Likely Benign	-2.25	Neutral	0.462	Possibly Damaging	0.599	Possibly Damaging	3.93	Benign	0.00	Affected			0.3048	0.3296		1	-1	-0.3	-22.05
c.88C>T	H30Y 2D AIThe SynGAP1 H30Y missense variant (ClinVar ID 972248.0) is listed as “Uncertain” and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumVar and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250					Uncertain		1				-3.047	Likely Benign	0.115	Likely Benign	Likely Benign										0.082	Likely Benign	-1.84	Neutral	0.273	Benign	0.478	Possibly Damaging	3.99	Benign	0.00	Affected	4.32	1	0.1572	0.4856		0	2	1.9	26.03
c.890A>C	K297T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K297T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are none, whereas those that predict a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy methods specifically show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.422041	Structured	0.272593	Uncertain	0.880	0.285	0.375											-10.110	Likely Pathogenic	0.987	Likely Pathogenic	Likely Pathogenic	1.55	Ambiguous	0.1	1.19	Ambiguous	1.37	Ambiguous	0.59	Ambiguous	0.551	Likely Pathogenic	-5.28	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.62	Pathogenic	0.01	Affected			0.2294	0.4024		0	-1	3.2	-27.07
c.890A>T	K297M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297M is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, and premPS. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized classifies the variant as Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports Likely Pathogenic; whereas Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, reports a Benign effect. Overall, the preponderance of evidence (10 pathogenic vs. 4 benign predictions) points to the variant being most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.422041	Structured	0.272593	Uncertain	0.880	0.285	0.375											-11.472	Likely Pathogenic	0.992	Likely Pathogenic	Likely Pathogenic	0.09	Likely Benign	0.1	0.32	Likely Benign	0.21	Likely Benign	0.49	Likely Benign	0.538	Likely Pathogenic	-5.20	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.61	Pathogenic	0.00	Affected			0.1438	0.4394		0	-1	5.8	3.02
c.891G>C	K297N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.422041	Structured	0.272593	Uncertain	0.880	0.285	0.375											-11.328	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	1.08	Ambiguous	0.1	1.60	Ambiguous	1.34	Ambiguous	1.15	Destabilizing	0.253	Likely Benign	-4.31	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.61	Pathogenic	0.01	Affected			0.3797	0.2265		1	0	0.4	-14.07
c.891G>T	K297N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, K297N is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.422041	Structured	0.272593	Uncertain	0.880	0.285	0.375											-11.328	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	1.08	Ambiguous	0.1	1.60	Ambiguous	1.34	Ambiguous	1.15	Destabilizing	0.253	Likely Benign	-4.31	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.61	Pathogenic	0.01	Affected			0.3797	0.2265		1	0	0.4	-14.07
c.893C>A	P298H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P298H missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Remaining tools (AlphaMissense‑Default, FoldX, Rosetta, Foldetta, premPS) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is uncertain. Overall, the majority of predictions (five pathogenic vs. three benign) and the SGM Consensus support a pathogenic interpretation. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.328603	Structured	0.268765	Uncertain	0.860	0.283	0.500											-9.777	Likely Pathogenic	0.443	Ambiguous	Likely Benign	1.57	Ambiguous	0.2	1.49	Ambiguous	1.53	Ambiguous	0.83	Ambiguous	0.313	Likely Benign	-2.37	Neutral	0.999	Probably Damaging	0.964	Probably Damaging	1.92	Pathogenic	0.04	Affected			0.1769	0.4943		0	-2	-1.6	40.02
c.895C>G	R299G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized indicates a benign change, but the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. With the majority of evidence pointing to a damaging effect, the variant is most likely pathogenic. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.321458	Structured	0.262979	Uncertain	0.819	0.295	0.500											-8.354	Likely Pathogenic	0.629	Likely Pathogenic	Likely Benign	3.58	Destabilizing	0.2	3.16	Destabilizing	3.37	Destabilizing	1.37	Destabilizing	0.248	Likely Benign	-3.84	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.79	Pathogenic	0.02	Affected			0.3361	0.4150		-3	-2	4.1	-99.14
c.896G>A	R299H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R299H is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437801‑G‑A). Functional prediction tools cluster into two groups: benign predictions from REVEL and AlphaMissense‑Optimized, and pathogenic predictions from FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; Rosetta, ESM1b, and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a tie between pathogenic and uncertain calls. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar uncertain designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.321458	Structured	0.262979	Uncertain	0.819	0.295	0.500					Conflicting		2	6-33437801-G-A	10	6.20e-6	-7.731	In-Between	0.388	Ambiguous	Likely Benign	3.97	Destabilizing	1.0	0.94	Ambiguous	2.46	Destabilizing	1.41	Destabilizing	0.238	Likely Benign	-3.35	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.69	Pathogenic	0.02	Affected	3.39	19	0.3293	0.2982		2	0	1.3	-19.05	211.2	72.5	-0.1	0.2	-0.2	0.3	X							Potentially Pathogenic	The guanidinium group of Arg299, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), forms hydrogen bonds that stabilize the tight turn. In the WT simulations, the Arg299 side chain hydrogen bonds with the loop backbone carbonyl groups (e.g., Ser302, Thr305, Leu274, Gly303), the hydroxyl group of Ser300, and even forms a salt bridge with the carboxylate group of Asp304.In the variant simulations, the imidazole ring of His299 (epsilon protonated state) hydrogen bonds with the carbonyl group of Asp304 and the hydroxyl group of Ser300. However, it does not form as many or as strong interactions as arginine, which could affect the initial formation of the secondary hairpin loop during folding. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant.Additionally, His299 prefers to hydrophobically interact with other hydrophobic residues inside the C2 domain core (e.g., Val306, Leu274), which destabilizes the C2 domain. Indeed, the β strand partially unfolds during the second simulation. Moreover, the positively charged Arg299 side chain faces the polar head group region of the inner leaflet membrane and could directly anchor the C2 domain to the membrane. In short, the residue swap could negatively affect both protein folding and the stability of the SynGAP-membrane association.
c.896G>C	R299P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299P is not reported in ClinVar or gnomAD, indicating no publicly available frequency data. Prediction tools cluster into benign and pathogenic groups: benign predictions include REVEL and AlphaMissense‑Optimized, while pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, SIFT, FATHMM, and AlphaMissense‑Default; ESM1b is uncertain. The SGM‑Consensus label is Likely Pathogenic. High‑accuracy tools give a clear signal: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta also predicts pathogenic. Overall, the predictions strongly favor a pathogenic interpretation, with no ClinVar status to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.321458	Structured	0.262979	Uncertain	0.819	0.295	0.500											-7.662	In-Between	0.722	Likely Pathogenic	Likely Benign	4.10	Destabilizing	0.2	3.01	Destabilizing	3.56	Destabilizing	1.19	Destabilizing	0.295	Likely Benign	-4.09	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.68	Pathogenic	0.02	Affected			0.2072	0.5379		0	-2	2.9	-59.07
c.896G>T	R299L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Stability‑based methods FoldX, Rosetta, Foldetta, and premPS returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of consensus predictions favor a pathogenic effect, and the high‑accuracy tools do not overturn this trend. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for R299L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.321458	Structured	0.262979	Uncertain	0.819	0.295	0.500											-5.171	Likely Benign	0.645	Likely Pathogenic	Likely Benign	1.37	Ambiguous	0.6	0.77	Ambiguous	1.07	Ambiguous	0.59	Ambiguous	0.356	Likely Benign	-4.03	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.65	Pathogenic	0.02	Affected			0.2027	0.5202		-3	-2	8.3	-43.03
c.898T>C	S300P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The remaining tools—FoldX, Foldetta, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.356642	Structured	0.256848	Uncertain	0.742	0.280	0.375											-7.379	In-Between	0.110	Likely Benign	Likely Benign	1.24	Ambiguous	1.0	0.06	Likely Benign	0.65	Ambiguous	0.50	Likely Benign	0.086	Likely Benign	-2.46	Neutral	0.784	Possibly Damaging	0.390	Benign	1.54	Pathogenic	0.02	Affected			0.2192	0.5585		1	-1	-0.8	10.04
c.899C>A	S300Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300Y has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Foldetta, premPS, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Two tools (AlphaMissense‑Default and Rosetta) are uncertain and do not influence the consensus. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not contradict any ClinVar status (none is available). Thus, based on current predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.356642	Structured	0.256848	Uncertain	0.742	0.280	0.375											-10.464	Likely Pathogenic	0.422	Ambiguous	Likely Benign	-0.08	Likely Benign	0.4	0.55	Ambiguous	0.24	Likely Benign	0.28	Likely Benign	0.116	Likely Benign	-2.52	Deleterious	0.975	Probably Damaging	0.686	Possibly Damaging	1.52	Pathogenic	0.01	Affected			0.0678	0.5395		-3	-2	-0.5	76.10
c.899C>G	S300C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300C is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437804‑C‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Rosetta and Foldetta give uncertain results and are therefore not considered evidence for either side. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of reliable predictions indicate a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.356642	Structured	0.256848	Uncertain	0.742	0.280	0.375								6-33437804-C-G			-6.749	Likely Benign	0.108	Likely Benign	Likely Benign	0.31	Likely Benign	0.2	1.45	Ambiguous	0.88	Ambiguous	0.34	Likely Benign	0.129	Likely Benign	-2.45	Neutral	0.975	Probably Damaging	0.815	Possibly Damaging	1.55	Pathogenic	0.01	Affected	3.47	19	0.1005	0.6493		-1	0	3.3	16.06
c.899C>T	S300F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S300F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The remaining tool, AlphaMissense‑Default, gives an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions lean toward pathogenicity, while two high‑accuracy methods support a benign effect. Thus, the variant is most likely pathogenic based on the current computational evidence, which does not contradict its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.356642	Structured	0.256848	Uncertain	0.742	0.280	0.375					Uncertain		1				-10.222	Likely Pathogenic	0.353	Ambiguous	Likely Benign	-0.29	Likely Benign	0.4	0.16	Likely Benign	-0.07	Likely Benign	0.04	Likely Benign	0.117	Likely Benign	-2.66	Deleterious	0.975	Probably Damaging	0.596	Possibly Damaging	1.52	Pathogenic	0.01	Affected	3.47	19	0.0579	0.5701		-3	-2	3.6	60.10	233.6	-67.6	-0.1	0.0	0.4	0.2	X	X						Potentially Pathogenic	The hydroxyl group of the Ser300 side chain, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), hydrogen bonds with the guanidinium group of Arg299 and the backbone amide group and side chain of Ser302. Thus, in the WT simulations, it contributes to the β hairpin stability. In the variant simulations, the phenol ring of Phe300 cannot form any side chain-related hydrogen bonds, and Arg299 is moved away from its central hairpin loop position.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel.
c.89A>C	H30P 2D AIThe SynGAP1 H30P missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250											-1.933	Likely Benign	0.077	Likely Benign	Likely Benign										0.202	Likely Benign	-2.77	Deleterious	0.676	Possibly Damaging	0.599	Possibly Damaging	3.89	Benign	0.00	Affected			0.2527	0.4723		0	-2	1.6	-40.02
c.89A>G	H30R 2D AIThe SynGAP1 missense variant H30R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250											-2.156	Likely Benign	0.186	Likely Benign	Likely Benign										0.138	Likely Benign	-2.17	Neutral	0.462	Possibly Damaging	0.599	Possibly Damaging	3.94	Benign	0.00	Affected			0.2762	0.3590		2	0	-1.3	19.05
c.89A>T	H30L 2D AIThe SynGAP1 H30L missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250											-2.073	Likely Benign	0.117	Likely Benign	Likely Benign										0.163	Likely Benign	-2.88	Deleterious	0.462	Possibly Damaging	0.599	Possibly Damaging	3.94	Benign	0.00	Affected			0.1523	0.5793		-2	-3	7.0	-23.98
c.8G>A	R3K 2D AIThe SynGAP1 missense variant R3K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect. The prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.550331	Binding	0.358	0.920	0.875											-4.378	Likely Benign	0.254	Likely Benign	Likely Benign										0.062	Likely Benign	-0.45	Neutral	0.001	Benign	0.000	Benign	4.09	Benign	0.00	Affected			0.5842	0.4564	Weaken	3	2	0.6	-28.01
c.8G>C	R3T 2D AIThe SynGAP1 missense variant R3T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.550331	Binding	0.358	0.920	0.875											-3.693	Likely Benign	0.285	Likely Benign	Likely Benign										0.053	Likely Benign	-0.55	Neutral	0.208	Benign	0.018	Benign	4.01	Benign	0.00	Affected			0.1809	0.5145		-1	-1	3.8	-55.08
c.8G>T	R3M 2D AIThe SynGAP1 missense variant R3M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus methods give a consistent benign signal: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and Foldetta data are unavailable. Overall, the majority of evidence supports a benign classification, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.550331	Binding	0.358	0.920	0.875											-4.655	Likely Benign	0.618	Likely Pathogenic	Likely Benign										0.097	Likely Benign	0.00	Neutral	0.872	Possibly Damaging	0.162	Benign	3.96	Benign	0.00	Affected			0.1906	0.4795		0	-1	6.4	-24.99
c.905C>A	S302Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are SIFT, polyPhen‑2 HumDiv, and ESM1b. Two tools give uncertain results: AlphaMissense‑Default and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta also predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.414856	Structured	0.263489	Uncertain	0.616	0.258	0.375											-9.674	Likely Pathogenic	0.355	Ambiguous	Likely Benign	-0.02	Likely Benign	0.1	0.56	Ambiguous	0.27	Likely Benign	-0.17	Likely Benign	0.070	Likely Benign	-1.03	Neutral	0.801	Possibly Damaging	0.383	Benign	4.07	Benign	0.01	Affected			0.0882	0.5990		-3	-2	-0.5	76.10
c.905C>G	S302C 2D AIThe SynGAP1 missense variant S302C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, premPS, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain predictions come from Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for S302C, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.414856	Structured	0.263489	Uncertain	0.616	0.258	0.375											-7.290	In-Between	0.105	Likely Benign	Likely Benign	0.32	Likely Benign	0.5	1.24	Ambiguous	0.78	Ambiguous	-0.04	Likely Benign	0.070	Likely Benign	-0.83	Neutral	0.833	Possibly Damaging	0.455	Possibly Damaging	4.05	Benign	0.02	Affected			0.1221	0.6514		0	-1	3.3	16.06
c.905C>T	S302F 2D AIThe SynGAP1 missense variant S302F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and ESM1b; Rosetta’s output is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Taken together, the majority of evidence supports a benign impact for S302F, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.414856	Structured	0.263489	Uncertain	0.616	0.258	0.375											-9.483	Likely Pathogenic	0.321	Likely Benign	Likely Benign	-0.04	Likely Benign	0.5	0.71	Ambiguous	0.34	Likely Benign	-0.21	Likely Benign	0.073	Likely Benign	-0.92	Neutral	0.570	Possibly Damaging	0.383	Benign	4.06	Benign	0.01	Affected			0.0705	0.6092		-3	-2	3.6	60.10
c.907G>T	G303W 2D 3DClick to see structure in 3D Viewer AIClinVar reports no entry for this SynGAP1 G303W variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta’s stability prediction is also unavailable. Overall, the evidence is evenly split between benign and pathogenic predictions, providing no clear bias toward either outcome. This balanced prediction does not contradict ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.450668	Structured	0.271087	Uncertain	0.630	0.254	0.250											-9.041	Likely Pathogenic	0.579	Likely Pathogenic	Likely Benign	1.69	Ambiguous	0.3	1.11	Ambiguous	1.40	Ambiguous	0.28	Likely Benign	0.157	Likely Benign	-1.63	Neutral	0.983	Probably Damaging	0.813	Possibly Damaging	3.93	Benign	0.00	Affected			0.0663	0.4553		-7	-2	-0.5	129.16
c.908G>A	G303E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303E is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437813‑G‑A). Across the available in‑silico predictors, benign calls are made by REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by SIFT and ESM1b; the remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Default) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta remains uncertain. Taken together, the majority of evidence points to a benign effect; this conclusion is not contradicted by any ClinVar annotation, as no pathogenic classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.450668	Structured	0.271087	Uncertain	0.630	0.254	0.250								6-33437813-G-A	3	1.86e-6	-9.339	Likely Pathogenic	0.549	Ambiguous	Likely Benign	1.87	Ambiguous	0.5	0.37	Likely Benign	1.12	Ambiguous	0.89	Ambiguous	0.063	Likely Benign	-1.56	Neutral	0.001	Benign	0.005	Benign	4.04	Benign	0.05	Affected	3.55	18	0.1155	0.4172		-2	0	-3.1	72.06
c.908G>T	G303V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign) all indicate a tolerated change. Pathogenic signals arise only from SIFT and FoldX, while Rosetta and Foldetta are inconclusive. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields Likely Benign, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.450668	Structured	0.271087	Uncertain	0.630	0.254	0.250											-3.046	Likely Benign	0.198	Likely Benign	Likely Benign	3.06	Destabilizing	0.6	-0.72	Ambiguous	1.17	Ambiguous	0.14	Likely Benign	0.071	Likely Benign	-1.57	Neutral	0.011	Benign	0.017	Benign	3.96	Benign	0.01	Affected			0.1002	0.4577		-1	-3	4.6	42.08
c.90C>A	H30Q 2D AIThe SynGAP1 H30Q missense change is catalogued in gnomAD (ID 6‑33423499‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: six methods (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score all indicate a benign effect, while three tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT) predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus (derived from the four benign‑predicting tools) also yields a benign verdict. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with ClinVar, which currently contains no classification for H30Q. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250								6-33423499-C-A	1	6.20e-7	-3.016	Likely Benign	0.142	Likely Benign	Likely Benign										0.068	Likely Benign	-2.21	Neutral	0.462	Possibly Damaging	0.599	Possibly Damaging	3.93	Benign	0.00	Affected	4.32	1	0.2409	0.4422		0	3	-0.3	-9.01
c.90C>G	H30Q 2D AIThe SynGAP1 missense variant H30Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.570702	Disordered	0.438063	Uncertain	0.373	0.883	0.250											-3.016	Likely Benign	0.142	Likely Benign	Likely Benign										0.068	Likely Benign	-2.21	Neutral	0.462	Possibly Damaging	0.599	Possibly Damaging	3.93	Benign	0.00	Affected	4.32	1	0.2409	0.4422		0	3	-0.3	-9.01
c.910G>A	D304N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D304N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250					Uncertain		1				-6.194	Likely Benign	0.391	Ambiguous	Likely Benign	0.30	Likely Benign	0.1	-0.08	Likely Benign	0.11	Likely Benign	0.21	Likely Benign	0.345	Likely Benign	-4.18	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.81	Pathogenic	0.03	Affected	3.38	23	0.1353	0.7205		1	2	0.0	-0.98
c.910G>C	D304H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304H missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into three groups: benign predictions come from REVEL, Rosetta, and premPS; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; the remaining tools (FoldX, Foldetta, AlphaMissense‑Optimized) give uncertain results. High‑accuracy assessments reinforce this pattern: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which is currently absent. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250											-8.160	Likely Pathogenic	0.822	Likely Pathogenic	Ambiguous	0.89	Ambiguous	0.1	0.16	Likely Benign	0.53	Ambiguous	0.45	Likely Benign	0.417	Likely Benign	-5.67	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.75	Pathogenic	0.01	Affected			0.1660	0.7498		1	-1	0.3	22.05
c.910G>T	D304Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304Y missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, Foldetta, and premPS, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. With the majority of evidence pointing toward pathogenicity, the variant is most likely pathogenic; this assessment does not conflict with ClinVar, which contains no entry for D304Y. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250											-10.495	Likely Pathogenic	0.845	Likely Pathogenic	Ambiguous	0.60	Ambiguous	0.2	0.14	Likely Benign	0.37	Likely Benign	0.37	Likely Benign	0.468	Likely Benign	-6.29	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.76	Pathogenic	0.00	Affected			0.0623	0.6566		-4	-3	2.2	48.09
c.911A>C	D304A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304A variant has no ClinVar entry and is not listed in gnomAD. Prediction tools that classify it as benign include premPS, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact. This prediction does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250											-6.258	Likely Benign	0.604	Likely Pathogenic	Likely Benign	1.00	Ambiguous	0.1	0.54	Ambiguous	0.77	Ambiguous	0.39	Likely Benign	0.523	Likely Pathogenic	-5.97	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.80	Pathogenic	0.02	Affected			0.4457	0.6642		0	-2	5.3	-44.01
c.911A>G	D304G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default, FoldX, Rosetta, and Foldetta are uncertain and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta remaining uncertain. Overall, the majority of tools (five pathogenic vs. four benign) and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250											-2.713	Likely Benign	0.546	Ambiguous	Likely Benign	1.02	Ambiguous	0.2	0.95	Ambiguous	0.99	Ambiguous	0.47	Likely Benign	0.380	Likely Benign	-5.32	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.75	Pathogenic	0.02	Affected			0.4590	0.6451		1	-1	3.1	-58.04
c.911A>T	D304V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304V missense variant is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include Rosetta and premPS, while the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for D304V. This conclusion is not contradicted by ClinVar, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250											-8.280	Likely Pathogenic	0.803	Likely Pathogenic	Ambiguous	1.35	Ambiguous	0.3	0.14	Likely Benign	0.75	Ambiguous	0.35	Likely Benign	0.541	Likely Pathogenic	-6.22	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.81	Pathogenic	0.00	Affected			0.0971	0.6999		-2	-3	7.7	-15.96
c.912C>A	D304E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304E missense variant has no ClinVar entry and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence supports a benign effect, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250											-2.715	Likely Benign	0.233	Likely Benign	Likely Benign	0.34	Likely Benign	0.1	0.21	Likely Benign	0.28	Likely Benign	0.48	Likely Benign	0.186	Likely Benign	-3.29	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.77	Pathogenic	0.04	Affected			0.1504	0.6998		3	2	0.0	14.03
c.912C>G	D304E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304E missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Overall, the balance of evidence favors a benign classification, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.352862	Structured	0.285053	Uncertain	0.764	0.271	0.250											-2.715	Likely Benign	0.233	Likely Benign	Likely Benign	0.34	Likely Benign	0.1	0.21	Likely Benign	0.28	Likely Benign	0.48	Likely Benign	0.186	Likely Benign	-3.29	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.77	Pathogenic	0.04	Affected			0.1504	0.6998		3	2	0.0	14.03
c.914C>T	T305I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437819‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Overall, the balance of evidence from high‑confidence predictors leans toward a benign impact, and this assessment does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.359901	Structured	0.299706	Uncertain	0.872	0.274	0.125					Uncertain		1	6-33437819-C-T	1	6.20e-7	-5.222	Likely Benign	0.305	Likely Benign	Likely Benign	0.37	Likely Benign	0.2	0.58	Ambiguous	0.48	Likely Benign	0.25	Likely Benign	0.224	Likely Benign	-2.90	Deleterious	0.997	Probably Damaging	0.929	Probably Damaging	1.70	Pathogenic	0.04	Affected	3.40	20	0.0939	0.5693		-1	0	5.2	12.05
c.916G>T	V306F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306F is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, and AlphaMissense‑Optimized, whereas the remaining tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a pathogenic effect. Overall, the majority of evidence supports a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.363090	Structured	0.315026	Uncertain	0.896	0.287	0.125											-9.311	Likely Pathogenic	0.700	Likely Pathogenic	Likely Benign	13.59	Destabilizing	1.4	6.99	Destabilizing	10.29	Destabilizing	0.23	Likely Benign	0.336	Likely Benign	-3.28	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.74	Pathogenic	0.01	Affected			0.0535	0.3318		-1	-1	-1.4	48.04
c.917T>A	V306D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306D is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All available in‑silico predictors that were evaluated return a pathogenic or likely‑pathogenic assessment: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.363090	Structured	0.315026	Uncertain	0.896	0.287	0.125					Uncertain		1				-18.289	Likely Pathogenic	0.986	Likely Pathogenic	Likely Pathogenic	4.40	Destabilizing	0.3	4.29	Destabilizing	4.35	Destabilizing	2.44	Destabilizing	0.530	Likely Pathogenic	-5.44	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.74	Pathogenic	0.00	Affected	3.38	19	0.1317	0.0768		-2	-3	-7.7	15.96	212.3	-18.3	-0.2	0.4	0.0	0.2	X		X				X	Potentially Pathogenic	The isopropyl group of Val396, located at the beginning of an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Leu274, Trp308, Ala271) in the WT simulations. However, in the variant simulations, the negatively charged carboxylate group of the Asp306 side chain is not suitable for this hydrophobic niche. Consequently, the side chain moves out to interact with Ser300 in the β strand (res. Met289-Arg299) and the guanidinium group of Arg299 in the β hairpin loop.In the third simulation, the residue swap disrupts the C2 domain secondary structure and tertiary assembly to a large degree when the amino group of the Lys297 side chain rotates to form a salt bridge with Asp306. This drastic effect could potentially reflect the challenge presented by the residue swap during the C2 domain folding. Because the residue swap affects the C2 domain structure, the SynGAP-membrane association could also be impacted. However, this is beyond the scope of the solvent-only simulations to unravel.
c.917T>C	V306A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas the remaining tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome; ESM1b is uncertain and therefore not counted. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and a pathogenic prediction from Foldetta. Taken together, the preponderance of evidence indicates that V306A is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.363090	Structured	0.315026	Uncertain	0.896	0.287	0.125											-7.924	In-Between	0.599	Likely Pathogenic	Likely Benign	2.76	Destabilizing	0.1	3.00	Destabilizing	2.88	Destabilizing	2.25	Destabilizing	0.300	Likely Benign	-2.94	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.77	Pathogenic	0.05	Affected			0.2687	0.1989		0	0	-2.4	-28.05
c.917T>G	V306G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign effect. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. All available evidence points to a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.363090	Structured	0.315026	Uncertain	0.896	0.287	0.125											-12.313	Likely Pathogenic	0.795	Likely Pathogenic	Ambiguous	4.39	Destabilizing	0.2	5.89	Destabilizing	5.14	Destabilizing	2.46	Destabilizing	0.529	Likely Pathogenic	-5.48	Deleterious	0.998	Probably Damaging	1.000	Probably Damaging	1.78	Pathogenic	0.00	Affected			0.1874	0.2035		-1	-3	-4.6	-42.08
c.919T>A	F307I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307I is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign are FoldX, Rosetta, and Foldetta. Tools that predict it as pathogenic include SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments give AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Benign. Overall, the majority of predictions (10/13) indicate pathogenicity, while only three tools suggest benign. Therefore, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-13.114	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	0.49	Likely Benign	0.2	0.19	Likely Benign	0.34	Likely Benign	0.61	Ambiguous	0.632	Likely Pathogenic	-5.52	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	2.06	Pathogenic	0.01	Affected			0.2531	0.3036		1	0	1.7	-34.02
c.919T>C	F307L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta and Foldetta, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (FoldX and premPS) give uncertain results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized and the SGM Consensus both indicate a likely pathogenic effect, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the bulk of evidence points to a pathogenic impact, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-10.173	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.54	Ambiguous	0.1	0.14	Likely Benign	0.34	Likely Benign	0.57	Ambiguous	0.597	Likely Pathogenic	-5.52	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	2.04	Pathogenic	0.01	Affected			0.2800	0.4207		2	0	1.0	-34.02
c.919T>G	F307V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307V is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include Rosetta and premPS, whereas the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the consensus score SGM‑Consensus all classify the change as pathogenic or likely pathogenic. High‑accuracy methods give a pathogenic call from AlphaMissense‑Optimized, a likely pathogenic result from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an inconclusive result from Foldetta (combining FoldX‑MD and Rosetta). No prediction is missing or inconclusive enough to alter the overall assessment. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-12.262	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	0.91	Ambiguous	0.1	0.10	Likely Benign	0.51	Ambiguous	0.36	Likely Benign	0.605	Likely Pathogenic	-6.43	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	2.29	Pathogenic	0.05	Affected			0.2523	0.3393		-1	-1	1.4	-48.04
c.91C>G	R31G 2D AIThe SynGAP1 missense variant R31G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for R31G, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.549308	Disordered	0.437905	Uncertain	0.324	0.878	0.250											-3.259	Likely Benign	0.269	Likely Benign	Likely Benign										0.141	Likely Benign	-1.77	Neutral	0.686	Possibly Damaging	0.630	Possibly Damaging	3.97	Benign	0.00	Affected			0.3389	0.3942		-3	-2	4.1	-99.14
c.920T>A	F307Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307Y is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict the ClinVar status, which currently contains no assertion for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-9.870	Likely Pathogenic	0.889	Likely Pathogenic	Ambiguous	0.36	Likely Benign	0.1	-0.21	Likely Benign	0.08	Likely Benign	0.11	Likely Benign	0.596	Likely Pathogenic	-2.76	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	1.96	Pathogenic	0.05	Affected			0.1570	0.2325		7	3	-4.1	16.00
c.920T>C	F307S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. In silico predictors that provide a definitive call all classify the variant as pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely pathogenic verdict. Predictions that are inconclusive or uncertain include FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-12.282	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	1.58	Ambiguous	0.2	1.22	Ambiguous	1.40	Ambiguous	0.99	Ambiguous	0.766	Likely Pathogenic	-7.32	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.97	Pathogenic	0.01	Affected			0.4576	0.0758		-3	-2	-3.6	-60.10
c.920T>G	F307C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F307C missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). In silico predictors overwhelmingly indicate a deleterious effect: all tools that provide a definitive call—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The only predictions that are inconclusive are FoldX, Rosetta, and Foldetta, which are treated as unavailable. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Based on the consensus of the available predictions, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-11.484	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	1.36	Ambiguous	0.1	1.44	Ambiguous	1.40	Ambiguous	1.05	Destabilizing	0.754	Likely Pathogenic	-7.35	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.92	Pathogenic	0.00	Affected			0.2729	0.1628		-4	-2	-0.3	-44.04
c.921C>A	F307L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta and Foldetta, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (FoldX and premPS) give uncertain results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized and the SGM Consensus both indicate a likely pathogenic effect, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the bulk of evidence points to a pathogenic impact, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-10.173	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.54	Ambiguous	0.1	0.14	Likely Benign	0.34	Likely Benign	0.57	Ambiguous	0.529	Likely Pathogenic	-5.52	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	2.04	Pathogenic	0.01	Affected			0.2800	0.4207		2	0	1.0	-34.02
c.921C>G	F307L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta and Foldetta, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic. Uncertain results are reported by FoldX and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the consensus of the majority of tools points to a pathogenic effect, and this is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.298791	Structured	0.327302	Uncertain	0.900	0.315	0.125											-10.173	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	0.54	Ambiguous	0.1	0.14	Likely Benign	0.34	Likely Benign	0.57	Ambiguous	0.529	Likely Pathogenic	-5.52	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	2.04	Pathogenic	0.01	Affected			0.2800	0.4207		2	0	1.0	-34.02
c.922T>A	W308R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.333942	Uncertain	0.907	0.314	0.125											-12.264	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	5.40	Destabilizing	0.5	4.27	Destabilizing	4.84	Destabilizing	1.88	Destabilizing	0.868	Likely Pathogenic	-12.87	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.48	Pathogenic	0.00	Affected	3.38	19	0.4751	0.0361		2	-3	-3.6	-30.03	290.4	-26.7	-0.1	0.1	0.0	0.2	X		X				X	Potentially Pathogenic	The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The guanidinium group of Arg308 is comparably sized to the tryptophan it replaced; however, it is also positively charged.In the variant simulations, the charged side chain remains buried deep in the hydrophobic part of the C2 domain, where it forms new hydrogen bonds with the backbone carbonyl atoms of surrounding residues (e.g., Val306, Ile268). However, the residue swap is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association.
c.922T>C	W308R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308R is listed in ClinVar (ID 391294.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.333942	Uncertain	0.907	0.314	0.125					Pathogenic		1				-12.264	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	5.40	Destabilizing	0.5	4.27	Destabilizing	4.84	Destabilizing	1.88	Destabilizing	0.868	Likely Pathogenic	-12.87	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.48	Pathogenic	0.00	Affected	3.38	19	0.4751	0.0361		2	-3	-3.6	-30.03	290.4	-26.7	-0.1	0.1	0.0	0.2	X		X				X	Potentially Pathogenic	The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The guanidinium group of Arg308 is comparably sized to the tryptophan it replaced; however, it is also positively charged.In the variant simulations, the charged side chain remains buried deep in the hydrophobic part of the C2 domain, where it forms new hydrogen bonds with the backbone carbonyl atoms of surrounding residues (e.g., Val306, Ile268). However, the residue swap is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association.
c.922T>G	W308G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308G is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. No tool predicts a benign effect, so the benign group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.333942	Uncertain	0.907	0.314	0.125											-16.271	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	6.88	Destabilizing	0.2	5.07	Destabilizing	5.98	Destabilizing	1.97	Destabilizing	0.860	Likely Pathogenic	-11.95	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	0.48	Pathogenic	0.00	Affected			0.4884	0.1644		-7	-2	0.5	-129.16
c.923G>C	W308S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308S is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.333942	Uncertain	0.907	0.314	0.125											-15.425	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	6.42	Destabilizing	0.2	5.31	Destabilizing	5.87	Destabilizing	1.93	Destabilizing	0.861	Likely Pathogenic	-12.87	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.48	Pathogenic	0.00	Affected			0.5089	0.1406	Weaken	-2	-3	0.1	-99.14
c.923G>T	W308L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates “Likely Pathogenic.” Only Rosetta and premPS yield uncertain results, which are treated as unavailable evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No tools predict benign effects. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.333942	Uncertain	0.907	0.314	0.125											-13.349	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	3.53	Destabilizing	0.5	1.52	Ambiguous	2.53	Destabilizing	0.53	Ambiguous	0.811	Likely Pathogenic	-11.95	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	0.49	Pathogenic	0.00	Affected			0.2731	0.2754		-2	-2	4.7	-73.05
c.924G>C	W308C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308C is listed in ClinVar as Pathogenic (ClinVar ID 981381.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Pathogenic”; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.333942	Uncertain	0.907	0.314	0.125					Pathogenic/Likely path.		2				-12.791	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	5.56	Destabilizing	0.3	4.38	Destabilizing	4.97	Destabilizing	1.26	Destabilizing	0.738	Likely Pathogenic	-11.95	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.48	Pathogenic	0.00	Affected	3.38	19	0.4390	0.1621		-8	-2	3.4	-83.07	230.8	60.5	-0.3	0.1	-0.4	0.4							X	Potentially Pathogenic	The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The introduced Cys308 is smaller than the tryptophan it replaced. The thiol group of the Cys308 side chain is well-suited for the inner hydrophobic part of the C2 domain. Although the negative effects are essentially missing from the simulations, the side chain size difference between the residues is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association.
c.924G>T	W308C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308C is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a deleterious effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.328603	Structured	0.333942	Uncertain	0.907	0.314	0.125											-12.791	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	5.56	Destabilizing	0.3	4.38	Destabilizing	4.97	Destabilizing	1.26	Destabilizing	0.738	Likely Pathogenic	-11.95	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	0.48	Pathogenic	0.00	Affected	3.38	19	0.4390	0.1621		-8	-2	3.4	-83.07	230.8	60.5	-0.3	0.1	-0.4	0.4							X	Potentially Pathogenic	The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The introduced Cys308 is smaller than the tryptophan it replaced. The thiol group of the Cys308 side chain is well-suited for the inner hydrophobic part of the C2 domain. Although the negative effects are essentially missing from the simulations, the side chain size difference between the residues is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association.
c.925G>C	G309R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely pathogenic outcome. No tool in the dataset predicts a benign effect. Uncertainty remains for FoldX, Rosetta, Foldetta, and premPS, which are listed as uncertain and do not influence the overall assessment. High‑accuracy evaluations show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.275179	Structured	0.338439	Uncertain	0.882	0.342	0.125											-14.375	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	1.99	Ambiguous	0.5	0.52	Ambiguous	1.26	Ambiguous	0.55	Ambiguous	0.572	Likely Pathogenic	-7.35	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.70	Pathogenic	0.04	Affected			0.0964	0.5097		-3	-2	-4.1	99.14
c.925G>T	G309C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a deleterious effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score, all of which classify the change as pathogenic or likely pathogenic. Tools with inconclusive results—Rosetta, Foldetta, and premPS—return uncertain outcomes and do not alter the overall assessment. High‑accuracy methods further support a damaging effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta’s stability analysis is inconclusive. Taken together, the evidence strongly favors a pathogenic interpretation, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.275179	Structured	0.338439	Uncertain	0.882	0.342	0.125											-14.331	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	2.60	Destabilizing	0.4	1.09	Ambiguous	1.85	Ambiguous	0.67	Ambiguous	0.656	Likely Pathogenic	-8.27	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.66	Pathogenic	0.00	Affected			0.1378	0.4574		-3	-3	2.9	46.09
c.926G>T	G309V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309V is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.275179	Structured	0.338439	Uncertain	0.882	0.342	0.125											-13.595	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.55	Destabilizing	0.5	3.61	Destabilizing	4.08	Destabilizing	0.76	Ambiguous	0.531	Likely Pathogenic	-8.27	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.67	Pathogenic	0.00	Affected			0.1256	0.3910		-1	-3	4.6	42.08
c.928G>A	E310K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310K is listed in ClinVar with an uncertain significance (ID 981613) and is not reported in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX‑MD (uncertain), 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 is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Consequently, the variant is most likely pathogenic according to the available predictions, which does not contradict the ClinVar uncertain status but suggests a pathogenic interpretation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.346136	Uncertain	0.914	0.337	0.125					Conflicting		5				-14.601	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	1.97	Ambiguous	1.2	3.66	Destabilizing	2.82	Destabilizing	1.02	Destabilizing	0.764	Likely Pathogenic	-3.68	Deleterious	1.000	Probably Damaging	0.995	Probably Damaging	1.19	Pathogenic	0.01	Affected	3.38	19	0.2496	0.8453		0	1	-0.4	-0.94	213.4	58.0	0.1	0.0	0.2	0.1		X						Potentially Pathogenic	The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the side chain hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand (res. Met289-Arg299). Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the amino group of the Lys310 side chain hydrogen bonds with the GAP domain residues and forms a salt bridge with Glu613. Although no apparent negative effects are seen due to the residue swap, it is possible that the loss of hydrogen bonding with the hydroxyl group of the Thr295 side chain causes problems during folding, potentially compromising the twisting of the β sheet.
c.928G>C	E310Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign are Rosetta and Foldetta, whereas the remaining tools—REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict pathogenicity. FoldX and premPS give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized reports a pathogenic effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Likely Pathogenic; Foldetta, a protein‑folding stability approach combining FoldX‑MD and Rosetta, predicts a benign outcome. Overall, the majority of evidence points to a pathogenic impact, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.346136	Uncertain	0.914	0.337	0.125											-11.093	Likely Pathogenic	0.981	Likely Pathogenic	Likely Pathogenic	1.16	Ambiguous	0.5	-0.38	Likely Benign	0.39	Likely Benign	0.85	Ambiguous	0.688	Likely Pathogenic	-2.76	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.24	Pathogenic	0.01	Affected			0.1334	0.8341		2	2	0.0	-0.98
c.929A>C	E310A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E310A missense variant is not reported in ClinVar or gnomAD. Prediction tools largely converge on a pathogenic effect: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, while premPS is the sole benign predictor. Uncertain calls come from FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus labels it likely pathogenic, and Foldetta remains inconclusive. With the overwhelming majority of evidence pointing to deleterious impact and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.346136	Uncertain	0.914	0.337	0.125											-13.878	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	1.65	Ambiguous	0.6	1.65	Ambiguous	1.65	Ambiguous	0.50	Likely Benign	0.850	Likely Pathogenic	-5.52	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.16	Pathogenic	0.01	Affected			0.3980	0.8097		0	-1	5.3	-58.04
c.929A>G	E310G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310G is listed in ClinVar as Pathogenic (ClinVar ID 2732842.0) and is not reported in gnomAD. Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only premPS predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Consequently, the variant is most likely pathogenic, and this prediction is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.346136	Uncertain	0.914	0.337	0.125					Pathogenic		1				-14.132	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	2.38	Destabilizing	0.7	3.56	Destabilizing	2.97	Destabilizing	0.36	Likely Benign	0.848	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	1.12	Pathogenic	0.00	Affected	3.38	19	0.2736	0.6932		-2	0	3.1	-72.06
c.929A>T	E310V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E310V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are Rosetta and premPS, while the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. FoldX and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that E310V is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.346136	Uncertain	0.914	0.337	0.125											-15.494	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	1.08	Ambiguous	0.9	0.06	Likely Benign	0.57	Ambiguous	0.14	Likely Benign	0.871	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.12	Pathogenic	0.00	Affected			0.0849	0.8729		-2	-2	7.7	-29.98
c.92G>A	R31Q 2D AIThe SynGAP1 missense variant R31Q is listed in ClinVar (ID 1977609.0) with an “Uncertain” status and is present in gnomAD (6‑33423501‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification and suggests the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.549308	Disordered	0.437905	Uncertain	0.324	0.878	0.250					Uncertain		1	6-33423501-G-A	7	4.34e-6	-4.434	Likely Benign	0.136	Likely Benign	Likely Benign										0.051	Likely Benign	-0.92	Neutral	0.829	Possibly Damaging	0.614	Possibly Damaging	4.01	Benign	0.00	Affected	4.32	1	0.3605	0.3355		1	1	1.0	-28.06
c.92G>C	R31P 2D AIThe SynGAP1 missense variant R31P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of computational evidence points to a benign impact for R31P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.549308	Disordered	0.437905	Uncertain	0.324	0.878	0.250											-3.185	Likely Benign	0.300	Likely Benign	Likely Benign										0.209	Likely Benign	-1.64	Neutral	0.841	Possibly Damaging	0.809	Possibly Damaging	3.96	Benign	0.00	Affected			0.2220	0.5005		0	-2	2.9	-59.07
c.92G>T	R31L 2D AIThe SynGAP1 missense variant R31L is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict pathogenic. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools specifically indicate benign: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta data are missing. Overall, the majority of reliable predictions lean toward a benign effect, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.549308	Disordered	0.437905	Uncertain	0.324	0.878	0.250											-3.147	Likely Benign	0.360	Ambiguous	Likely Benign										0.149	Likely Benign	-1.79	Neutral	0.686	Possibly Damaging	0.630	Possibly Damaging	4.01	Benign	0.00	Affected			0.2264	0.5148		-3	-2	8.3	-43.03
c.930G>C	E310D 2D 3DClick to see structure in 3D Viewer AISynGAP1 E310D is reported in ClinVar (ID 975473.0) as Pathogenic and is not found in gnomAD. Prediction tools that assess the variant’s effect all converge on a deleterious outcome: REVEL, FoldX (uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, leaving no tool in the benign category. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also reports Pathogenic. The single uncertain result from FoldX is treated as unavailable. Overall, the variant is most likely pathogenic, and this assessment is consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.346136	Uncertain	0.914	0.337	0.125					Likely Pathogenic		1				-11.218	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	1.87	Ambiguous	0.5	2.39	Destabilizing	2.13	Destabilizing	1.04	Destabilizing	0.666	Likely Pathogenic	-2.76	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.19	Pathogenic	0.02	Affected	3.38	19	0.1981	0.5222		3	2	0.0	-14.03	232.6	27.2	0.1	0.0	0.1	0.1						X		Potentially Benign	The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand. Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 potentially plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the carboxylate group of Asp310 can form the same interactions as glutamate; however, due to its one hydrocarbon shorter length, the connections are less stable or less optimal.
c.930G>T	E310D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity uniformly favor a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL (Pathogenic), Rosetta (Pathogenic), Foldetta (Pathogenic), premPS (Pathogenic), PROVEAN (Pathogenic), polyPhen‑2 HumDiv (Pathogenic), polyPhen‑2 HumVar (Pathogenic), SIFT (Pathogenic), ESM1b (Pathogenic), FATHMM (Pathogenic), AlphaMissense‑Default (Pathogenic), and AlphaMissense‑Optimized (Pathogenic). No tool predicts a benign outcome; the only inconclusive result is FoldX (Uncertain). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for E310D. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.222385	Structured	0.346136	Uncertain	0.914	0.337	0.125											-11.218	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	1.87	Ambiguous	0.5	2.39	Destabilizing	2.13	Destabilizing	1.04	Destabilizing	0.666	Likely Pathogenic	-2.76	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.19	Pathogenic	0.02	Affected	3.38	19	0.1981	0.5222		3	2	0.0	-14.03	232.6	27.2	0.1	0.0	0.1	0.1						X		Potentially Benign	The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand. Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 potentially plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the carboxylate group of Asp310 can form the same interactions as glutamate; however, due to its one hydrocarbon shorter length, the connections are less stable or less optimal.
c.931C>G	H311D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess evolutionary conservation and protein function uniformly indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. The majority‑vote consensus (SGM‑Consensus) also reports it as likely pathogenic. Tools that evaluate structural stability give inconclusive results: FoldX, Rosetta, Foldetta, and premPS are listed as uncertain. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (derived from the same set of predictors) reports likely pathogenic, while Foldetta’s combined FoldX‑MD/Rosetta stability analysis remains uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect, which is consistent with the absence of a benign ClinVar annotation and the lack of population frequency data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.229226	Structured	0.354792	Uncertain	0.902	0.314	0.125											-13.513	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	1.27	Ambiguous	0.0	1.83	Ambiguous	1.55	Ambiguous	0.89	Ambiguous	0.633	Likely Pathogenic	-6.94	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.94	Pathogenic	0.02	Affected			0.2301	0.2008		1	-1	-0.3	-22.05
c.931C>T	H311Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools with uncertain or inconclusive results—Rosetta, Foldetta, and AlphaMissense‑Default—are treated as unavailable for pathogenicity assessment. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the predictions are split, with five tools favoring benign, five favoring pathogenic, and three inconclusive. Based on the available evidence, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.229226	Structured	0.354792	Uncertain	0.902	0.314	0.125											-4.513	Likely Benign	0.342	Ambiguous	Likely Benign	-0.06	Likely Benign	0.2	-1.58	Ambiguous	-0.82	Ambiguous	0.18	Likely Benign	0.456	Likely Benign	-3.80	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.86	Pathogenic	0.02	Affected			0.0965	0.4180		0	2	1.9	26.03
c.932A>C	H311P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign outcome; the remaining predictions are uncertain (FoldX, Foldetta, premPS, AlphaMissense‑Optimized). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the majority of evidence points to a deleterious impact on protein function. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for H311P. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.229226	Structured	0.354792	Uncertain	0.902	0.314	0.125											-10.454	Likely Pathogenic	0.869	Likely Pathogenic	Ambiguous	1.57	Ambiguous	0.6	2.39	Destabilizing	1.98	Ambiguous	0.74	Ambiguous	0.724	Likely Pathogenic	-7.76	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.87	Pathogenic	0.01	Affected			0.2173	0.4172		0	-2	1.6	-40.02
c.932A>T	H311L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311L missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include AlphaMissense‑Optimized, Foldetta, premPS, and Rosetta. Tools that predict a pathogenic outcome are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta predicting a benign effect. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.229226	Structured	0.354792	Uncertain	0.902	0.314	0.125											-10.119	Likely Pathogenic	0.575	Likely Pathogenic	Likely Benign	-0.53	Ambiguous	0.0	-0.04	Likely Benign	-0.29	Likely Benign	0.43	Likely Benign	0.663	Likely Pathogenic	-7.99	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.87	Pathogenic	0.02	Affected			0.0961	0.5292		-2	-3	7.0	-23.98
c.933C>A	H311Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and premPS. The high‑accuracy consensus methods give mixed signals: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, more tools (seven) predict pathogenicity than benign (four), and the SGM Consensus supports a pathogenic classification, while Foldetta offers a contrary benign prediction. The variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict the absence of a ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.229226	Structured	0.354792	Uncertain	0.902	0.314	0.125											-8.656	Likely Pathogenic	0.792	Likely Pathogenic	Ambiguous	0.15	Likely Benign	0.1	0.39	Likely Benign	0.27	Likely Benign	0.92	Ambiguous	0.414	Likely Benign	-5.95	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.94	Pathogenic	0.03	Affected			0.1490	0.3775		3	0	-0.3	-9.01
c.933C>G	H311Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311Q missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. With seven pathogenic versus four benign predictions, the overall consensus leans toward pathogenicity. This conclusion does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.229226	Structured	0.354792	Uncertain	0.902	0.314	0.125											-8.656	Likely Pathogenic	0.792	Likely Pathogenic	Ambiguous	0.15	Likely Benign	0.1	0.39	Likely Benign	0.27	Likely Benign	0.92	Ambiguous	0.414	Likely Benign	-5.95	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.94	Pathogenic	0.03	Affected			0.1490	0.3775		3	0	-0.3	-9.01
c.934T>A	F312I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312I is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect, so the benign group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-12.000	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	2.09	Destabilizing	0.3	3.10	Destabilizing	2.60	Destabilizing	1.72	Destabilizing	0.872	Likely Pathogenic	-5.52	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.23	Pathogenic	0.01	Affected			0.1997	0.2842		1	0	1.7	-34.02
c.934T>C	F312L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” The only tool with an inconclusive result is FoldX, which is listed as “Uncertain.” No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-9.891	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.16	Ambiguous	0.3	2.91	Destabilizing	2.04	Destabilizing	1.27	Destabilizing	0.852	Likely Pathogenic	-5.52	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	1.32	Pathogenic	0.05	Affected			0.2149	0.3813		2	0	1.0	-34.02
c.934T>G	F312V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312V is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the change as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-12.206	Likely Pathogenic	0.993	Likely Pathogenic	Likely Pathogenic	2.13	Destabilizing	0.1	3.46	Destabilizing	2.80	Destabilizing	1.80	Destabilizing	0.877	Likely Pathogenic	-6.43	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.25	Pathogenic	0.00	Affected			0.1998	0.2810		-1	-1	1.4	-48.04
c.935T>A	F312Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a deleterious effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default, all of which classify the change as pathogenic. No tool in the dataset predicts a benign outcome. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta provide uncertain results. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-7.571	In-Between	0.949	Likely Pathogenic	Ambiguous	1.04	Ambiguous	0.1	0.89	Ambiguous	0.97	Ambiguous	0.99	Ambiguous	0.744	Likely Pathogenic	-2.76	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	1.21	Pathogenic	0.02	Affected			0.1443	0.2728		7	3	-4.1	16.00
c.935T>C	F312S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All available in‑silico predictors classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, with no contradiction to ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-14.075	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	3.74	Destabilizing	0.3	5.64	Destabilizing	4.69	Destabilizing	2.70	Destabilizing	0.880	Likely Pathogenic	-7.35	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.17	Pathogenic	0.00	Affected			0.3563	0.1578		-3	-2	-3.6	-60.10
c.935T>G	F312C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312C is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Based on the unanimous pathogenic predictions and the absence of benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-11.991	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	2.98	Destabilizing	0.3	4.97	Destabilizing	3.98	Destabilizing	1.46	Destabilizing	0.870	Likely Pathogenic	-7.35	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.16	Pathogenic	0.00	Affected			0.2293	0.2010		-4	-2	-0.3	-44.04
c.936C>A	F312L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” The only tool with an inconclusive result is FoldX, which is listed as “Uncertain.” No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-9.891	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.16	Ambiguous	0.3	2.91	Destabilizing	2.04	Destabilizing	1.27	Destabilizing	0.615	Likely Pathogenic	-5.52	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	1.32	Pathogenic	0.05	Affected			0.2149	0.3813		2	0	1.0	-34.02
c.936C>G	F312L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” The only tool with an inconclusive result is FoldX, which is listed as “Uncertain.” No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.225814	Structured	0.361163	Uncertain	0.915	0.317	0.000											-9.891	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	1.16	Ambiguous	0.3	2.91	Destabilizing	2.04	Destabilizing	1.27	Destabilizing	0.615	Likely Pathogenic	-5.52	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	1.32	Pathogenic	0.05	Affected			0.2149	0.3813		2	0	1.0	-34.02
c.937G>A	E313K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313K is listed in ClinVar as Benign (ClinVar ID 3695040.0) and is not reported in gnomAD. Prediction tools that report a benign effect are absent; all available predictors that provide a definitive call classify the variant as pathogenic. These include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus indicates Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is Uncertain. Based on the overwhelming pathogenic predictions, the variant is most likely pathogenic, which contradicts its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.170161	Structured	0.366526	Uncertain	0.898	0.304	0.125					Likely Benign		1				-12.902	Likely Pathogenic	0.959	Likely Pathogenic	Likely Pathogenic	0.64	Ambiguous	0.6	1.40	Ambiguous	1.02	Ambiguous	0.75	Ambiguous	0.575	Likely Pathogenic	-3.31	Deleterious	1.000	Probably Damaging	0.995	Probably Damaging	1.90	Pathogenic	0.02	Affected			0.2540	0.7708		0	1	-0.4	-0.94
c.937G>C	E313Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 E313Q is listed in ClinVar with an Uncertain significance status and is not reported in gnomAD. Prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, PROVEAN, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized indicates a benign effect, Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign stability, whereas the SGM‑Consensus remains pathogenic. Overall, the balance of evidence leans toward pathogenicity, and this assessment does not contradict the ClinVar designation of Uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.170161	Structured	0.366526	Uncertain	0.898	0.304	0.125					Uncertain		1				-11.420	Likely Pathogenic	0.629	Likely Pathogenic	Likely Benign	0.19	Likely Benign	0.1	0.55	Ambiguous	0.37	Likely Benign	0.50	Likely Benign	0.505	Likely Pathogenic	-2.42	Neutral	1.000	Probably Damaging	0.998	Probably Damaging	1.88	Pathogenic	0.05	Affected			0.1523	0.7396		2	2	0.0	-0.98
c.938A>C	E313A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313A is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized, whereas the remaining pathogenic‑or‑likely‑pathogenic predictors are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.170161	Structured	0.366526	Uncertain	0.898	0.304	0.125											-14.591	Likely Pathogenic	0.747	Likely Pathogenic	Likely Benign	1.07	Ambiguous	0.3	0.97	Ambiguous	1.02	Ambiguous	0.62	Ambiguous	0.680	Likely Pathogenic	-4.88	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.88	Pathogenic	0.02	Affected			0.3416	0.6743		0	-1	5.3	-58.04
c.938A>G	E313G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313G is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—all of which classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. Taken together, the overwhelming consensus from both general and high‑accuracy predictors indicates that E313G is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.170161	Structured	0.366526	Uncertain	0.898	0.304	0.125											-14.615	Likely Pathogenic	0.912	Likely Pathogenic	Ambiguous	2.00	Destabilizing	0.5	2.42	Destabilizing	2.21	Destabilizing	0.79	Ambiguous	0.750	Likely Pathogenic	-5.50	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	1.83	Pathogenic	0.01	Affected			0.2638	0.6680		0	-2	3.1	-72.06
c.938A>T	E313V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E313V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas a majority of tools (REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the preponderance of evidence points to a pathogenic effect for E313V. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.170161	Structured	0.366526	Uncertain	0.898	0.304	0.125											-13.169	Likely Pathogenic	0.821	Likely Pathogenic	Ambiguous	0.34	Likely Benign	0.1	-0.02	Likely Benign	0.16	Likely Benign	0.21	Likely Benign	0.655	Likely Pathogenic	-5.73	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.93	Pathogenic	0.05	Affected			0.1132	0.7900		-2	-2	7.7	-29.98
c.940T>A	F314I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a pathogenic effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict deleterious or pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. Tools with uncertain or inconclusive results include Rosetta, Foldetta, and ESM1b. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, while Foldetta’s stability prediction is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this is consistent with the lack of ClinVar annotation (i.e., no benign classification). Therefore, the variant is most likely pathogenic, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-7.059	In-Between	0.992	Likely Pathogenic	Likely Pathogenic	2.23	Destabilizing	0.4	1.08	Ambiguous	1.66	Ambiguous	1.31	Destabilizing	0.534	Likely Pathogenic	-4.98	Deleterious	0.997	Probably Damaging	0.994	Probably Damaging	1.26	Pathogenic	0.01	Affected			0.2052	0.2308		1	0	1.7	-34.02
c.940T>C	F314L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that F314L is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-6.004	Likely Benign	0.998	Likely Pathogenic	Likely Pathogenic	0.87	Ambiguous	0.1	0.82	Ambiguous	0.85	Ambiguous	1.21	Destabilizing	0.476	Likely Benign	-4.85	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	1.30	Pathogenic	0.05	Affected			0.2204	0.3089		2	0	1.0	-34.02
c.940T>G	F314V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). All available in silico predictors classify the variant as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect, so the benign group is empty. High‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta—each return a pathogenic prediction. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-8.907	Likely Pathogenic	0.991	Likely Pathogenic	Likely Pathogenic	3.31	Destabilizing	0.4	2.54	Destabilizing	2.93	Destabilizing	1.44	Destabilizing	0.594	Likely Pathogenic	-5.90	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.26	Pathogenic	0.00	Affected			0.2054	0.2075		-1	-1	1.4	-48.04
c.941T>A	F314Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and Rosetta, whereas a majority of tools (SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive—AlphaMissense‑Optimized, FoldX, and Foldetta—are treated as unavailable. High‑accuracy assessments further support pathogenicity: the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, while Foldetta’s combined stability analysis is uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-13.297	Likely Pathogenic	0.918	Likely Pathogenic	Ambiguous	1.33	Ambiguous	0.1	0.29	Likely Benign	0.81	Ambiguous	1.28	Destabilizing	0.374	Likely Benign	-2.62	Deleterious	0.997	Probably Damaging	0.987	Probably Damaging	1.20	Pathogenic	0.02	Affected			0.1427	0.2173		7	3	-4.1	16.00
c.941T>C	F314S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314S (located in the C2 domain) is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Thus, the variant is most likely pathogenic based on predictions, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-14.371	Likely Pathogenic	1.000	Likely Pathogenic	Likely Pathogenic	4.51	Destabilizing	0.4	3.36	Destabilizing	3.94	Destabilizing	2.59	Destabilizing	0.735	Likely Pathogenic	-6.95	Deleterious	0.999	Probably Damaging	0.996	Probably Damaging	1.15	Pathogenic	0.00	Affected			0.4113	0.0600		-3	-2	-3.6	-60.10
c.941T>G	F314C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. All available evidence points to a damaging effect. Consequently, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-12.458	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	3.37	Destabilizing	0.3	2.64	Destabilizing	3.01	Destabilizing	2.49	Destabilizing	0.674	Likely Pathogenic	-6.89	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.13	Pathogenic	0.00	Affected			0.2401	0.1075		-4	-2	-0.3	-44.04
c.942T>A	F314L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that F314L is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-6.004	Likely Benign	0.998	Likely Pathogenic	Likely Pathogenic	0.87	Ambiguous	0.1	0.82	Ambiguous	0.85	Ambiguous	1.21	Destabilizing	0.336	Likely Benign	-4.85	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	1.30	Pathogenic	0.05	Affected			0.2204	0.3089		2	0	1.0	-34.02
c.942T>G	F314L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that F314L is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.173081	Structured	0.374049	Uncertain	0.900	0.271	0.125											-6.004	Likely Benign	0.998	Likely Pathogenic	Likely Pathogenic	0.87	Ambiguous	0.1	0.82	Ambiguous	0.85	Ambiguous	1.21	Destabilizing	0.336	Likely Benign	-4.85	Deleterious	0.992	Probably Damaging	0.987	Probably Damaging	1.30	Pathogenic	0.05	Affected			0.2204	0.3089		2	0	1.0	-34.02
c.946A>C	N316H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N316H is not reported in ClinVar (status: None) and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, and AlphaMissense‑Optimized. Tools that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts a benign effect; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (pathogenic), FATHMM (pathogenic), and PROVEAN (pathogenic), indicates a likely pathogenic outcome; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign impact. FoldX and premPS are inconclusive. Overall, the balance of evidence from the majority of prediction tools points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.118441	Structured	0.385187	Uncertain	0.817	0.246	0.125											-8.141	Likely Pathogenic	0.440	Ambiguous	Likely Benign	0.72	Ambiguous	0.4	0.07	Likely Benign	0.40	Likely Benign	0.62	Ambiguous	0.306	Likely Benign	-3.56	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.76	Pathogenic	0.02	Affected			0.1555	0.7702		2	1	0.3	23.04
c.946A>T	N316Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316Y is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign impact. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.118441	Structured	0.385187	Uncertain	0.817	0.246	0.125											-11.226	Likely Pathogenic	0.767	Likely Pathogenic	Likely Benign	0.53	Ambiguous	0.5	-0.09	Likely Benign	0.22	Likely Benign	0.50	Likely Benign	0.454	Likely Benign	-5.70	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.81	Pathogenic	0.01	Affected			0.0574	0.6971		-2	-2	2.2	49.07
c.947A>T	N316I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and premPS, whereas the majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. No prediction is missing or inconclusive beyond the uncertain AlphaMissense‑Optimized result. Based on the preponderance of pathogenic predictions and the high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.118441	Structured	0.385187	Uncertain	0.817	0.246	0.125											-11.164	Likely Pathogenic	0.899	Likely Pathogenic	Ambiguous	2.74	Destabilizing	0.2	4.10	Destabilizing	3.42	Destabilizing	0.18	Likely Benign	0.318	Likely Benign	-6.37	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	2.00	Pathogenic	0.03	Affected			0.0734	0.7422		-2	-3	8.0	-0.94
c.949C>A	L317M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L317M missense variant is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools show a split: benign calls come from REVEL, FoldX, Foldetta, and PROVEAN, whereas pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta predicts a benign effect on protein stability. No evidence from ClinVar contradicts these findings. Overall, the preponderance of pathogenic predictions and the SGM‑Consensus result suggest that the variant is most likely pathogenic, though the benign signal from Foldetta and other tools indicates uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.106997	Structured	0.394031	Uncertain	0.874	0.240	0.125											-9.558	Likely Pathogenic	0.788	Likely Pathogenic	Ambiguous	0.14	Likely Benign	0.1	0.84	Ambiguous	0.49	Likely Benign	0.94	Ambiguous	0.250	Likely Benign	-1.84	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.71	Pathogenic	0.04	Affected			0.0937	0.3122		4	2	-1.9	18.03
c.949C>G	L317V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L317V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely disagree: benign calls come from REVEL and AlphaMissense‑Optimized, while pathogenic calls are made by FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized predicting Benign, SGM‑Consensus predicting Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an Uncertain result. Overall, the majority of evidence points toward pathogenicity, with only two tools indicating benign. Because ClinVar contains no entry, there is no conflict with existing clinical interpretation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.106997	Structured	0.394031	Uncertain	0.874	0.240	0.125											-8.406	Likely Pathogenic	0.403	Ambiguous	Likely Benign	2.51	Destabilizing	0.1	0.97	Ambiguous	1.74	Ambiguous	1.12	Destabilizing	0.298	Likely Benign	-2.76	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	1.74	Pathogenic	0.03	Affected			0.1518	0.2950		2	1	0.4	-14.03
c.94A>C	T32P 2D AIThe SynGAP1 missense variant T32P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, two tools—polyPhen‑2 HumDiv and SIFT—classify the change as pathogenic. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; no Foldetta stability data are available. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.437154	Uncertain	0.349	0.879	0.375											-2.958	Likely Benign	0.055	Likely Benign	Likely Benign										0.102	Likely Benign	-0.94	Neutral	0.604	Possibly Damaging	0.185	Benign	4.14	Benign	0.00	Affected			0.2327	0.5818		0	-1	-0.9	-3.99
c.94A>G	T32A 2D AIThe SynGAP1 missense variant T32A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.437154	Uncertain	0.349	0.879	0.375											-3.330	Likely Benign	0.072	Likely Benign	Likely Benign										0.047	Likely Benign	-0.63	Neutral	0.043	Benign	0.016	Benign	4.21	Benign	0.00	Affected			0.4174	0.4742		1	0	2.5	-30.03
c.94A>T	T32S 2D AIThe SynGAP1 missense variant T32S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.437154	Uncertain	0.349	0.879	0.375											-2.618	Likely Benign	0.072	Likely Benign	Likely Benign										0.062	Likely Benign	-0.39	Neutral	0.171	Benign	0.050	Benign	4.18	Benign	0.00	Affected			0.3603	0.5174		1	1	-0.1	-14.03
c.950T>A	L317Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L317Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on these predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.106997	Structured	0.394031	Uncertain	0.874	0.240	0.125											-13.424	Likely Pathogenic	0.995	Likely Pathogenic	Likely Pathogenic	2.87	Destabilizing	0.2	2.47	Destabilizing	2.67	Destabilizing	1.61	Destabilizing	0.607	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.75	Pathogenic	0.00	Affected			0.1252	0.1251		-2	-2	-7.3	14.97
c.950T>C	L317P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L317P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tools predict a benign effect, so the benign group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.106997	Structured	0.394031	Uncertain	0.874	0.240	0.125											-14.778	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	3.61	Destabilizing	1.4	4.29	Destabilizing	3.95	Destabilizing	1.26	Destabilizing	0.654	Likely Pathogenic	-6.43	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.82	Pathogenic	0.00	Affected			0.3405	0.1153		-3	-3	-5.4	-16.04
c.950T>G	L317R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L317R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.106997	Structured	0.394031	Uncertain	0.874	0.240	0.125											-14.185	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	3.33	Destabilizing	0.2	2.01	Destabilizing	2.67	Destabilizing	1.63	Destabilizing	0.569	Likely Pathogenic	-5.52	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.75	Pathogenic	0.00	Affected			0.1501	0.0893		-3	-2	-8.3	43.03
c.952C>A	P318T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P318T is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly favor a deleterious effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenic or likely pathogenic. No tool in the dataset predicts a benign outcome; the only inconclusive results come from Rosetta, Foldetta, and premPS, which are treated as unavailable evidence. High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is uncertain. Consequently, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.111485	Structured	0.400936	Uncertain	0.858	0.234	0.000											-10.759	Likely Pathogenic	0.962	Likely Pathogenic	Likely Pathogenic	2.03	Destabilizing	0.2	1.54	Ambiguous	1.79	Ambiguous	0.84	Ambiguous	0.680	Likely Pathogenic	-7.09	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.84	Pathogenic	0.01	Affected			0.1583	0.6044		0	-1	0.9	3.99
c.952C>G	P318A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P318A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign outcome. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while AlphaMissense‑Optimized remains uncertain and Foldetta is also uncertain. Taken together, the overwhelming majority of evidence points to a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.111485	Structured	0.400936	Uncertain	0.858	0.234	0.000											-9.642	Likely Pathogenic	0.872	Likely Pathogenic	Ambiguous	1.90	Ambiguous	0.2	1.69	Ambiguous	1.80	Ambiguous	0.94	Ambiguous	0.546	Likely Pathogenic	-7.12	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.91	Pathogenic	0.04	Affected			0.3760	0.5585		1	-1	3.4	-26.04
c.952C>T	P318S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P318S is present in gnomAD (variant ID 6‑33437857‑C‑T) but has no ClinVar entry. Functional prediction tools uniformly indicate a deleterious effect. Pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta and Foldetta. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta remains uncertain. Taken together, the overwhelming majority of evidence supports a pathogenic classification, and this conclusion is consistent with the absence of a ClinVar record rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.111485	Structured	0.400936	Uncertain	0.858	0.234	0.000								6-33437857-C-T	1	6.19e-7	-9.954	Likely Pathogenic	0.956	Likely Pathogenic	Likely Pathogenic	2.22	Destabilizing	0.1	1.71	Ambiguous	1.97	Ambiguous	1.00	Destabilizing	0.626	Likely Pathogenic	-7.05	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.87	Pathogenic	0.03	Affected	3.38	23	0.3692	0.5653		-1	1	0.8	-10.04
c.953C>A	P318Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P318Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity. Only FoldX, Rosetta, and Foldetta provide uncertain results and are therefore not considered evidence for benign impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Consequently, the variant is most likely pathogenic based on the consensus of predictive algorithms, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.111485	Structured	0.400936	Uncertain	0.858	0.234	0.000											-11.403	Likely Pathogenic	0.976	Likely Pathogenic	Likely Pathogenic	1.64	Ambiguous	0.2	1.29	Ambiguous	1.47	Ambiguous	1.18	Destabilizing	0.638	Likely Pathogenic	-7.05	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.83	Pathogenic	0.01	Affected			0.1467	0.4731		0	-1	-1.9	31.01
c.953C>G	P318R 2D 3DClick to see structure in 3D Viewer AISynGAP1 P318R is not reported in ClinVar and is absent from gnomAD. In silico predictors that classify the variant as benign: none. Those that predict pathogenicity include SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions from FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy tools give a consistent pathogenic signal: AlphaMissense‑Optimized reports pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; Foldetta remains inconclusive. Overall, the consensus of the majority of predictors supports a pathogenic effect. This conclusion is not contradicted by ClinVar status, which is currently unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.111485	Structured	0.400936	Uncertain	0.858	0.234	0.000											-14.132	Likely Pathogenic	0.987	Likely Pathogenic	Likely Pathogenic	1.20	Ambiguous	0.1	0.70	Ambiguous	0.95	Ambiguous	1.01	Destabilizing	0.643	Likely Pathogenic	-8.01	Deleterious	1.000	Probably Damaging	1.000	Probably Damaging	1.84	Pathogenic	0.01	Affected			0.1308	0.3310		0	-2	-2.9	59.07
c.953C>T	P318L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P318L is listed in ClinVar with an uncertain significance (ClinVar ID 956570.0) and is present in gnomAD (6‑33437858‑C‑T). Functional prediction tools that agree on a benign effect are Rosetta and premPS. The remaining tools—REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Taken together, the preponderance of evidence points to a pathogenic effect for P318L, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.111485	Structured	0.400936	Uncertain	0.858	0.234	0.000					Uncertain		3	6-33437858-C-T	3	1.86e-6	-10.090	Likely Pathogenic	0.958	Likely Pathogenic	Likely Pathogenic	1.33	Ambiguous	0.1	0.26	Likely Benign	0.80	Ambiguous	0.43	Likely Benign	0.624	Likely Pathogenic	-8.96	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.82	Pathogenic	0.03	Affected	3.38	23	0.2166	0.6941		-3	-3	5.4	16.04	228.6	-68.9	-0.7	0.7	-0.4	0.1						X		Potentially Benign	The cyclic five-membered pyrrolidine ring of Pro318, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Asp330-Ala322, res. Thr305-Asn315), packs against the hydrophobic side chain of Ile205 at the end of the anti-parallel β sheet in the PH domain. In the variant simulations, the iso-butyl side chain of Leu318 is unable to do the same, potentially weakening the PH and C2 domain association. Importantly, the residue swap could also affect loop formation during folding, as proline can make tighter turns than leucine. Because the residue swap could affect the C2 domain stability, it could also negatively impact the SynGAP-membrane association.
c.959T>G	V320G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools cluster into two agreement groups: the single benign prediction comes from REVEL, while the pathogenic group includes FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain; the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—returns pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. Overall, the preponderance of evidence indicates that V320G is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.185198	Structured	0.419626	Uncertain	0.905	0.266	0.125											-9.043	Likely Pathogenic	0.816	Likely Pathogenic	Ambiguous	2.15	Destabilizing	1.1	1.87	Ambiguous	2.01	Destabilizing	1.48	Destabilizing	0.438	Likely Benign	-5.74	Deleterious	0.958	Probably Damaging	0.999	Probably Damaging	1.89	Pathogenic	0.02	Affected			0.1688	0.1949		-1	-3	-4.6	-42.08
c.95C>A	T32N 2D AIThe SynGAP1 missense variant T32N is catalogued in gnomAD (ID 6‑33423504‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.437154	Uncertain	0.349	0.879	0.375								6-33423504-C-A	2	1.24e-6	-3.466	Likely Benign	0.090	Likely Benign	Likely Benign										0.040	Likely Benign	-1.01	Neutral	0.604	Possibly Damaging	0.140	Benign	4.15	Benign	0.00	Affected	4.32	1	0.1681	0.5264		0	0	-2.8	13.00
c.95C>G	T32S 2D AIThe SynGAP1 missense variant T32S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.437154	Uncertain	0.349	0.879	0.375											-2.618	Likely Benign	0.072	Likely Benign	Likely Benign										0.024	Likely Benign	-0.39	Neutral	0.171	Benign	0.050	Benign	4.18	Benign	0.00	Affected			0.3603	0.5174		1	1	-0.1	-14.03
c.95C>T	T32I 2D AIThe SynGAP1 missense variant T32I is reported in gnomAD (ID 6‑33423504‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also reports likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for T32I, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.437154	Uncertain	0.349	0.879	0.375								6-33423504-C-T	1	6.20e-7	-3.689	Likely Benign	0.213	Likely Benign	Likely Benign										0.024	Likely Benign	-0.57	Neutral	0.049	Benign	0.026	Benign	4.26	Benign	0.00	Affected	4.32	1	0.1081	0.6403		-1	0	5.2	12.05
c.961C>G	R321G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, AlphaMissense‑Default, AlphaMissense‑Optimized, and premPS. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, while the high‑accuracy subset is mixed, with one benign, one pathogenic, and one uncertain result. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.175930	Structured	0.423273	Uncertain	0.931	0.297	0.125											-10.554	Likely Pathogenic	0.293	Likely Benign	Likely Benign	0.90	Ambiguous	0.1	0.28	Likely Benign	0.59	Ambiguous	0.49	Likely Benign	0.430	Likely Benign	-3.70	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.92	Pathogenic	0.04	Affected			0.3224	0.2898		-3	-2	4.1	-99.14
c.961C>T	R321C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33437866‑C‑T). Prediction tools that agree on a benign effect include REVEL, premPS, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Five tools (SGM‑Consensus, FoldX, Rosetta, AlphaMissense‑Default, and Foldetta) report uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (six out of eleven) support a pathogenic impact, while three support benign and five are inconclusive. Thus, the variant is most likely pathogenic based on current computational evidence, and this does not contradict its ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.175930	Structured	0.423273	Uncertain	0.931	0.297	0.125					Conflicting		2	6-33437866-C-T	9	5.58e-6	-10.025	Likely Pathogenic	0.387	Ambiguous	Likely Benign	0.57	Ambiguous	0.1	0.56	Ambiguous	0.57	Ambiguous	0.18	Likely Benign	0.495	Likely Benign	-4.59	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.89	Pathogenic	0.01	Affected	3.38	23	0.3313	0.2516		-3	-4	7.0	-53.05
c.962G>C	R321P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. FoldX and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools (8/12) predict pathogenicity, whereas 4/12 predict benign, with two high‑accuracy tools supporting benign and one supporting pathogenic. Thus, the variant is most likely pathogenic based on the preponderance of evidence, and this assessment does not contradict ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.175930	Structured	0.423273	Uncertain	0.931	0.297	0.125											-11.576	Likely Pathogenic	0.740	Likely Pathogenic	Likely Benign	1.22	Ambiguous	0.3	-0.77	Ambiguous	0.23	Likely Benign	0.41	Likely Benign	0.488	Likely Benign	-3.59	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.92	Pathogenic	0.03	Affected			0.2186	0.3661		0	-2	2.9	-59.07
c.962G>T	R321L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SIFT, polyPhen‑2 (HumDiv and HumVar), PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign; FoldX and Rosetta individually are inconclusive. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.175930	Structured	0.423273	Uncertain	0.931	0.297	0.125											-11.709	Likely Pathogenic	0.551	Ambiguous	Likely Benign	0.54	Ambiguous	0.0	-0.58	Ambiguous	-0.02	Likely Benign	0.18	Likely Benign	0.451	Likely Benign	-4.06	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.93	Pathogenic	0.03	Affected			0.1745	0.4048		-3	-2	8.3	-43.03
c.967C>A	L323M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L323M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—Foldetta, premPS, AlphaMissense‑Default, ESM1b, and Rosetta—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Taken together, the evidence leans toward a benign impact for the variant, and this assessment does not contradict any ClinVar annotation, as none exists for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.268042	Structured	0.428564	Uncertain	0.956	0.369	0.000											-7.065	In-Between	0.427	Ambiguous	Likely Benign	0.11	Likely Benign	0.1	1.82	Ambiguous	0.97	Ambiguous	0.93	Ambiguous	0.270	Likely Benign	-1.02	Neutral	0.997	Probably Damaging	0.939	Probably Damaging	0.64	Pathogenic	0.03	Affected			0.0637	0.3010		4	2	-1.9	18.03
c.968T>A	L323Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L323Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—return pathogenic or likely pathogenic calls. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.268042	Structured	0.428564	Uncertain	0.956	0.369	0.000											-14.487	Likely Pathogenic	0.996	Likely Pathogenic	Likely Pathogenic	3.19	Destabilizing	0.2	3.28	Destabilizing	3.24	Destabilizing	1.85	Destabilizing	0.728	Likely Pathogenic	-4.54	Deleterious	0.999	Probably Damaging	0.977	Probably Damaging	0.59	Pathogenic	0.00	Affected			0.0915	0.0758		-2	-2	-7.3	14.97
c.968T>C	L323P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L323P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.268042	Structured	0.428564	Uncertain	0.956	0.369	0.000					Uncertain		1				-12.507	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	3.39	Destabilizing	0.6	8.46	Destabilizing	5.93	Destabilizing	2.20	Destabilizing	0.762	Likely Pathogenic	-4.80	Deleterious	0.999	Probably Damaging	0.977	Probably Damaging	0.59	Pathogenic	0.01	Affected	4.29	398	0.3678	0.1221		-3	-3	-5.4	-16.04	201.9	68.2	0.0	0.1	0.6	0.3	X							Potentially Pathogenic	The iso-butyl side chain of Leu323, located at the beginning of an anti-parallel β sheet strand (res. Ala322-Asp330), packs against multiple hydrophobic leucine residues (e.g., Leu264, Leu266, Leu284, Leu286). In contrast, in the variant simulations, the less bulky cyclic five-membered pyrrolidine ring of Pro323 cannot fill the hydrophobic space as effectively as the branched hydrocarbon side chain of leucine. Notably, the backbone amide group of Leu323 forms a hydrogen bond with the backbone carbonyl group of Cys285. Pro323 cannot form this bond due to the absence of the backbone amide group, resulting in partial unfolding of the anti-parallel β sheet end in the variant simulations.
c.968T>G	L323R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L323R is listed in ClinVar (ID 978601.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Consequently, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.268042	Structured	0.428564	Uncertain	0.956	0.369	0.000					Likely Pathogenic		1				-14.568	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	3.75	Destabilizing	0.4	4.47	Destabilizing	4.11	Destabilizing	2.15	Destabilizing	0.692	Likely Pathogenic	-4.70	Deleterious	0.999	Probably Damaging	0.969	Probably Damaging	0.59	Pathogenic	0.01	Affected	3.39	22	0.1066	0.0600		-3	-2	-8.3	43.03	261.8	-61.6	-0.4	0.2	0.8	0.2	X		X				X	Potentially Pathogenic	The iso-butyl side chain of Leu323, located at the beginning of an anti-parallel β sheet strand (res. Ala322-Asp330), packs against multiple hydrophobic leucine residues (e.g., Leu264, Leu266, Leu284, Leu286). In contrast, in the variant simulations, the positively charged guanidinium group of the Arg323 side chain is unsuitable for the hydrophobic niche. Consequently, the side chain either rotates away from the center of the C2 domain or, if it remains within the C2 domain core, it reorients nearby residues to form hydrogen bonds. Regardless, the residue swap extensively disrupts the C2 domain structure.
c.973C>A	L325M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and premPS. Two tools give uncertain results: Foldetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. No prediction or folding stability result is missing or inconclusive. Overall, the majority of tools (six pathogenic vs five benign) lean toward pathogenicity, but the high‑accuracy methods and several benign predictions introduce uncertainty. Thus, the variant is most likely pathogenic based on the collective evidence, and this assessment is not contradicted by any ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.352862	Structured	0.424577	Uncertain	0.955	0.436	0.000											-6.725	Likely Benign	0.445	Ambiguous	Likely Benign	0.22	Likely Benign	0.0	2.04	Destabilizing	1.13	Ambiguous	1.05	Destabilizing	0.306	Likely Benign	-0.86	Neutral	0.997	Probably Damaging	0.939	Probably Damaging	1.36	Pathogenic	0.01	Affected			0.0934	0.3942		4	2	-1.9	18.03
c.974T>A	L325Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—return pathogenic or likely pathogenic calls. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.352862	Structured	0.424577	Uncertain	0.955	0.436	0.000											-17.005	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	3.23	Destabilizing	0.0	2.68	Destabilizing	2.96	Destabilizing	2.02	Destabilizing	0.547	Likely Pathogenic	-3.97	Deleterious	0.999	Probably Damaging	0.977	Probably Damaging	1.33	Pathogenic	0.00	Affected			0.1235	0.1405		-2	-2	-7.3	14.97
c.974T>C	L325P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325P is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.352862	Structured	0.424577	Uncertain	0.955	0.436	0.000											-16.130	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	5.49	Destabilizing	0.3	7.27	Destabilizing	6.38	Destabilizing	1.89	Destabilizing	0.607	Likely Pathogenic	-4.37	Deleterious	0.999	Probably Damaging	0.977	Probably Damaging	1.33	Pathogenic	0.00	Affected			0.3393	0.1903		-3	-3	-5.4	-16.04
c.974T>G	L325R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. No predictions or stability results are missing or inconclusive. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status (no ClinVar entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.352862	Structured	0.424577	Uncertain	0.955	0.436	0.000											-16.612	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	4.34	Destabilizing	0.3	4.11	Destabilizing	4.23	Destabilizing	1.94	Destabilizing	0.551	Likely Pathogenic	-4.39	Deleterious	0.999	Probably Damaging	0.969	Probably Damaging	1.33	Pathogenic	0.00	Affected			0.1405	0.1047		-3	-2	-8.3	43.03
c.976C>T	H326Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas a majority of tools (REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic effect for H326Y, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.342579	Structured	0.418150	Uncertain	0.944	0.455	0.000											-10.896	Likely Pathogenic	0.855	Likely Pathogenic	Ambiguous	0.03	Likely Benign	0.4	0.25	Likely Benign	0.14	Likely Benign	0.07	Likely Benign	0.562	Likely Pathogenic	-5.32	Deleterious	0.997	Probably Damaging	0.992	Probably Damaging	1.92	Pathogenic	0.02	Affected			0.0796	0.4323		0	2	1.9	26.03
c.977A>C	H326P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; pathogenic predictions are reported by REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). The only inconclusive result is premPS, which is listed as Uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Pathogenic. Based on the consensus of these predictions, the variant is most likely pathogenic, and this conclusion is consistent with the absence of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.342579	Structured	0.418150	Uncertain	0.944	0.455	0.000											-18.452	Likely Pathogenic	0.997	Likely Pathogenic	Likely Pathogenic	2.67	Destabilizing	0.3	2.59	Destabilizing	2.63	Destabilizing	0.88	Ambiguous	0.711	Likely Pathogenic	-8.73	Deleterious	0.999	Probably Damaging	0.998	Probably Damaging	1.92	Pathogenic	0.03	Affected			0.2383	0.4492		0	-2	1.6	-40.02
c.979C>A	L327M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L327M missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, AlphaMissense‑Optimized, and Foldetta, whereas those that predict a pathogenic outcome are SGM‑Consensus, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta predicting a benign effect. Overall, the majority of tools indicate a pathogenic effect, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.409189	Uncertain	0.939	0.490	0.000											-10.320	Likely Pathogenic	0.727	Likely Pathogenic	Likely Benign	0.20	Likely Benign	0.0	0.72	Ambiguous	0.46	Likely Benign	1.07	Destabilizing	0.320	Likely Benign	-1.61	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.53	Pathogenic	0.01	Affected			0.0806	0.3807		4	2	-1.9	18.03
c.97C>A	Q33K 2D AIThe SynGAP1 missense variant Q33K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.436712	Uncertain	0.342	0.860	0.375											-0.317	Likely Benign	0.217	Likely Benign	Likely Benign										0.026	Likely Benign	-0.53	Neutral	0.019	Benign	0.021	Benign	4.24	Benign	0.00	Affected			0.2366	0.4514		1	1	-0.4	0.04
c.97C>G	Q33E 2D AIThe SynGAP1 missense variant Q33E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign status: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.436712	Uncertain	0.342	0.860	0.375											0.191	Likely Benign	0.110	Likely Benign	Likely Benign										0.024	Likely Benign	-0.13	Neutral	0.017	Benign	0.014	Benign	4.25	Benign	0.00	Affected			0.1773	0.3326		2	2	0.0	0.98
c.980T>A	L327Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L327Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. With all available evidence pointing to a harmful impact and no ClinVar entry to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.409189	Uncertain	0.939	0.490	0.000											-14.243	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	3.03	Destabilizing	0.1	2.17	Destabilizing	2.60	Destabilizing	2.11	Destabilizing	0.605	Likely Pathogenic	-5.26	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.52	Pathogenic	0.00	Affected			0.1131	0.1042		-2	-2	-7.3	14.97
c.980T>C	L327P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L327P (ClinVar ID 660421) is classified as Pathogenic in ClinVar and is not reported in gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, leaving no tools in the benign category. High‑accuracy assessments further support this: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is Pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.409189	Uncertain	0.939	0.490	0.000					Pathogenic/Likely path.		4				-16.602	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	5.38	Destabilizing	0.1	4.00	Destabilizing	4.69	Destabilizing	2.62	Destabilizing	0.658	Likely Pathogenic	-5.97	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.52	Pathogenic	0.01	Affected	3.38	23	0.3921	0.1703		-3	-3	-5.4	-16.04	221.7	69.4	0.1	0.0	0.6	0.1	X							Potentially Pathogenic	The backbone amide group of Leu327, located in the middle of an anti-parallel β sheet strand (res. Ala322-Asp330), forms a hydrogen bond with the carbonyl group of Gly344 on a neighboring β strand (res. Lys336-Pro349) in the WT simulations. In contrast, in the variant simulations, the introduction of Pro327 destabilizes the hydrogen bonding between the two anti-parallel β strands because proline lacks the backbone amide group altogether. Additionally, in the WT simulations, the iso-butyl side chain of Leu327 packs against multiple hydrophobic residues (e.g., Leu274, V400, Val343), whereas the less bulky cyclic five-membered pyrrolidine ring of Pro327 cannot fill the same space as effectively. Thus, although no large-scale unfolding is observed during the variant simulations, the residue swap is likely to cause severe problems for the correct C2 domain folding, which could also affect the SynGAP-membrane association.	10.1016/j.ajhg.2020.11.011
c.980T>G	L327R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L327R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a destabilizing, pathogenic effect. All available predictions are concordant and indicate a likely pathogenic impact. Thus, based on the current computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.335645	Structured	0.409189	Uncertain	0.939	0.490	0.000											-13.403	Likely Pathogenic	0.998	Likely Pathogenic	Likely Pathogenic	4.46	Destabilizing	0.3	4.75	Destabilizing	4.61	Destabilizing	1.95	Destabilizing	0.619	Likely Pathogenic	-5.28	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.52	Pathogenic	0.00	Affected			0.1281	0.1085		-3	-2	-8.3	43.03
c.982T>A	Y328N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.411940	Structured	0.392519	Uncertain	0.916	0.497	0.000											-13.778	Likely Pathogenic	0.994	Likely Pathogenic	Likely Pathogenic	2.72	Destabilizing	0.1	3.88	Destabilizing	3.30	Destabilizing	2.06	Destabilizing	0.548	Likely Pathogenic	-8.07	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.53	Pathogenic	0.01	Affected			0.2374	0.0703		-2	-2	-2.2	-49.07
c.982T>C	Y328H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.411940	Structured	0.392519	Uncertain	0.916	0.497	0.000											-10.885	Likely Pathogenic	0.983	Likely Pathogenic	Likely Pathogenic	2.08	Destabilizing	0.0	2.43	Destabilizing	2.26	Destabilizing	1.35	Destabilizing	0.516	Likely Pathogenic	-4.53	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.54	Pathogenic	0.02	Affected			0.2572	0.0703		0	2	-1.9	-26.03
c.982T>G	Y328D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328D is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classifies the substitution as pathogenic; no tool predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.411940	Structured	0.392519	Uncertain	0.916	0.497	0.000											-13.701	Likely Pathogenic	0.999	Likely Pathogenic	Likely Pathogenic	4.32	Destabilizing	0.2	4.97	Destabilizing	4.65	Destabilizing	1.87	Destabilizing	0.680	Likely Pathogenic	-8.93	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.52	Pathogenic	0.01	Affected			0.4233	0.0703		-4	-3	-2.2	-48.09
c.983A>C	Y328S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328S is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact on protein stability. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.411940	Structured	0.392519	Uncertain	0.916	0.497	0.000											-12.358	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	3.13	Destabilizing	0.1	4.55	Destabilizing	3.84	Destabilizing	1.80	Destabilizing	0.586	Likely Pathogenic	-8.01	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.54	Pathogenic	0.01	Affected			0.4924	0.2449		-3	-2	0.5	-76.10
c.983A>G	Y328C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (integrating FoldX‑MD and Rosetta outputs) also reports a pathogenic outcome. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.411940	Structured	0.392519	Uncertain	0.916	0.497	0.000											-12.385	Likely Pathogenic	0.975	Likely Pathogenic	Likely Pathogenic	2.52	Destabilizing	0.1	3.74	Destabilizing	3.13	Destabilizing	1.40	Destabilizing	0.523	Likely Pathogenic	-8.01	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.55	Pathogenic	0.01	Affected			0.3154	0.2882		0	-2	3.8	-60.04
c.985C>A	R329S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R329S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the majority of available predictions support a pathogenic impact. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.376086	Uncertain	0.887	0.479	0.250											-10.731	Likely Pathogenic	0.984	Likely Pathogenic	Likely Pathogenic	1.80	Ambiguous	0.3	0.78	Ambiguous	1.29	Ambiguous	0.78	Ambiguous	0.192	Likely Benign	-3.36	Deleterious	0.653	Possibly Damaging	0.226	Benign	4.07	Benign	0.04	Affected			0.2886	0.3625		0	-1	3.7	-69.11
c.985C>G	R329G 2D 3DClick to see structure in 3D Viewer AISynGAP1 R329G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls are made by FoldX, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments give an overall pathogenic signal: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta is inconclusive. Taken together, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.376086	Uncertain	0.887	0.479	0.250											-12.426	Likely Pathogenic	0.927	Likely Pathogenic	Ambiguous	2.21	Destabilizing	0.3	1.58	Ambiguous	1.90	Ambiguous	0.92	Ambiguous	0.204	Likely Benign	-4.78	Deleterious	0.653	Possibly Damaging	0.293	Benign	4.03	Benign	0.04	Affected			0.3147	0.3037		-3	-2	4.1	-99.14
c.985C>T	R329C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R329C is reported in gnomAD (ID 6‑33437890‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, Rosetta, Foldetta, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools remain inconclusive: premPS and AlphaMissense‑Optimized. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta) as benign. Overall, six tools favor pathogenicity versus five favor benign, with one uncertain. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.376086	Uncertain	0.887	0.479	0.250								6-33437890-C-T	2	1.24e-6	-9.433	Likely Pathogenic	0.865	Likely Pathogenic	Ambiguous	0.44	Likely Benign	0.1	0.40	Likely Benign	0.42	Likely Benign	0.69	Ambiguous	0.313	Likely Benign	-5.70	Deleterious	0.999	Probably Damaging	0.825	Possibly Damaging	3.98	Benign	0.00	Affected	3.41	15	0.3553	0.2921		-3	-4	7.0	-53.05
c.986G>A	R329H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R329H is listed in ClinVar with an uncertain significance (ClinVar ID 2074400.0) and is present in gnomAD (ID 6‑33437891‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the balance of predictions favors a pathogenic impact, which does not contradict the ClinVar uncertain status but suggests the variant is more likely deleterious. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.376086	Uncertain	0.887	0.479	0.250					Uncertain		1	6-33437891-G-A	2	1.24e-6	-10.154	Likely Pathogenic	0.769	Likely Pathogenic	Likely Benign	2.53	Destabilizing	0.7	0.71	Ambiguous	1.62	Ambiguous	0.82	Ambiguous	0.155	Likely Benign	-3.17	Deleterious	0.995	Probably Damaging	0.778	Possibly Damaging	4.04	Benign	0.05	Affected	3.41	15	0.2955	0.1961		2	0	1.3	-19.05	220.4	81.4	0.1	0.1	0.2	0.3								Uncertain	The guanidinium group of Arg329, located at the end of an anti-parallel β sheet strand (res. Ala322-Asp330), faces the negatively charged lipid bilayer surface. While the residue swap does not cause any apparent negative effects on the protein structure in the variant simulations, it could adversely affect the SynGAP-membrane association in reality. The positively charged Arg329 side chain forms hydrogen bonds with other loop residues (e.g., Ser371, Asp338) that are expected to dynamically interact with the membrane head group region. However, this phenomenon is beyond the scope of the solvent-only simulations to unravel. Notably, histidine can also be double protonated and positively charged, but this alternative protonation state was not considered in the variant simulations.
c.986G>C	R329P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R329P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of algorithms predict a pathogenic outcome: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic,” and premPS is uncertain. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. Overall, the evidence overwhelmingly points to a pathogenic effect for R329P, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.376086	Uncertain	0.887	0.479	0.250											-14.528	Likely Pathogenic	0.965	Likely Pathogenic	Likely Pathogenic	3.06	Destabilizing	0.2	4.99	Destabilizing	4.03	Destabilizing	0.73	Ambiguous	0.350	Likely Benign	-4.28	Deleterious	0.902	Possibly Damaging	0.544	Possibly Damaging	4.00	Benign	0.01	Affected			0.2215	0.4099		0	-2	2.9	-59.07
c.986G>T	R329L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R329L has no ClinVar entry and is not reported in gnomAD. Consensus from standard prediction tools shows a split: benign calls come from REVEL, FoldX, FATHMM, and polyPhen‑2 HumVar, while pathogenic calls arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Predictions marked uncertain (Rosetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of tools lean toward pathogenicity, but the folding‑stability evidence suggests a benign effect. Given the lack of ClinVar annotation, there is no contradiction. The variant is most likely pathogenic based on the preponderance of pathogenic predictions, though the benign folding‑stability result introduces uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.384043	Structured	0.376086	Uncertain	0.887	0.479	0.250											-10.186	Likely Pathogenic	0.907	Likely Pathogenic	Ambiguous	-0.09	Likely Benign	0.4	0.53	Ambiguous	0.22	Likely Benign	0.54	Ambiguous	0.219	Likely Benign	-4.81	Deleterious	0.653	Possibly Damaging	0.361	Benign	4.02	Benign	0.01	Affected			0.1827	0.4121		-3	-2	8.3	-43.03
c.988G>A	D330N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330N missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious interpretation: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic,” while AlphaMissense‑Optimized and Foldetta yield uncertain results and are treated as unavailable. No folding‑stability methods (FoldX, Rosetta, premPS) provide decisive evidence. Overall, the preponderance of pathogenic predictions strongly suggests that D330N is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.380708	Structured	0.360008	Uncertain	0.805	0.488	0.250											-12.993	Likely Pathogenic	0.909	Likely Pathogenic	Ambiguous	1.61	Ambiguous	0.2	0.59	Ambiguous	1.10	Ambiguous	0.59	Ambiguous	0.350	Likely Benign	-3.46	Deleterious	0.980	Probably Damaging	0.721	Possibly Damaging	1.01	Pathogenic	0.02	Affected			0.1252	0.4263		2	1	0.0	-0.98
c.988G>C	D330H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330H missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into three groups: benign predictions are limited to REVEL; pathogenic predictions include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, FoldX, and the SGM‑Consensus (Likely Pathogenic). Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Taken together, the overwhelming majority of evidence points to a pathogenic impact for D330H. This conclusion is not contradicted by any ClinVar annotation, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.380708	Structured	0.360008	Uncertain	0.805	0.488	0.250											-13.926	Likely Pathogenic	0.980	Likely Pathogenic	Likely Pathogenic	2.29	Destabilizing	0.6	1.32	Ambiguous	1.81	Ambiguous	0.61	Ambiguous	0.425	Likely Benign	-4.67	Deleterious	0.998	Probably Damaging	0.961	Probably Damaging	0.96	Pathogenic	0.01	Affected			0.1608	0.4843		1	-1	0.3	22.05
c.988G>T	D330Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D330Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and premPS, whereas the remaining tools—including SGM‑Consensus, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; FoldX is uncertain and therefore not counted. High‑accuracy methods all support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is pathogenic. Taken together, the overwhelming majority of evidence indicates that D330Y is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.380708	Structured	0.360008	Uncertain	0.805	0.488	0.250											-14.200	Likely Pathogenic	0.956	Likely Pathogenic	Likely Pathogenic	1.98	Ambiguous	0.6	2.90	Destabilizing	2.44	Destabilizing	0.35	Likely Benign	0.472	Likely Benign	-6.47	Deleterious	0.998	Probably Damaging	0.948	Probably Damaging	0.89	Pathogenic	0.00	Affected			0.0539	0.4689		-4	-3	2.2	48.09
c.989A>G	D330G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D330G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, whereas the majority of algorithms predict a pathogenic impact: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two predictors (AlphaMissense‑Optimized and premPS) give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, classifies the variant as pathogenic. Overall, the preponderance of evidence indicates that D330G is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.380708	Structured	0.360008	Uncertain	0.805	0.488	0.250											-13.064	Likely Pathogenic	0.950	Likely Pathogenic	Ambiguous	2.69	Destabilizing	0.2	2.17	Destabilizing	2.43	Destabilizing	0.63	Ambiguous	0.373	Likely Benign	-5.03	Deleterious	0.980	Probably Damaging	0.782	Possibly Damaging	0.94	Pathogenic	0.01	Affected			0.3935	0.5015		1	-1	3.1	-58.04
c.989A>T	D330V 2D 3DClick to see structure in 3D Viewer AISynGAP1 D330V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and premPS, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, and AlphaMissense‑Default. Uncertain predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are treated as unavailable. High‑accuracy assessments show that the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized and Foldetta provide inconclusive results and are therefore not considered evidence. Overall, the preponderance of evidence points to a pathogenic effect for D330V, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.380708	Structured	0.360008	Uncertain	0.805	0.488	0.250											-13.176	Likely Pathogenic	0.950	Likely Pathogenic	Ambiguous	2.06	Destabilizing	0.5	0.57	Ambiguous	1.32	Ambiguous	0.45	Likely Benign	0.428	Likely Benign	-6.40	Deleterious	0.994	Probably Damaging	0.892	Possibly Damaging	0.89	Pathogenic	0.01	Affected			0.0862	0.4633		-2	-3	7.7	-15.96
c.98A>C	Q33P 2D AIThe SynGAP1 missense variant Q33P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.436712	Uncertain	0.342	0.860	0.375											0.546	Likely Benign	0.049	Likely Benign	Likely Benign										0.098	Likely Benign	-0.75	Neutral	0.000	Benign	0.000	Benign	4.21	Benign	0.00	Affected			0.2445	0.5623		0	-1	1.9	-31.01
c.98A>G	Q33R 2D AIThe SynGAP1 missense variant Q33R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The predictions do not contradict ClinVar status, as ClinVar contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.436712	Uncertain	0.342	0.860	0.375											0.561	Likely Benign	0.171	Likely Benign	Likely Benign										0.035	Likely Benign	-0.82	Neutral	0.084	Benign	0.046	Benign	4.20	Benign	0.00	Affected			0.1936	0.2773		1	1	-1.0	28.06
c.98A>T	Q33L 2D AIThe SynGAP1 missense variant Q33L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.436712	Uncertain	0.342	0.860	0.375											0.253	Likely Benign	0.174	Likely Benign	Likely Benign										0.075	Likely Benign	-1.24	Neutral	0.084	Benign	0.033	Benign	4.18	Benign	0.00	Affected			0.1127	0.6214		-2	-2	7.3	-14.97
c.994G>C	D332H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D332H has no ClinVar entry and is absent from gnomAD. Functional prediction tools that agree on a benign effect are Rosetta and premPS, whereas the majority of predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify the change as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Taken together, the preponderance of evidence indicates that D332H is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.339168	Structured	0.336528	Uncertain	0.537	0.445	0.375											-13.255	Likely Pathogenic	0.973	Likely Pathogenic	Likely Pathogenic	1.50	Ambiguous	0.4	-0.28	Likely Benign	0.61	Ambiguous	0.22	Likely Benign	0.505	Likely Pathogenic	-5.63	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.23	Pathogenic	0.01	Affected			0.1005	0.4542		1	-1	0.3	22.05
c.994G>T	D332Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D332Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and premPS, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a likely pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. Overall, the majority of evidence points to a pathogenic impact for D332Y, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.339168	Structured	0.336528	Uncertain	0.537	0.445	0.375											-14.210	Likely Pathogenic	0.966	Likely Pathogenic	Likely Pathogenic	1.15	Ambiguous	0.6	-0.07	Likely Benign	0.54	Ambiguous	0.41	Likely Benign	0.485	Likely Benign	-7.33	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.20	Pathogenic	0.00	Affected			0.0372	0.4018		-4	-3	2.2	48.09
c.995A>C	D332A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and Rosetta, while the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.339168	Structured	0.336528	Uncertain	0.537	0.445	0.375											-12.290	Likely Pathogenic	0.876	Likely Pathogenic	Ambiguous	1.19	Ambiguous	0.2	0.32	Likely Benign	0.76	Ambiguous	0.54	Ambiguous	0.458	Likely Benign	-6.45	Deleterious	1.000	Probably Damaging	0.998	Probably Damaging	1.24	Pathogenic	0.02	Affected			0.2998	0.4176		0	-2	5.3	-44.01
c.995A>T	D332V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, and premPS, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain results come from FoldX, Rosetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.339168	Structured	0.336528	Uncertain	0.537	0.445	0.375											-13.710	Likely Pathogenic	0.933	Likely Pathogenic	Ambiguous	1.39	Ambiguous	0.1	-0.52	Ambiguous	0.44	Likely Benign	0.50	Likely Benign	0.484	Likely Benign	-7.27	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.21	Pathogenic	0.03	Affected			0.0573	0.4132		-2	-3	7.7	-15.96
c.998A>T	K333I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K333I missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX and premPS, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta and Foldetta give uncertain results. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.311707	Structured	0.330781	Uncertain	0.537	0.447	0.500											-14.517	Likely Pathogenic	0.985	Likely Pathogenic	Likely Pathogenic	0.30	Likely Benign	0.0	0.95	Ambiguous	0.63	Ambiguous	0.43	Likely Benign	0.544	Likely Pathogenic	-6.49	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.89	Pathogenic	0.03	Affected			0.0931	0.3521		-2	-3	8.4	-15.01
c.99A>C	Q33H 2D AIThe SynGAP1 missense variant Q33H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.436712	Uncertain	0.342	0.860	0.375											-0.450	Likely Benign	0.133	Likely Benign	Likely Benign										0.054	Likely Benign	-0.95	Neutral	0.704	Possibly Damaging	0.198	Benign	4.16	Benign	0.00	Affected			0.1856	0.4509		3	0	0.3	9.01
c.99A>T	Q33H 2D AIThe SynGAP1 missense variant Q33H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.707965	Disordered	0.436712	Uncertain	0.342	0.860	0.375											-0.450	Likely Benign	0.133	Likely Benign	Likely Benign										0.054	Likely Benign	-0.95	Neutral	0.704	Possibly Damaging	0.198	Benign	4.16	Benign	0.00	Affected			0.1856	0.4509		3	0	0.3	9.01
c.9G>C	R3S 2D AIThe SynGAP1 missense variant R3S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect. The prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.550331	Binding	0.358	0.920	0.875											-2.296	Likely Benign	0.310	Likely Benign	Likely Benign										0.111	Likely Benign	-0.53	Neutral	0.115	Benign	0.013	Benign	4.02	Benign	0.00	Affected	4.32	1	0.3148	0.4732		-1	0	3.7	-69.11
c.9G>T	R3S 2D AIThe SynGAP1 missense variant R3S is reported in gnomAD (ID 6‑33420273‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus itself is benign; Foldetta results are not available. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign		0.538167	Disordered	0.550331	Binding	0.358	0.920	0.875								6-33420273-G-T	1	6.50e-7	-2.296	Likely Benign	0.310	Likely Benign	Likely Benign										0.111	Likely Benign	-0.53	Neutral	0.115	Benign	0.013	Benign	4.02	Benign	0.00	Affected	4.32	1	0.3148	0.4732		-1	0	3.7	-69.11
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	-0.37	Likely Benign	0.1	-0.53	Ambiguous	-0.45	Likely Benign	0.39	Likely Benign	0.247	Likely Benign	-2.62	Deleterious	0.999	Probably Damaging	0.995	Probably Damaging	1.76	Pathogenic	0.07	Tolerated			0.4647	0.0976		3	2	-0.6	28.01
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	0.68	Ambiguous	0.1	0.72	Ambiguous	0.70	Ambiguous	0.14	Likely Benign	0.184	Likely Benign	-3.30	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.89	Pathogenic	0.11	Tolerated			0.2598	0.4005		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	1.01	Ambiguous	0.1	0.44	Likely Benign	0.73	Ambiguous	0.20	Likely Benign	0.194	Likely Benign	-4.77	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	2.01	Pathogenic	0.10	Tolerated			0.3000	0.3554		-3	-2	4.1	-99.14
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	3.23	Destabilizing	0.8	5.73	Destabilizing	4.48	Destabilizing	0.43	Likely Benign	0.250	Likely Benign	-4.22	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.69	Pathogenic	0.09	Tolerated			0.1866	0.4497		0	-2	2.9	-59.07
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	0.00	Likely Benign	0.0	-0.15	Likely Benign	-0.08	Likely Benign	0.52	Ambiguous	0.038	Likely Benign	-2.01	Neutral	0.002	Benign	0.005	Benign	1.69	Pathogenic	0.12	Tolerated	3.38	22	0.4899	0.1240		2	3	-0.6	28.01
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	-0.30	Likely Benign	0.2	1.07	Ambiguous	0.39	Likely Benign	0.12	Likely Benign	0.142	Likely Benign	-2.36	Neutral	0.997	Probably Damaging	0.992	Probably Damaging	1.70	Pathogenic	0.07	Tolerated			0.3913	0.1134		3	2	-0.6	28.01
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	0.12	Likely Benign	0.1	0.36	Likely Benign	0.24	Likely Benign	-0.02	Likely Benign	0.280	Likely Benign	-4.38	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.87	Pathogenic	0.11	Tolerated			0.2945	0.1315		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	0.12	Likely Benign	0.1	0.36	Likely Benign	0.24	Likely Benign	-0.02	Likely Benign	0.280	Likely Benign	-4.38	Deleterious	0.999	Probably Damaging	0.997	Probably Damaging	1.87	Pathogenic	0.11	Tolerated			0.2945	0.1315		1	0	0.4	-14.07
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	1.22	Ambiguous	0.3	1.11	Ambiguous	1.17	Ambiguous	0.16	Likely Benign	0.479	Likely Benign	-5.74	Deleterious	0.625	Possibly Damaging	0.192	Benign	1.73	Pathogenic	0.11	Tolerated			0.3830	0.5988		0	-2	5.3	-44.01
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	0.85	Ambiguous	0.3	0.31	Likely Benign	0.58	Ambiguous	-0.01	Likely Benign	0.080	Likely Benign	-1.95	Neutral	0.002	Benign	0.005	Benign	1.85	Pathogenic	0.55	Tolerated			0.1584	0.5397		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	0.85	Ambiguous	0.3	0.31	Likely Benign	0.58	Ambiguous	-0.01	Likely Benign	0.080	Likely Benign	-1.95	Neutral	0.002	Benign	0.005	Benign	1.85	Pathogenic	0.55	Tolerated			0.1584	0.5397		3	2	0.0	14.03
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	0.32	Likely Benign	0.0	0.10	Likely Benign	0.21	Likely Benign	-0.04	Likely Benign	0.512	Likely Pathogenic	-4.73	Deleterious	0.991	Probably Damaging	0.795	Possibly Damaging	1.94	Pathogenic	0.10	Tolerated			0.1900	0.3020		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	-0.15	Likely Benign	0.1	0.46	Likely Benign	0.16	Likely Benign	0.08	Likely Benign	0.134	Likely Benign	-2.05	Neutral	0.046	Benign	0.040	Benign	1.94	Pathogenic	0.48	Tolerated			0.4197	0.0976		3	2	-0.6	28.01
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	0.84	Ambiguous	0.2	0.96	Ambiguous	0.90	Ambiguous	-0.54	Ambiguous	0.105	Likely Benign	0.62	Neutral	0.454	Possibly Damaging	0.192	Benign	1.93	Pathogenic	0.47	Tolerated	3.42	13	0.1740	0.7297		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	0.32	Likely Benign	0.5	-0.58	Ambiguous	-0.13	Likely Benign	0.46	Likely Benign	0.279	Likely Benign	-1.48	Neutral	0.891	Possibly Damaging	0.575	Possibly Damaging	1.91	Pathogenic	0.25	Tolerated			0.2178	0.5468		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	0.15	Likely Benign	0.0	0.27	Likely Benign	0.21	Likely Benign	-0.46	Likely Benign	0.083	Likely Benign	1.62	Neutral	0.007	Benign	0.008	Benign	1.93	Pathogenic	0.51	Tolerated	3.42	13	0.2852	0.6309		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	0.63	Ambiguous	0.4	1.55	Ambiguous	1.09	Ambiguous	0.06	Likely Benign	0.138	Likely Benign	-0.33	Neutral	0.625	Possibly Damaging	0.252	Benign	1.91	Pathogenic	0.39	Tolerated			0.1418	0.2160		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	0.66	Ambiguous	0.2	1.44	Ambiguous	1.05	Ambiguous	0.50	Likely Benign	0.044	Likely Benign	-0.34	Neutral	0.267	Benign	0.127	Benign	1.92	Pathogenic	0.42	Tolerated			0.2355	0.4470		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	0.69	Ambiguous	0.3	0.32	Likely Benign	0.51	Ambiguous	0.40	Likely Benign	0.102	Likely Benign	-1.81	Neutral	0.801	Possibly Damaging	0.315	Benign	2.09	Pathogenic	0.57	Tolerated			0.1197	0.5780		0	0	2.4	28.05
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	0.41	Likely Benign	0.3	-1.46	Ambiguous	-0.53	Ambiguous	-0.67	Ambiguous	0.343	Likely Benign	0.73	Neutral	0.454	Possibly Damaging	0.192	Benign	0.37	Pathogenic	0.72	Tolerated			0.2416	0.4215		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	0.28	Likely Benign	0.2	-1.25	Ambiguous	-0.49	Likely Benign	0.18	Likely Benign	0.379	Likely Benign	-1.03	Neutral	0.801	Possibly Damaging	0.417	Benign	0.34	Pathogenic	0.17	Tolerated			0.0838	0.3618		-3	-2	-4.1	99.14
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	0.28	Likely Benign	0.1	-1.32	Ambiguous	-0.52	Ambiguous	-0.04	Likely Benign	0.295	Likely Benign	-0.11	Neutral	0.454	Possibly Damaging	0.192	Benign	0.34	Pathogenic	0.25	Tolerated	3.42	13	0.1727	0.2241		-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	0.16	Likely Benign	0.4	-1.23	Ambiguous	-0.54	Ambiguous	-0.03	Likely Benign	0.239	Likely Benign	-1.13	Neutral	0.625	Possibly Damaging	0.192	Benign	0.43	Pathogenic	0.15	Tolerated			0.3562	0.3979		1	0	2.2	14.03
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	1.63	Ambiguous	0.1	1.33	Ambiguous	1.48	Ambiguous	0.73	Ambiguous	0.453	Likely Benign	-3.61	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.72	Pathogenic	0.06	Tolerated	3.37	25	0.2491	0.0862		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	1.60	Ambiguous	0.1	2.70	Destabilizing	2.15	Destabilizing	0.13	Likely Benign	0.668	Likely Pathogenic	-7.19	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	1.71	Pathogenic	0.07	Tolerated			0.3925	0.0862		-4	-3	-2.2	-48.09
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	-0.13	Likely Benign	0.1	0.42	Likely Benign	0.15	Likely Benign	0.05	Likely Benign	0.160	Likely Benign	-2.67	Deleterious	0.999	Probably Damaging	0.992	Probably Damaging	2.03	Pathogenic	0.26	Tolerated			0.2626	0.3615		7	3	4.1	-16.00
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	-0.27	Likely Benign	0.0	-0.04	Likely Benign	-0.16	Likely Benign	-0.39	Likely Benign	0.020	Likely Benign	-0.14	Neutral	0.159	Benign	0.084	Benign	1.98	Pathogenic	0.27	Tolerated	3.37	25	0.1095	0.4536		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.
c.1027G>C	V343L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V343L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict benign or likely benign. Only FATHMM predicts a pathogenic outcome, while FoldX and Rosetta provide uncertain results and are therefore not considered decisive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of ClinVar reporting. 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											-6.268	Likely Benign	0.310	Likely Benign	Likely Benign	-0.93	Ambiguous	0.2	0.66	Ambiguous	-0.14	Likely Benign	0.16	Likely Benign	0.033	Likely Benign	-1.09	Neutral	0.005	Benign	0.013	Benign	2.12	Pathogenic	0.64	Tolerated			0.1361	0.5008		2	1	-0.4	14.03
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	5.11	Destabilizing	0.4	4.23	Destabilizing	4.67	Destabilizing	0.58	Ambiguous	0.873	Likely Pathogenic	-5.38	Deleterious	1.000	Probably Damaging	0.999	Probably Damaging	-0.32	Pathogenic	0.10	Tolerated			0.3964	0.5685		1	0	2.2	14.03
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	0.75	Ambiguous	0.1	0.80	Ambiguous	0.78	Ambiguous	0.54	Ambiguous	0.101	Likely Benign	-0.97	Neutral	0.802	Possibly Damaging	0.122	Benign	1.73	Pathogenic	0.07	Tolerated			0.0677	0.3246		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	1.31	Ambiguous	0.0	0.18	Likely Benign	0.75	Ambiguous	0.92	Ambiguous	0.126	Likely Benign	-1.96	Neutral	0.802	Possibly Damaging	0.277	Benign	1.77	Pathogenic	0.06	Tolerated			0.1411	0.3455		2	1	0.4	-14.03
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	0.05	Likely Benign	0.2	1.10	Ambiguous	0.58	Ambiguous	0.60	Ambiguous	0.384	Likely Benign	-2.68	Deleterious	0.994	Probably Damaging	0.970	Probably Damaging	1.58	Pathogenic	0.09	Tolerated			0.1237	0.5348		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	0.05	Likely Benign	0.2	1.10	Ambiguous	0.58	Ambiguous	0.60	Ambiguous	0.386	Likely Benign	-2.68	Deleterious	0.994	Probably Damaging	0.970	Probably Damaging	1.58	Pathogenic	0.09	Tolerated			0.1237	0.5348		2	1	-0.4	14.03
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	0.55	Ambiguous	0.0	0.28	Likely Benign	0.42	Likely Benign	0.65	Ambiguous	0.236	Likely Benign	-2.41	Neutral	0.627	Possibly Damaging	0.139	Benign	1.63	Pathogenic	0.12	Tolerated			0.2000	0.5350		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	0.34	Likely Benign	0.1	0.70	Ambiguous	0.52	Ambiguous	0.70	Ambiguous	0.093	Likely Benign	-1.52	Neutral	0.031	Benign	0.016	Benign	1.68	Pathogenic	0.42	Tolerated	3.37	25	0.4032	0.4615		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	0.65	Ambiguous	0.1	0.82	Ambiguous	0.74	Ambiguous	-0.10	Likely Benign	0.104	Likely Benign	0.63	Neutral	0.002	Benign	0.001	Benign	1.75	Pathogenic	0.86	Tolerated			0.3205	0.4707		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	0.41	Likely Benign	0.1	0.46	Likely Benign	0.44	Likely Benign	-0.06	Likely Benign	0.059	Likely Benign	1.96	Neutral	0.001	Benign	0.001	Benign	1.67	Pathogenic	0.60	Tolerated	3.37	25	0.1070	0.4359		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	0.65	Ambiguous	0.1	0.82	Ambiguous	0.74	Ambiguous	-0.10	Likely Benign	0.054	Likely Benign	0.63	Neutral	0.002	Benign	0.001	Benign	1.75	Pathogenic	0.86	Tolerated			0.3205	0.4707		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	-0.79	Ambiguous	0.1	-0.94	Ambiguous	-0.87	Ambiguous	0.29	Likely Benign	0.079	Likely Benign	-3.12	Deleterious	0.627	Possibly Damaging	0.139	Benign	1.70	Pathogenic	0.08	Tolerated			0.0885	0.6298		0	-1	5.2	12.05
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	-0.58	Ambiguous	0.0	0.04	Likely Benign	-0.27	Likely Benign	0.24	Likely Benign	0.072	Likely Benign	-0.75	Neutral	0.264	Benign	0.030	Benign	1.89	Pathogenic	0.62	Tolerated			0.1088	0.4953		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	-0.58	Ambiguous	0.0	0.04	Likely Benign	-0.27	Likely Benign	0.24	Likely Benign	0.072	Likely Benign	-0.75	Neutral	0.264	Benign	0.030	Benign	1.89	Pathogenic	0.62	Tolerated			0.1088	0.4953		2	1	-0.4	14.03
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	2.46	Destabilizing	0.1	3.13	Destabilizing	2.80	Destabilizing	2.23	Destabilizing	0.175	Likely Benign	-3.42	Deleterious	0.622	Possibly Damaging	0.152	Benign	1.59	Pathogenic	0.14	Tolerated			0.3223	0.2437		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	1.37	Ambiguous	0.1	2.56	Destabilizing	1.97	Ambiguous	0.76	Ambiguous	0.246	Likely Benign	-6.12	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	1.57	Pathogenic	0.07	Tolerated			0.1615	0.6238		0	-1	0.9	3.99
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	1.92	Ambiguous	0.1	2.28	Destabilizing	2.10	Destabilizing	0.87	Ambiguous	0.277	Likely Benign	-6.13	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	1.66	Pathogenic	0.06	Tolerated	3.37	25	0.3771	0.5756		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	0.98	Ambiguous	0.1	1.87	Ambiguous	1.43	Ambiguous	0.91	Ambiguous	0.345	Likely Benign	-6.40	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	1.54	Pathogenic	0.06	Tolerated			0.1480	0.4766		0	-1	-1.9	31.01
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	-0.65	Ambiguous	0.1	0.40	Likely Benign	-0.13	Likely Benign	0.69	Ambiguous	0.075	Likely Benign	-1.95	Neutral	0.868	Possibly Damaging	0.383	Benign	1.63	Pathogenic	0.06	Tolerated			0.1005	0.4359		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	-1.31	Ambiguous	0.1	-0.34	Likely Benign	-0.83	Ambiguous	0.36	Likely Benign	0.042	Likely Benign	-1.63	Neutral	0.068	Benign	0.022	Benign	2.37	Pathogenic	0.27	Tolerated			0.1173	0.4958		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	-1.31	Ambiguous	0.1	-0.34	Likely Benign	-0.83	Ambiguous	0.36	Likely Benign	0.042	Likely Benign	-1.63	Neutral	0.068	Benign	0.022	Benign	2.37	Pathogenic	0.27	Tolerated			0.1173	0.4958		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	1.73	Ambiguous	0.2	2.61	Destabilizing	2.17	Destabilizing	1.93	Destabilizing	0.304	Likely Benign	-4.67	Deleterious	0.976	Probably Damaging	0.559	Possibly Damaging	1.61	Pathogenic	0.08	Tolerated			0.1078	0.1568		-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	1.42	Ambiguous	0.0	1.97	Ambiguous	1.70	Ambiguous	2.07	Destabilizing	0.096	Likely Benign	-2.73	Deleterious	0.435	Benign	0.115	Benign	1.64	Pathogenic	0.55	Tolerated			0.3207	0.2967		0	0	-2.4	-28.05
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	0.22	Likely Benign	0.0	0.80	Ambiguous	0.51	Ambiguous	0.49	Likely Benign	0.040	Likely Benign	-2.42	Neutral	0.524	Possibly Damaging	0.138	Benign	1.71	Pathogenic	0.06	Tolerated			0.1337	0.6713		1	0	-2.5	30.03
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	0.24	Likely Benign	0.0	0.25	Likely Benign	0.25	Likely Benign	0.27	Likely Benign	0.016	Likely Benign	-1.42	Neutral	0.080	Benign	0.023	Benign	1.88	Pathogenic	0.13	Tolerated			0.2558	0.5334		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	-0.02	Likely Benign	0.0	-0.12	Likely Benign	-0.07	Likely Benign	0.49	Likely Benign	0.114	Likely Benign	-3.61	Deleterious	0.842	Possibly Damaging	0.321	Benign	1.77	Pathogenic	0.11	Tolerated			0.1535	0.1386		0	-2	-5.3	44.01
c.1054A>C	T352P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T352P has no ClinVar entry and is not reported in gnomAD. Prediction tools that converge on a benign outcome include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, FATHMM, and Rosetta. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. Overall, the balance of evidence favors a benign interpretation; 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	0.137348	Structured	0.367886	Uncertain	0.926	0.329	0.000											-3.562	Likely Benign	0.138	Likely Benign	Likely Benign	1.04	Ambiguous	0.1	2.57	Destabilizing	1.81	Ambiguous	0.51	Ambiguous	0.159	Likely Benign	-2.31	Neutral	0.627	Possibly Damaging	0.196	Benign	1.72	Pathogenic	0.20	Tolerated			0.2244	0.5968		0	-1	-0.9	-3.99
c.1054A>G	T352A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, 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) yields a benign verdict; and Foldetta, integrating FoldX‑MD (benign) and Rosetta (uncertain), reports benign stability. Overall, the preponderance of evidence indicates that T352A is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.137348	Structured	0.367886	Uncertain	0.926	0.329	0.000											-1.952	Likely Benign	0.055	Likely Benign	Likely Benign	0.12	Likely Benign	0.0	0.50	Ambiguous	0.31	Likely Benign	0.45	Likely Benign	0.032	Likely Benign	-1.09	Neutral	0.031	Benign	0.024	Benign	1.73	Pathogenic	0.29	Tolerated			0.4341	0.4938		1	0	2.5	-30.03
c.1054A>T	T352S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). 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. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is 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, also reports a benign effect. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, 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	0.137348	Structured	0.367886	Uncertain	0.926	0.329	0.000											-1.670	Likely Benign	0.062	Likely Benign	Likely Benign	-0.09	Likely Benign	0.0	0.26	Likely Benign	0.09	Likely Benign	-0.01	Likely Benign	0.098	Likely Benign	0.57	Neutral	0.002	Benign	0.002	Benign	1.81	Pathogenic	1.00	Tolerated			0.3583	0.4880		1	1	-0.1	-14.03
c.1055C>A	T352N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352N is listed in ClinVar as Benign (ClinVar ID 590151.0) and is present in the gnomAD database (gnomAD ID 6‑33437960‑C‑A). 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) uniformly report a benign effect, whereas only FATHMM predicts pathogenicity. 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 stability outputs, is also benign. No predictions or stability analyses are missing or inconclusive. 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	0.137348	Structured	0.367886	Uncertain	0.926	0.329	0.000					Likely Benign		1	6-33437960-C-A	2	1.24e-6	-4.817	Likely Benign	0.117	Likely Benign	Likely Benign	0.20	Likely Benign	0.0	-0.04	Likely Benign	0.08	Likely Benign	0.45	Likely Benign	0.027	Likely Benign	-0.92	Neutral	0.255	Benign	0.057	Benign	1.75	Pathogenic	0.19	Tolerated	3.37	25	0.1311	0.4358		0	0	-2.8	13.00	208.4	-14.5	-0.2	0.1	-0.1	0.0		X						Potentially Benign	Thr352 is located in a short α helical section within a loop connecting two β strands (res. Gly341-Pro349, res. Thr359-Pro364) originating from two different anti-parallel β sheets of the C2 domain. In the WT simulations, the side chain hydroxyl and backbone amide groups of Thr354 form hydrogen bonds with the backbone carbonyl group of Pro349 at the end of the preceding β strand. This arrangement likely stabilizes the α helical section and aids in folding, keeping the short secondary structure element intact in the variant simulations. However, the carboxamide group of the Asn352 side chain does not form hydrogen bonds with the backbone carbonyl group of Pro349. Instead, it packs against the cyclic ring and forms hydrogen bonds with the phenol group of the Tyr363 side chain in the other β strand.
c.1055C>G	T352S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). 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. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is 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, also reports a benign effect. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, 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	0.137348	Structured	0.367886	Uncertain	0.926	0.329	0.000											-1.670	Likely Benign	0.062	Likely Benign	Likely Benign	-0.09	Likely Benign	0.0	0.26	Likely Benign	0.09	Likely Benign	-0.01	Likely Benign	0.104	Likely Benign	0.57	Neutral	0.002	Benign	0.002	Benign	1.81	Pathogenic	1.00	Tolerated			0.3583	0.4880		1	1	-0.1	-14.03
c.1055C>T	T352I 2D AISynGAP1 T352I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, premPS, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. With seven benign versus five pathogenic predictions and two high‑accuracy benign versus one pathogenic, the evidence leans toward a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.137348	Structured	0.367886	Uncertain	0.926	0.329	0.000											-8.023	Likely Pathogenic	0.321	Likely Benign	Likely Benign	-0.54	Ambiguous	0.7	0.43	Likely Benign	-0.06	Likely Benign	0.09	Likely Benign	0.099	Likely Benign	-3.02	Deleterious	0.627	Possibly Damaging	0.196	Benign	1.67	Pathogenic	0.14	Tolerated			0.1009	0.6484		0	-1	5.2	12.05
c.1057C>G	L353V 2D AISynGAP1 missense variant L353V is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools predicting pathogenicity are FoldX and FATHMM, while Rosetta gives an uncertain result. The SGM‑Consensus, which aggregates the 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 benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the balance of evidence favors a benign effect; 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	C2	0.137348	Structured	0.373584	Uncertain	0.926	0.315	0.000											-2.100	Likely Benign	0.078	Likely Benign	Likely Benign	3.08	Destabilizing	0.9	1.48	Ambiguous	2.28	Destabilizing	-0.45	Likely Benign	0.074	Likely Benign	1.54	Neutral	0.002	Benign	0.002	Benign	1.46	Pathogenic	0.89	Tolerated			0.1567	0.3829		2	1	0.4	-14.03
c.1060G>A	A354T 2D AIThe SynGAP1 missense variant A354T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic effect. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign result. No predictions or folding‑stability analyses are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.203355	Structured	0.381329	Uncertain	0.882	0.335	0.125											-2.812	Likely Benign	0.070	Likely Benign	Likely Benign	0.37	Likely Benign	0.7	0.11	Likely Benign	0.24	Likely Benign	-0.52	Ambiguous	0.097	Likely Benign	1.72	Neutral	0.002	Benign	0.001	Benign	1.75	Pathogenic	0.45	Tolerated			0.1731	0.6496		1	0	-2.5	30.03
c.1060G>T	A354S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A354S 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 predict benign. Only FATHMM predicts a pathogenic outcome. 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, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Taken together, the overwhelming majority of evidence indicates that A354S 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	C2	0.203355	Structured	0.381329	Uncertain	0.882	0.335	0.125											-3.005	Likely Benign	0.081	Likely Benign	Likely Benign	0.02	Likely Benign	0.1	0.27	Likely Benign	0.15	Likely Benign	-0.10	Likely Benign	0.071	Likely Benign	0.28	Neutral	0.005	Benign	0.001	Benign	1.76	Pathogenic	0.21	Tolerated			0.2829	0.5117		1	1	-2.6	16.00
c.1061C>A	A354D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A354D is 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), and SIFT. Those that predict a pathogenic effect are FATHMM and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, and Rosetta) return uncertain results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors a pathogenic interpretation. Foldetta’s stability prediction is uncertain. Overall, the majority of consensus tools lean toward a benign effect, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.203355	Structured	0.381329	Uncertain	0.882	0.335	0.125											-7.914	In-Between	0.725	Likely Pathogenic	Likely Benign	0.22	Likely Benign	0.1	1.10	Ambiguous	0.66	Ambiguous	0.57	Ambiguous	0.087	Likely Benign	-1.49	Neutral	0.255	Benign	0.053	Benign	1.75	Pathogenic	0.07	Tolerated			0.1759	0.1345		0	-2	-5.3	44.01
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	1.00	Ambiguous	0.1	0.79	Ambiguous	0.90	Ambiguous	1.04	Destabilizing	0.292	Likely Benign	-5.28	Deleterious	0.993	Probably Damaging	0.982	Probably Damaging	1.84	Pathogenic	0.07	Tolerated			0.2891	0.4491		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	1.02	Ambiguous	0.0	1.80	Ambiguous	1.41	Ambiguous	1.06	Destabilizing	0.271	Likely Benign	-6.20	Deleterious	0.993	Probably Damaging	0.982	Probably Damaging	1.95	Pathogenic	0.08	Tolerated			0.3505	0.3793		-3	-2	4.1	-99.14
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	0.14	Likely Benign	0.2	0.31	Likely Benign	0.23	Likely Benign	0.31	Likely Benign	0.126	Likely Benign	-1.47	Neutral	0.495	Possibly Damaging	0.169	Benign	4.25	Benign	0.15	Tolerated			0.2052	0.3266		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	-0.23	Likely Benign	0.4	-0.27	Likely Benign	-0.25	Likely Benign	0.48	Likely Benign	0.208	Likely Benign	-1.90	Neutral	0.495	Possibly Damaging	0.169	Benign	4.22	Benign	0.08	Tolerated			0.2782	0.1976		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	-0.33	Likely Benign	0.2	0.08	Likely Benign	-0.13	Likely Benign	-0.07	Likely Benign	0.140	Likely Benign	-1.71	Neutral	0.936	Possibly Damaging	0.388	Benign	4.19	Benign	0.14	Tolerated	3.39	22	0.1010	0.4658		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	0.17	Likely Benign	0.9	3.52	Destabilizing	1.85	Ambiguous	-0.06	Likely Benign	0.197	Likely Benign	-2.70	Deleterious	0.936	Possibly Damaging	0.469	Possibly Damaging	4.18	Benign	0.17	Tolerated			0.2433	0.4468		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	-0.10	Likely Benign	0.3	1.07	Ambiguous	0.49	Likely Benign	0.32	Likely Benign	0.107	Likely Benign	-1.03	Neutral	0.495	Possibly Damaging	0.095	Benign	4.22	Benign	0.59	Tolerated			0.2147	0.2818		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	-0.18	Likely Benign	0.1	0.14	Likely Benign	-0.02	Likely Benign	0.10	Likely Benign	0.203	Likely Benign	-3.39	Deleterious	0.704	Possibly Damaging	0.169	Benign	4.20	Benign	0.25	Tolerated			0.1084	0.5971		-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	0.06	Likely Benign	0.2	-0.03	Likely Benign	0.02	Likely Benign	-0.35	Likely Benign	0.025	Likely Benign	1.42	Neutral	0.013	Benign	0.007	Benign	4.49	Benign	1.00	Tolerated			0.1716	0.3850		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	0.06	Likely Benign	0.2	-0.03	Likely Benign	0.02	Likely Benign	-0.35	Likely Benign	0.025	Likely Benign	1.42	Neutral	0.013	Benign	0.007	Benign	4.49	Benign	1.00	Tolerated			0.1716	0.3850		3	0	-0.3	-9.01
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	0.93	Ambiguous	0.2	1.66	Ambiguous	1.30	Ambiguous	0.95	Ambiguous	0.393	Likely Benign	-4.45	Deleterious	0.993	Probably Damaging	0.977	Probably Damaging	4.07	Benign	0.13	Tolerated			0.2331	0.2821		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	0.18	Likely Benign	0.1	1.62	Ambiguous	0.90	Ambiguous	0.97	Ambiguous	0.290	Likely Benign	-4.21	Deleterious	0.982	Probably Damaging	0.952	Probably Damaging	4.12	Benign	0.22	Tolerated			0.2555	0.3602		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	1.42	Ambiguous	0.2	1.68	Ambiguous	1.55	Ambiguous	0.93	Ambiguous	0.408	Likely Benign	-5.32	Deleterious	0.993	Probably Damaging	0.968	Probably Damaging	4.09	Benign	0.18	Tolerated			0.2222	0.2978		-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	0.42	Likely Benign	0.1	0.21	Likely Benign	0.32	Likely Benign	0.84	Ambiguous	0.231	Likely Benign	-2.17	Neutral	0.993	Probably Damaging	0.952	Probably Damaging	4.05	Benign	0.36	Tolerated			0.1467	0.2697		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	2.32	Destabilizing	0.2	1.97	Ambiguous	2.15	Destabilizing	1.14	Destabilizing	0.493	Likely Benign	-6.48	Deleterious	0.998	Probably Damaging	0.986	Probably Damaging	4.07	Benign	0.20	Tolerated			0.3891	0.1333		-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	1.68	Ambiguous	0.1	2.19	Destabilizing	1.94	Ambiguous	1.18	Destabilizing	0.460	Likely Benign	-6.36	Deleterious	0.999	Probably Damaging	0.993	Probably Damaging	4.02	Benign	0.06	Tolerated			0.2364	0.1800		-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	0.18	Likely Benign	0.1	1.62	Ambiguous	0.90	Ambiguous	0.97	Ambiguous	0.215	Likely Benign	-4.21	Deleterious	0.982	Probably Damaging	0.952	Probably Damaging	4.12	Benign	0.22	Tolerated			0.2555	0.3602		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	0.18	Likely Benign	0.1	1.62	Ambiguous	0.90	Ambiguous	0.97	Ambiguous	0.215	Likely Benign	-4.21	Deleterious	0.982	Probably Damaging	0.952	Probably Damaging	4.12	Benign	0.22	Tolerated			0.2555	0.3602		2	0	1.0	-34.02
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	0.97	Ambiguous	0.1	1.27	Ambiguous	1.12	Ambiguous	0.68	Ambiguous	0.248	Likely Benign	-2.36	Neutral	0.627	Possibly Damaging	0.091	Benign	1.78	Pathogenic	0.14	Tolerated			0.2352	0.5611		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	0.09	Likely Benign	0.0	0.73	Ambiguous	0.41	Likely Benign	0.45	Likely Benign	0.103	Likely Benign	-0.73	Neutral	0.000	Benign	0.001	Benign	1.79	Pathogenic	0.34	Tolerated			0.4215	0.4713		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	0.50	Ambiguous	0.0	0.73	Ambiguous	0.62	Ambiguous	0.66	Ambiguous	0.100	Likely Benign	-1.87	Neutral	0.146	Benign	0.024	Benign	1.76	Pathogenic	0.27	Tolerated			0.3637	0.4996		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	-0.65	Ambiguous	0.1	0.66	Ambiguous	0.01	Likely Benign	0.75	Ambiguous	0.163	Likely Benign	-2.23	Neutral	0.255	Benign	0.045	Benign	1.79	Pathogenic	0.24	Tolerated			0.1618	0.3483		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	-0.74	Ambiguous	0.1	-0.20	Likely Benign	-0.47	Likely Benign	0.54	Ambiguous	0.157	Likely Benign	-2.86	Deleterious	0.627	Possibly Damaging	0.091	Benign	1.75	Pathogenic	0.23	Tolerated			0.1323	0.3748		-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	-0.66	Ambiguous	0.1	-0.64	Ambiguous	-0.65	Ambiguous	-0.63	Ambiguous	0.085	Likely Benign	0.77	Neutral	0.070	Benign	0.006	Benign	1.80	Pathogenic	0.23	Tolerated	3.38	24	0.1123	0.5921		-1	0	5.2	12.05
c.1080G>C	E360D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360D is 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 SIFT. In contrast, a majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are therefore not considered evidence for either side. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus remains Likely Pathogenic, while Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E360D. 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	C2	0.250310	Structured	0.421183	Uncertain	0.955	0.498	0.250											-9.383	Likely Pathogenic	0.971	Likely Pathogenic	Likely Pathogenic	1.00	Ambiguous	0.0	0.63	Ambiguous	0.82	Ambiguous	0.11	Likely Benign	0.290	Likely Benign	-2.76	Deleterious	0.994	Probably Damaging	0.970	Probably Damaging	1.77	Pathogenic	0.07	Tolerated			0.2339	0.5735		3	2	0.0	-14.03
c.1080G>T	E360D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, premPS, and SIFT, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.250310	Structured	0.421183	Uncertain	0.955	0.498	0.250											-9.383	Likely Pathogenic	0.971	Likely Pathogenic	Likely Pathogenic	1.00	Ambiguous	0.0	0.63	Ambiguous	0.82	Ambiguous	0.11	Likely Benign	0.290	Likely Benign	-2.76	Deleterious	0.994	Probably Damaging	0.970	Probably Damaging	1.77	Pathogenic	0.07	Tolerated			0.2339	0.5735		3	2	0.0	-14.03
c.1081C>A	Q361K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q361K is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic outcome. High‑accuracy tools that integrate structural and evolutionary information—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta (combining FoldX‑MD and Rosetta outputs)—all return benign predictions. 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 annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.305330	Structured	0.427593	Uncertain	0.945	0.534	0.250											-5.147	Likely Benign	0.286	Likely Benign	Likely Benign	0.17	Likely Benign	0.0	0.36	Likely Benign	0.27	Likely Benign	-0.44	Likely Benign	0.217	Likely Benign	1.29	Neutral	0.969	Probably Damaging	0.930	Probably Damaging	1.73	Pathogenic	1.00	Tolerated			0.1739	0.4701		1	1	-0.4	0.04
c.1081C>G	Q361E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q361E is 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain predictions come from Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta remains uncertain. Taken together, the majority of evidence supports a benign impact for Q361E, 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	0.305330	Structured	0.427593	Uncertain	0.945	0.534	0.250											-7.544	In-Between	0.289	Likely Benign	Likely Benign	0.29	Likely Benign	0.0	1.02	Ambiguous	0.66	Ambiguous	0.21	Likely Benign	0.153	Likely Benign	-0.89	Neutral	0.969	Probably Damaging	0.930	Probably Damaging	1.70	Pathogenic	0.26	Tolerated			0.1217	0.3018		2	2	0.0	0.98
c.1082A>G	Q361R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q361R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, SIFT, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus itself is benign; and Foldetta, which integrates FoldX‑MD (Uncertain) and Rosetta (Benign), yields a benign prediction. Overall, the consensus of available computational evidence indicates that the variant is most likely benign, 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	C2	0.305330	Structured	0.427593	Uncertain	0.945	0.534	0.250											-6.898	Likely Benign	0.289	Likely Benign	Likely Benign	-0.88	Ambiguous	0.0	-0.07	Likely Benign	-0.48	Likely Benign	-0.20	Likely Benign	0.296	Likely Benign	-0.56	Neutral	0.987	Probably Damaging	0.953	Probably Damaging	1.71	Pathogenic	0.41	Tolerated			0.1321	0.2955		1	1	-1.0	28.06
c.1082A>T	Q361L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q361L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools (8 benign vs 5 pathogenic) favor a benign effect, and this consensus does not contradict the absence of a ClinVar classification. Thus, the variant is most likely benign based on current predictions, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.305330	Structured	0.427593	Uncertain	0.945	0.534	0.250											-10.678	Likely Pathogenic	0.238	Likely Benign	Likely Benign	0.12	Likely Benign	0.1	0.46	Likely Benign	0.29	Likely Benign	0.21	Likely Benign	0.406	Likely Benign	-3.95	Deleterious	0.987	Probably Damaging	0.953	Probably Damaging	1.71	Pathogenic	0.06	Tolerated			0.0720	0.5213		-2	-2	7.3	-14.97
c.1088A>T	Y363F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y363F is 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; premPS 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, seven tools predict benign while four predict pathogenic, with no evidence of pathogenicity from the most accurate methods. Therefore, 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.		C2	0.321458	Structured	0.435392	Uncertain	0.954	0.586	0.125											-6.621	Likely Benign	0.114	Likely Benign	Likely Benign	-0.23	Likely Benign	0.0	0.42	Likely Benign	0.10	Likely Benign	0.58	Ambiguous	0.293	Likely Benign	-3.42	Deleterious	0.997	Probably Damaging	0.970	Probably Damaging	1.74	Pathogenic	0.18	Tolerated			0.2781	0.3583		7	3	4.1	-16.00
c.1090C>A	P364T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P364T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Four tools (FoldX, Foldetta, premPS, ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (five benign versus four pathogenic) lean toward a benign classification, and this assessment 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.		C2	0.390993	Structured	0.439474	Uncertain	0.942	0.590	0.250											-7.951	In-Between	0.230	Likely Benign	Likely Benign	1.18	Ambiguous	0.6	0.47	Likely Benign	0.83	Ambiguous	0.53	Ambiguous	0.342	Likely Benign	-5.60	Deleterious	1.000	Probably Damaging	0.996	Probably Damaging	1.60	Pathogenic	0.09	Tolerated			0.1660	0.5726		0	-1	0.9	3.99
c.1090C>G	P364A 2D 3DClick to see structure in 3D Viewer AISynGAP1 P364A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Stability‑based methods (FoldX, Rosetta, premPS) give uncertain outcomes, and Foldetta is unavailable. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, does not provide a definitive result. Overall, the predictions are discordant; the majority of tools lean toward pathogenicity, but a substantial subset suggests benign. Based on the predictions, the variant is most likely pathogenic, and this does not contradict ClinVar status because there is no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.390993	Structured	0.439474	Uncertain	0.942	0.590	0.250											-8.077	Likely Pathogenic	0.135	Likely Benign	Likely Benign	0.79	Ambiguous	0.0	0.69	Ambiguous	0.74	Ambiguous	0.60	Ambiguous	0.320	Likely Benign	-6.10	Deleterious	0.999	Probably Damaging	0.994	Probably Damaging	1.56	Pathogenic	0.06	Tolerated			0.3496	0.5186		1	-1	3.4	-26.04
c.1091C>G	P364R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P364R missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; Foldetta’s stability analysis is uncertain. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) indicate 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	C2	0.390993	Structured	0.439474	Uncertain	0.942	0.590	0.250											-12.652	Likely Pathogenic	0.715	Likely Pathogenic	Likely Benign	0.95	Ambiguous	0.7	0.88	Ambiguous	0.92	Ambiguous	0.73	Ambiguous	0.416	Likely Benign	-6.76	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	1.57	Pathogenic	0.12	Tolerated			0.1520	0.3977		0	-2	-2.9	59.07
c.1091C>T	P364L 2D 3DClick to see structure in 3D Viewer AISynGAP1 P364L is reported in gnomAD (ID 6‑33437996‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, SIFT, AlphaMissense‑Optimized, and Foldetta; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Three tools—FoldX, Rosetta, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign. Overall, the balance of evidence slightly favors a benign effect, and this conclusion 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	0.390993	Structured	0.439474	Uncertain	0.942	0.590	0.250								6-33437996-C-T			-10.620	Likely Pathogenic	0.457	Ambiguous	Likely Benign	0.88	Ambiguous	0.9	-0.73	Ambiguous	0.08	Likely Benign	0.31	Likely Benign	0.387	Likely Benign	-7.78	Deleterious	1.000	Probably Damaging	0.997	Probably Damaging	1.54	Pathogenic	0.18	Tolerated	3.39	20	0.2200	0.6207		-3	-3	5.4	16.04
c.1093G>A	V365I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365I is reported in gnomAD (variant ID 6‑33437998‑G‑A) but has no ClinVar entry. Functional 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 indicate benign or tolerated. 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 (majority vote) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) reports a benign effect. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, V365I 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	0.414856	Structured	0.441505	Uncertain	0.923	0.608	0.250								6-33437998-G-A	4	2.65e-6	-5.943	Likely Benign	0.155	Likely Benign	Likely Benign	-0.65	Ambiguous	0.2	-0.11	Likely Benign	-0.38	Likely Benign	0.13	Likely Benign	0.036	Likely Benign	-0.47	Neutral	0.451	Benign	0.137	Benign	1.76	Pathogenic	0.10	Tolerated	3.38	21	0.0657	0.4447		3	4	0.3	14.03
c.1093G>C	V365L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365L is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess sequence conservation and functional impact uniformly classify the substitution as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity; only FoldX and Rosetta report uncertain stability changes, which are treated as unavailable evidence. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, reports a benign effect on protein folding stability. Based on the collective predictions, 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	C2	0.414856	Structured	0.441505	Uncertain	0.923	0.608	0.250											-6.141	Likely Benign	0.265	Likely Benign	Likely Benign	-0.72	Ambiguous	0.2	0.74	Ambiguous	0.01	Likely Benign	0.35	Likely Benign	0.065	Likely Benign	-1.71	Neutral	0.005	Benign	0.003	Benign	2.50	Benign	0.25	Tolerated	3.38	21	0.0852	0.5309		1	2	-0.4	14.03
c.1093G>T	V365L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365L is catalogued in gnomAD (ID 6‑33437998‑G‑T) but has no ClinVar entry. Across the available in‑silico predictors, the majority (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly classify the change as benign; only FoldX and Rosetta report uncertain stability effects, which are treated as unavailable evidence. High‑accuracy assessments reinforce this benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from the unanimous benign vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a benign impact. Consequently, the variant is most likely benign based on current computational evidence, and 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 Benign	C2	0.414856	Structured	0.441505	Uncertain	0.923	0.608	0.250								6-33437998-G-T	5	3.31e-6	-6.141	Likely Benign	0.265	Likely Benign	Likely Benign	-0.72	Ambiguous	0.2	0.74	Ambiguous	0.01	Likely Benign	0.35	Likely Benign	0.065	Likely Benign	-1.71	Neutral	0.005	Benign	0.003	Benign	2.50	Benign	0.25	Tolerated	3.38	21	0.0852	0.5309		1	2	-0.4	14.03
c.1096A>C	T366P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366P is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors leans toward a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign) all classify the substitution as tolerated. In contrast, polyPhen‑2 HumDiv, FATHMM, Rosetta, and the Foldetta stability analysis predict a damaging or pathogenic outcome. FoldX reports an uncertain effect and is therefore not considered evidence. High‑accuracy tools give mixed results: AlphaMissense‑Optimized and the SGM‑Consensus both indicate benign, whereas Foldetta predicts pathogenic. Overall, the majority of predictors (8 benign vs. 4 pathogenic) support a benign classification, and this is consistent with the lack of ClinVar evidence. 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.	Likely Benign	C2	0.414856	Structured	0.441902	Uncertain	0.897	0.642	0.250											-6.483	Likely Benign	0.226	Likely Benign	Likely Benign	1.75	Ambiguous	0.5	3.10	Destabilizing	2.43	Destabilizing	0.47	Likely Benign	0.150	Likely Benign	-2.49	Neutral	0.627	Possibly Damaging	0.139	Benign	1.70	Pathogenic	0.24	Tolerated			0.2250	0.6251		0	-1	-0.9	-3.99
c.1096A>G	T366A 2D AIThe SynGAP1 missense variant T366A is not reported in ClinVar and is absent from gnomAD. Consensus among most in silico predictors indicates a benign effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated. Only FATHMM predicts a pathogenic outcome, while Foldetta, premPS, and Rosetta are inconclusive and are treated as unavailable evidence. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign, and Foldetta provides no definitive stability change. Overall, the computational evidence overwhelmingly favors a benign classification, and this is consistent with the absence of any ClinVar assertion. Therefore, the variant is most likely benign, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.414856	Structured	0.441902	Uncertain	0.897	0.642	0.250											-3.983	Likely Benign	0.082	Likely Benign	Likely Benign	0.21	Likely Benign	0.5	0.86	Ambiguous	0.54	Ambiguous	0.51	Ambiguous	0.046	Likely Benign	-0.94	Neutral	0.031	Benign	0.016	Benign	1.73	Pathogenic	0.45	Tolerated			0.4141	0.4785		1	0	2.5	-30.03
c.1096A>T	T366S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366S 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and Foldetta are inconclusive. 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 conflict with 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 Benign	C2	0.414856	Structured	0.441902	Uncertain	0.897	0.642	0.250											-3.273	Likely Benign	0.085	Likely Benign	Likely Benign	0.13	Likely Benign	0.1	0.92	Ambiguous	0.53	Ambiguous	0.27	Likely Benign	0.058	Likely Benign	0.00	Neutral	0.005	Benign	0.001	Benign	1.73	Pathogenic	0.78	Tolerated			0.3549	0.4878		1	1	-0.1	-14.03
c.1097C>A	T366N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change T366N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, 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 FATHMM—suggest a pathogenic effect, while premPS remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies the variant as benign. Taken together, the majority of evidence supports a benign impact and is consistent with the absence of any ClinVar pathogenic annotation. 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	C2	0.414856	Structured	0.441902	Uncertain	0.897	0.642	0.250											-5.694	Likely Benign	0.176	Likely Benign	Likely Benign	0.06	Likely Benign	0.0	0.36	Likely Benign	0.21	Likely Benign	0.92	Ambiguous	0.038	Likely Benign	-1.72	Neutral	0.454	Possibly Damaging	0.038	Benign	1.72	Pathogenic	0.34	Tolerated			0.1595	0.4934		0	0	-2.8	13.00
c.1097C>G	T366S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366S 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and Foldetta are inconclusive. 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 conflict with 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 Benign	C2	0.414856	Structured	0.441902	Uncertain	0.897	0.642	0.250											-3.273	Likely Benign	0.085	Likely Benign	Likely Benign	0.13	Likely Benign	0.1	0.92	Ambiguous	0.53	Ambiguous	0.27	Likely Benign	0.051	Likely Benign	0.00	Neutral	0.005	Benign	0.001	Benign	1.73	Pathogenic	0.78	Tolerated			0.3549	0.4878		1	1	-0.1	-14.03
c.1097C>T	T366I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366I is reported in gnomAD (6‑33438002‑C‑T) and has no ClinVar entry. 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 score (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) yields a benign majority; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. No other tools provide conclusive evidence for pathogenicity. Based on the aggregate 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	C2	0.414856	Structured	0.441902	Uncertain	0.897	0.642	0.250								6-33438002-C-T	1	6.20e-7	-4.921	Likely Benign	0.279	Likely Benign	Likely Benign	-0.62	Ambiguous	0.1	-0.31	Likely Benign	-0.47	Likely Benign	-0.14	Likely Benign	0.058	Likely Benign	-1.22	Neutral	0.002	Benign	0.001	Benign	1.77	Pathogenic	0.26	Tolerated	3.38	23	0.1062	0.6215		-1	0	5.2	12.05
c.1099C>A	L367M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L367M 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 outcome are polyPhen‑2 HumDiv and FATHMM. The remaining predictions are uncertain: Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also likely benign; Foldetta remains inconclusive. Overall, the majority of evidence supports a benign classification, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.370445	Structured	0.441805	Uncertain	0.790	0.657	0.250											-4.968	Likely Benign	0.111	Likely Benign	Likely Benign	0.22	Likely Benign	0.1	0.92	Ambiguous	0.57	Ambiguous	-0.04	Likely Benign	0.078	Likely Benign	0.12	Neutral	0.947	Possibly Damaging	0.360	Benign	1.63	Pathogenic	0.13	Tolerated			0.1402	0.3947		4	2	-1.9	18.03
c.1099C>G	L367V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L367V 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, and 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 preponderance of evidence points to a benign effect for L367V, 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	0.370445	Structured	0.441805	Uncertain	0.790	0.657	0.250											-2.383	Likely Benign	0.066	Likely Benign	Likely Benign	1.48	Ambiguous	0.2	1.72	Ambiguous	1.60	Ambiguous	0.15	Likely Benign	0.040	Likely Benign	0.19	Neutral	0.410	Benign	0.104	Benign	1.67	Pathogenic	0.13	Tolerated			0.2321	0.3285		2	1	0.4	-14.03
c.1102C>T	P368S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P368S is 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 and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and FATHMM. The remaining methods (FoldX, Rosetta, Foldetta, premPS) yield 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 uncertain, so these do not alter the overall interpretation. Overall, the majority of evidence points to a benign impact. Thus, the variant is most likely benign, and this conclusion does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.363090	Structured	0.439989	Uncertain	0.580	0.677	0.250											-4.790	Likely Benign	0.247	Likely Benign	Likely Benign	1.68	Ambiguous	0.4	1.60	Ambiguous	1.64	Ambiguous	0.52	Ambiguous	0.090	Likely Benign	-5.12	Deleterious	0.384	Benign	0.113	Benign	1.80	Pathogenic	0.10	Tolerated			0.3700	0.5635		1	-1	0.8	-10.04
c.1105A>C	T369P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T369P 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, 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, while FoldX and Foldetta are uncertain. 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 T369P, 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	0.468512	Structured	0.437011	Uncertain	0.417	0.707	0.500											-2.743	Likely Benign	0.066	Likely Benign	Likely Benign	1.20	Ambiguous	2.1	0.18	Likely Benign	0.69	Ambiguous	0.17	Likely Benign	0.138	Likely Benign	-2.09	Neutral	0.396	Benign	0.142	Benign	1.83	Pathogenic	0.16	Tolerated			0.2589	0.6046		0	-1	-0.9	-3.99
c.1105A>G	T369A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T369A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and Foldetta 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 further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that T369A 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	0.468512	Structured	0.437011	Uncertain	0.417	0.707	0.500											-1.957	Likely Benign	0.056	Likely Benign	Likely Benign	0.09	Likely Benign	0.1	1.18	Ambiguous	0.64	Ambiguous	0.26	Likely Benign	0.090	Likely Benign	-1.93	Neutral	0.012	Benign	0.016	Benign	1.72	Pathogenic	0.30	Tolerated			0.4538	0.5053		1	0	2.5	-30.03
c.1105A>T	T369S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T369S is 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, also predicts benign. No predictions or 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 (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.468512	Structured	0.437011	Uncertain	0.417	0.707	0.500											-2.018	Likely Benign	0.071	Likely Benign	Likely Benign	-0.07	Likely Benign	0.1	0.34	Likely Benign	0.14	Likely Benign	0.18	Likely Benign	0.097	Likely Benign	-0.81	Neutral	0.001	Benign	0.001	Benign	1.78	Pathogenic	0.39	Tolerated			0.3746	0.4994		1	1	-0.1	-14.03
c.1106C>A	T369K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T369K is 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FATHMM and AlphaMissense‑Default. Foldetta and Rosetta give uncertain results, which 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 (two benign vs two pathogenic). Foldetta’s stability prediction is uncertain. Overall, the majority of evidence (nine benign vs two 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.		C2	0.468512	Structured	0.437011	Uncertain	0.417	0.707	0.500											-5.884	Likely Benign	0.616	Likely Pathogenic	Likely Benign	-0.10	Likely Benign	0.1	1.13	Ambiguous	0.52	Ambiguous	0.27	Likely Benign	0.102	Likely Benign	-1.87	Neutral	0.118	Benign	0.054	Benign	1.84	Pathogenic	0.34	Tolerated			0.1387	0.3855		0	-1	-3.2	27.07
c.1106C>G	T369R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T369R is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438011‑C‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FATHMM and AlphaMissense‑Default. Rosetta and Foldetta are uncertain, so their results 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 evidence (nine benign vs two 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.		C2	0.468512	Structured	0.437011	Uncertain	0.417	0.707	0.500								6-33438011-C-G	3	1.93e-6	-6.772	Likely Benign	0.571	Likely Pathogenic	Likely Benign	-0.27	Likely Benign	0.1	1.48	Ambiguous	0.61	Ambiguous	0.29	Likely Benign	0.148	Likely Benign	-2.15	Neutral	0.244	Benign	0.107	Benign	1.72	Pathogenic	0.32	Tolerated	3.42	19	0.1217	0.3737		-1	-1	-3.8	55.08
c.1106C>T	T369I 2D AIThe SynGAP1 missense variant T369I is 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, providing no definitive evidence. 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; there is no conflict with ClinVar status, which contains no entry for this variant. 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	0.468512	Structured	0.437011	Uncertain	0.417	0.707	0.500											-6.759	Likely Benign	0.289	Likely Benign	Likely Benign	0.60	Ambiguous	0.8	1.41	Ambiguous	1.01	Ambiguous	-0.08	Likely Benign	0.078	Likely Benign	-2.37	Neutral	0.396	Benign	0.142	Benign	1.72	Pathogenic	0.13	Tolerated			0.1106	0.7207		0	-1	5.2	12.05
c.1108G>A	G370S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G370S is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6‑33438013‑G‑A). Consensus predictions from standard in silico tools cluster into two groups: benign (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (FoldX, FATHMM). Two tools report uncertainty: Rosetta and Foldetta. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Benign; Foldetta remains uncertain. 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.	Likely Benign	C2	0.461924	Structured	0.434325	Uncertain	0.359	0.720	0.500					Uncertain		1	6-33438013-G-A	15	9.31e-6	-3.533	Likely Benign	0.081	Likely Benign	Likely Benign	2.83	Destabilizing	2.0	1.05	Ambiguous	1.94	Ambiguous	-0.02	Likely Benign	0.282	Likely Benign	0.47	Neutral	0.000	Benign	0.000	Benign	1.33	Pathogenic	0.77	Tolerated	3.42	19	0.2664	0.5086		1	0	-0.4	30.03	196.6	-49.6	0.9	2.2	-0.1	0.4								Uncertain	Gly370 is located in the Gly-rich Ω loop (res. Pro364- Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because, the Ω loop is assumed to be directly interacting with the membrane, it is only seen to move arbitrarily throughout the WT solvent simulations. The Ω loop is potentially playing a crucial loop in the SynGAP-membrane complex association, stability and dynamics, regardless, this aspect cannot be addressed through the solvent simulations only. The Ω-loops are known to have a major role in protein functions that requires flexibility and thus, they are rich in glycines, prolines and to a lesser extent, hydrophilic residues to ensure maximum flexibility. Thus, Ser370 in the variant is potentially tolerated in the Ω loop. However, since the effect on the Gly-rich Ω loop dynamics can only be well-studied through the SynGAP-membrane complex, no definite conclusions can be withdrawn.
c.1108G>C	G370R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370R 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, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are SGM‑Consensus, FoldX, ESM1b, FATHMM, AlphaMissense‑Default, and Foldetta; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Overall, the balance of evidence leans toward pathogenicity, with two of the three high‑accuracy tools supporting this view. The variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.461924	Structured	0.434325	Uncertain	0.359	0.720	0.500											-8.375	Likely Pathogenic	0.731	Likely Pathogenic	Likely Benign	3.62	Destabilizing	3.7	1.72	Ambiguous	2.67	Destabilizing	0.22	Likely Benign	0.373	Likely Benign	-0.80	Neutral	0.016	Benign	0.002	Benign	1.32	Pathogenic	0.55	Tolerated			0.0978	0.4313		-3	-2	-4.1	99.14
c.1108G>T	G370C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370C has no ClinVar entry and is not reported in gnomAD. Functional prediction tools fall into two groups: benign predictions come from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from REVEL, FoldX, Rosetta, Foldetta, and FATHMM. ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. No prediction or stability result is missing. Overall, the majority of tools predict a benign effect, and the high‑accuracy consensus also leans benign, while only one high‑accuracy method (Foldetta) suggests pathogenicity. Thus, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.461924	Structured	0.434325	Uncertain	0.359	0.720	0.500											-7.071	In-Between	0.119	Likely Benign	Likely Benign	3.01	Destabilizing	2.1	2.03	Destabilizing	2.52	Destabilizing	0.29	Likely Benign	0.511	Likely Pathogenic	-1.00	Neutral	0.353	Benign	0.010	Benign	1.32	Pathogenic	0.06	Tolerated			0.1245	0.4412		-3	-3	2.9	46.09
c.1109G>A	G370D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370D is 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 FoldX, FATHMM, and AlphaMissense‑Default. The high‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts benign, Foldetta (a folding‑stability method that integrates FoldX‑MD and Rosetta outputs) predicts pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it yields an equal split of benign and pathogenic calls. Overall, the majority of evidence points to a benign impact, 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	0.461924	Structured	0.434325	Uncertain	0.359	0.720	0.500											-5.332	Likely Benign	0.597	Likely Pathogenic	Likely Benign	3.64	Destabilizing	3.8	0.83	Ambiguous	2.24	Destabilizing	0.30	Likely Benign	0.372	Likely Benign	-0.44	Neutral	0.007	Benign	0.001	Benign	1.32	Pathogenic	0.64	Tolerated			0.1632	0.1494		1	-1	-3.1	58.04
c.1109G>C	G370A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370A 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, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from FoldX, Foldetta, and FATHMM, while Rosetta remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicating a likely benign outcome, and Foldetta suggesting a pathogenic impact via combined FoldX‑MD and Rosetta stability analysis. Overall, the majority of evidence points to a benign effect, with only a minority of tools predicting pathogenicity. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.461924	Structured	0.434325	Uncertain	0.359	0.720	0.500											-3.334	Likely Benign	0.080	Likely Benign	Likely Benign	2.44	Destabilizing	1.3	1.62	Ambiguous	2.03	Destabilizing	-0.14	Likely Benign	0.304	Likely Benign	0.54	Neutral	0.000	Benign	0.000	Benign	1.33	Pathogenic	0.79	Tolerated			0.3883	0.5247		1	0	2.2	14.03
c.1109G>T	G370V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster into two groups: benign (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Benign) and pathogenic (FoldX, Rosetta, Foldetta, and FATHMM). High‑accuracy assessments further refine this picture: AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic outcome. Overall, the majority of evidence points toward a benign 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 Benign	C2	0.461924	Structured	0.434325	Uncertain	0.359	0.720	0.500											-5.328	Likely Benign	0.094	Likely Benign	Likely Benign	4.98	Destabilizing	3.8	5.61	Destabilizing	5.30	Destabilizing	-0.43	Likely Benign	0.427	Likely Benign	0.03	Neutral	0.000	Benign	0.000	Benign	1.32	Pathogenic	0.29	Tolerated			0.1306	0.4198		-1	-3	4.6	42.08
c.1111A>C	S371R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change S371R is catalogued in gnomAD (ID 6‑33438016‑A‑C) but has no ClinVar entry. Functional prediction programs largely agree on a benign effect: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus score (Likely Benign) all report a non‑pathogenic outcome. Only AlphaMissense‑Default predicts a pathogenic effect, while FoldX and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) is benign. Taken together, the majority of evidence supports a benign classification, and this 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	0.444081	Structured	0.432086	Uncertain	0.294	0.746	0.375								6-33438016-A-C			-6.415	Likely Benign	0.762	Likely Pathogenic	Likely Benign	0.51	Ambiguous	1.2	-0.25	Likely Benign	0.13	Likely Benign	0.57	Ambiguous	0.295	Likely Benign	-1.17	Neutral	0.396	Benign	0.099	Benign	5.35	Benign	0.26	Tolerated	3.52	18	0.1362	0.4131		-1	0	-3.7	69.11
c.1111A>G	S371G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371G is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined—REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized—classifies the substitution as benign. No pathogenic predictions are present. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also 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 is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.444081	Structured	0.432086	Uncertain	0.294	0.746	0.375											-2.073	Likely Benign	0.053	Likely Benign	Likely Benign	0.47	Likely Benign	0.3	0.49	Likely Benign	0.48	Likely Benign	0.35	Likely Benign	0.164	Likely Benign	-1.32	Neutral	0.213	Benign	0.067	Benign	4.63	Benign	0.17	Tolerated			0.3192	0.5295		1	0	0.4	-30.03
c.1112G>A	S371N 2D AIThe SynGAP1 missense variant S371N is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta remains uncertain. High‑accuracy assessments are consistent: AlphaMissense‑Optimized classifies the variant as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign 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	C2	0.444081	Structured	0.432086	Uncertain	0.294	0.746	0.375											-5.950	Likely Benign	0.160	Likely Benign	Likely Benign	0.21	Likely Benign	0.8	-0.59	Ambiguous	-0.19	Likely Benign	0.25	Likely Benign	0.208	Likely Benign	-0.31	Neutral	0.666	Possibly Damaging	0.067	Benign	4.64	Benign	0.27	Tolerated			0.2068	0.5100		1	1	-2.7	27.03
c.1112G>C	S371T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371T is not reported in ClinVar and is absent from gnomAD. All available in silico predictors classify the substitution as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.444081	Structured	0.432086	Uncertain	0.294	0.746	0.375											-4.512	Likely Benign	0.072	Likely Benign	Likely Benign	0.38	Likely Benign	0.1	-0.27	Likely Benign	0.06	Likely Benign	0.05	Likely Benign	0.173	Likely Benign	-0.65	Neutral	0.213	Benign	0.067	Benign	4.64	Benign	0.22	Tolerated			0.2245	0.6462		1	1	0.1	14.03
c.1112G>T	S371I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX and Rosetta, 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) also yields benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a benign effect. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.444081	Structured	0.432086	Uncertain	0.294	0.746	0.375											-6.888	Likely Benign	0.207	Likely Benign	Likely Benign	0.50	Ambiguous	0.4	-0.50	Ambiguous	0.00	Likely Benign	-0.11	Likely Benign	0.433	Likely Benign	-1.06	Neutral	0.028	Benign	0.016	Benign	4.62	Benign	0.07	Tolerated			0.1423	0.5924		-1	-2	5.3	26.08
c.1113T>A	S371R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the substitution as benign, while AlphaMissense‑Optimized also predicts benign. Only AlphaMissense‑Default indicates a pathogenic outcome; FoldX and premPS are inconclusive. 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 (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the majority of evidence supports a benign impact, and this 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	0.444081	Structured	0.432086	Uncertain	0.294	0.746	0.375											-6.415	Likely Benign	0.762	Likely Pathogenic	Likely Benign	0.51	Ambiguous	1.2	-0.25	Likely Benign	0.13	Likely Benign	0.57	Ambiguous	0.344	Likely Benign	-1.17	Neutral	0.396	Benign	0.099	Benign	5.35	Benign	0.26	Tolerated	3.52	18	0.1362	0.4131		-1	0	-3.7	69.11
c.1113T>G	S371R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371R is reported in gnomAD (variant ID 6‑33438018‑T‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM‑Consensus is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No prediction or stability result is missing or inconclusive. Overall, the evidence strongly favors a benign classification, and this 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	0.444081	Structured	0.432086	Uncertain	0.294	0.746	0.375								6-33438018-T-G	1	1.18e-6	-6.415	Likely Benign	0.762	Likely Pathogenic	Likely Benign	0.51	Ambiguous	1.2	-0.25	Likely Benign	0.13	Likely Benign	0.57	Ambiguous	0.340	Likely Benign	-1.17	Neutral	0.396	Benign	0.099	Benign	5.35	Benign	0.26	Tolerated	3.52	18	0.1362	0.4131		-1	0	-3.7	69.11
c.1115G>A	G372E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372E is 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are REVEL, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while Foldetta predicts pathogenic. The SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split and is treated as unavailable. Overall, the majority of evidence (seven benign vs. five pathogenic) supports 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.		C2	0.433034	Structured	0.430335	Uncertain	0.322	0.774	0.375											-6.682	Likely Benign	0.604	Likely Pathogenic	Likely Benign	1.58	Ambiguous	0.4	2.91	Destabilizing	2.25	Destabilizing	0.34	Likely Benign	0.566	Likely Pathogenic	-0.81	Neutral	0.001	Benign	0.001	Benign	-0.74	Pathogenic	0.08	Tolerated			0.1606	0.4103		0	-2	-3.1	72.06
c.1115G>T	G372V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372V is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (variant ID 6-33438020-G-T). Functional prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are REVEL, FoldX, Rosetta, FATHMM, and Foldetta. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, while Foldetta (combining FoldX‑MD and Rosetta stability outputs) indicates a pathogenic effect. Overall, the majority of predictions support a benign classification, and there is no conflict with ClinVar status because the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.433034	Structured	0.430335	Uncertain	0.322	0.774	0.375								6-33438020-G-T			-5.898	Likely Benign	0.126	Likely Benign	Likely Benign	2.81	Destabilizing	0.3	2.91	Destabilizing	2.86	Destabilizing	0.02	Likely Benign	0.535	Likely Pathogenic	-0.92	Neutral	0.003	Benign	0.000	Benign	-0.74	Pathogenic	0.06	Tolerated	3.52	18	0.1663	0.4198		-3	-1	4.6	42.08
c.1120T>A	S374T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S374T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on benign impact include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain but does not indicate destabilization. Overall, the evidence strongly favors a benign effect for S374T, 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	C2	0.642678	Disordered	0.428948	Uncertain	0.333	0.812	0.625											-5.415	Likely Benign	0.088	Likely Benign	Likely Benign	0.39	Likely Benign	0.1	0.80	Ambiguous	0.60	Ambiguous	-0.02	Likely Benign	0.176	Likely Benign	-0.47	Neutral	0.118	Benign	0.049	Benign	5.32	Benign	0.12	Tolerated			0.2212	0.6466		1	1	0.1	14.03
c.1123G>A	G375R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G375R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized, whereas tools that predict pathogenicity are FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. 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 (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions (7 pathogenic vs. 5 benign) indicate a likely pathogenic effect, and 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	0.604312	Disordered	0.428340	Uncertain	0.301	0.836	0.625											-8.955	Likely Pathogenic	0.609	Likely Pathogenic	Likely Benign	2.97	Destabilizing	1.3	12.66	Destabilizing	7.82	Destabilizing	0.36	Likely Benign	0.497	Likely Benign	-1.15	Neutral	0.845	Possibly Damaging	0.523	Possibly Damaging	1.32	Pathogenic	0.11	Tolerated			0.1335	0.4513		-3	-2	-4.1	99.14
c.1123G>C	G375R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G375R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, whereas Foldetta indicates a destabilizing, pathogenic change, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as likely pathogenic. Overall, the majority of evidence 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	C2	0.604312	Disordered	0.428340	Uncertain	0.301	0.836	0.625											-8.955	Likely Pathogenic	0.609	Likely Pathogenic	Likely Benign	2.97	Destabilizing	1.3	12.66	Destabilizing	7.82	Destabilizing	0.36	Likely Benign	0.497	Likely Benign	-1.15	Neutral	0.845	Possibly Damaging	0.523	Possibly Damaging	1.32	Pathogenic	0.11	Tolerated			0.1335	0.4513		-3	-2	-4.1	99.14
c.1124G>A	G375E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G375E is 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, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, FATHMM, and AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenic, and Foldetta also predicts pathogenic. Overall, the majority of tools, including the high‑accuracy ones, indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.604312	Disordered	0.428340	Uncertain	0.301	0.836	0.625											-7.780	In-Between	0.600	Likely Pathogenic	Likely Benign	2.89	Destabilizing	1.4	9.47	Destabilizing	6.18	Destabilizing	0.45	Likely Benign	0.545	Likely Pathogenic	-1.07	Neutral	0.845	Possibly Damaging	0.244	Benign	1.32	Pathogenic	0.09	Tolerated			0.1619	0.4299		0	-2	-3.1	72.06
c.1124G>C	G375A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G375A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the majority of evidence points to a benign effect; 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	0.604312	Disordered	0.428340	Uncertain	0.301	0.836	0.625											-5.986	Likely Benign	0.096	Likely Benign	Likely Benign	2.52	Destabilizing	1.0	3.16	Destabilizing	2.84	Destabilizing	-0.09	Likely Benign	0.419	Likely Benign	-0.61	Neutral	0.020	Benign	0.008	Benign	1.33	Pathogenic	0.27	Tolerated			0.3991	0.5242		1	0	2.2	14.03
c.1124G>T	G375V 2D AIThe SynGAP1 missense variant G375V is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions (premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Benign) and pathogenic predictions (REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, and FATHMM). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also benign, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a pathogenic effect. No prediction is missing or inconclusive. Overall, the majority of tools and the consensus score suggest a benign effect, but the Foldetta result introduces uncertainty. 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.	Likely Benign	C2	0.604312	Disordered	0.428340	Uncertain	0.301	0.836	0.625											-6.149	Likely Benign	0.149	Likely Benign	Likely Benign	3.93	Destabilizing	3.5	7.55	Destabilizing	5.74	Destabilizing	0.02	Likely Benign	0.547	Likely Pathogenic	-0.92	Neutral	0.845	Possibly Damaging	0.186	Benign	1.32	Pathogenic	0.06	Tolerated			0.1653	0.4193		-1	-3	4.6	42.08
c.1126G>A	G376S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G376S is reported in gnomAD (ID 6‑33438031‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Pathogenic predictions arise from FoldX, polyPhen‑2 (HumDiv and HumVar), and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates benign, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of evidence points to a benign effect; this conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.680603	Disordered	0.428979	Uncertain	0.326	0.869	0.625								6-33438031-G-A	1	6.21e-7	-4.913	Likely Benign	0.087	Likely Benign	Likely Benign	2.30	Destabilizing	0.5	-0.45	Likely Benign	0.93	Ambiguous	0.32	Likely Benign	0.471	Likely Benign	-0.73	Neutral	1.000	Probably Damaging	0.998	Probably Damaging	1.33	Pathogenic	0.22	Tolerated	4.32	12	0.2831	0.4801		0	1	-0.4	30.03
c.1126G>C	G376R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G376R is 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, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Foldetta reports an uncertain outcome. 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 (8 pathogenic vs. 5 benign) and the consensus from 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.	Likely Pathogenic	C2	0.680603	Disordered	0.428979	Uncertain	0.326	0.869	0.625											-8.500	Likely Pathogenic	0.658	Likely Pathogenic	Likely Benign	3.48	Destabilizing	1.3	-0.46	Likely Benign	1.51	Ambiguous	0.30	Likely Benign	0.589	Likely Pathogenic	-1.21	Neutral	1.000	Probably Damaging	0.999	Probably Damaging	1.32	Pathogenic	0.09	Tolerated			0.1316	0.4027		-3	-2	-4.1	99.14
c.1127G>A	G376D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G376D is 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, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. The remaining tools—Rosetta, Foldetta, premPS, and ESM1b—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain stability change. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.680603	Disordered	0.428979	Uncertain	0.326	0.869	0.625											-7.125	In-Between	0.569	Likely Pathogenic	Likely Benign	3.10	Destabilizing	1.1	-1.08	Ambiguous	1.01	Ambiguous	0.52	Ambiguous	0.572	Likely Pathogenic	-1.05	Neutral	1.000	Probably Damaging	0.998	Probably Damaging	1.32	Pathogenic	0.09	Tolerated			0.1938	0.1235		1	-1	-3.1	58.04
c.1129A>C	M377L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377L is catalogued in gnomAD (ID 6‑33438034‑A‑C) but has no entry in ClinVar. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign. Only Rosetta yields an uncertain result, which is treated as unavailable. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, reports benign. No tool predicts pathogenicity. Consequently, the variant is most likely benign, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.675549	Disordered	0.431183	Uncertain	0.324	0.884	0.625								6-33438034-A-C	1	1.95e-6	-2.394	Likely Benign	0.082	Likely Benign	Likely Benign	0.13	Likely Benign	0.1	0.69	Ambiguous	0.41	Likely Benign	0.16	Likely Benign	0.175	Likely Benign	-0.32	Neutral	0.000	Benign	0.001	Benign	5.46	Benign	0.58	Tolerated	4.32	12	0.2516	0.4885		2	4	1.9	-18.03
c.1129A>G	M377V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377V is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (gnomAD ID 6‑33438034‑A‑G). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable. High‑accuracy assessments confirm the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, while Foldetta remains uncertain. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.675549	Disordered	0.431183	Uncertain	0.324	0.884	0.625								6-33438034-A-G			-1.507	Likely Benign	0.073	Likely Benign	Likely Benign	0.92	Ambiguous	0.3	1.27	Ambiguous	1.10	Ambiguous	0.48	Likely Benign	0.161	Likely Benign	-0.31	Neutral	0.000	Benign	0.000	Benign	5.46	Benign	0.15	Tolerated	4.32	12	0.4530	0.4096		1	2	2.3	-32.06
c.1129A>T	M377L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377L is reported in gnomAD (variant ID 6‑33438034‑A‑T) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus all classify the change as benign or likely benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. No inconclusive or missing predictions are present. Based on the collective evidence, the variant is most likely benign, and this assessment 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	0.675549	Disordered	0.431183	Uncertain	0.324	0.884	0.625								6-33438034-A-T			-2.394	Likely Benign	0.082	Likely Benign	Likely Benign	0.13	Likely Benign	0.1	0.69	Ambiguous	0.41	Likely Benign	0.16	Likely Benign	0.186	Likely Benign	-0.32	Neutral	0.000	Benign	0.001	Benign	5.46	Benign	0.58	Tolerated	4.32	12	0.2516	0.4885		2	4	1.9	-18.03
c.1130T>A	M377K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377K is 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, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are Rosetta and Foldetta. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome, while premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. 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	0.675549	Disordered	0.431183	Uncertain	0.324	0.884	0.625											-3.718	Likely Benign	0.226	Likely Benign	Likely Benign	0.20	Likely Benign	0.2	4.44	Destabilizing	2.32	Destabilizing	0.62	Ambiguous	0.440	Likely Benign	-0.26	Neutral	0.002	Benign	0.003	Benign	5.46	Benign	0.07	Tolerated			0.2423	0.1671		0	-1	-5.8	-3.02
c.1130T>G	M377R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377R is present in gnomAD (6‑33438035‑T‑G) and has no ClinVar entry. Prediction tools that report a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are Rosetta and Foldetta. The high‑accuracy consensus (SGM‑Consensus) is “Likely Benign,” derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—all of which are benign. AlphaMissense‑Optimized also predicts benign, whereas Foldetta predicts pathogenic. Overall, the majority of evidence points to a benign impact, 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 Benign	C2	0.675549	Disordered	0.431183	Uncertain	0.324	0.884	0.625								6-33438035-T-G			-3.150	Likely Benign	0.219	Likely Benign	Likely Benign	0.49	Likely Benign	0.4	4.81	Destabilizing	2.65	Destabilizing	0.69	Ambiguous	0.471	Likely Benign	-0.64	Neutral	0.004	Benign	0.009	Benign	5.46	Benign	0.18	Tolerated	4.32	12	0.2369	0.1918		-1	0	-6.4	24.99
c.1131G>A	M377I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377I (ClinVar ID 3803473.0, status = Uncertain) is present in gnomAD (ID = 6‑33438036‑G‑A). 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 in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the computational evidence strongly favors a benign classification, which does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.675549	Disordered	0.431183	Uncertain	0.324	0.884	0.625					Uncertain		1	6-33438036-G-A	1	6.23e-7	-2.895	Likely Benign	0.212	Likely Benign	Likely Benign	0.76	Ambiguous	0.3	0.54	Ambiguous	0.65	Ambiguous	0.24	Likely Benign	0.227	Likely Benign	-0.41	Neutral	0.000	Benign	0.001	Benign	5.46	Benign	0.26	Tolerated	4.32	12	0.2240	0.4133		1	2	2.6	-18.03
c.1131G>C	M377I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus classify the change as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result and is therefore not considered evidence for pathogenicity. Overall, the collective evidence points to a benign impact for M377I, 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	C2	0.675549	Disordered	0.431183	Uncertain	0.324	0.884	0.625											-2.895	Likely Benign	0.212	Likely Benign	Likely Benign	0.76	Ambiguous	0.3	0.54	Ambiguous	0.65	Ambiguous	0.24	Likely Benign	0.227	Likely Benign	-0.41	Neutral	0.000	Benign	0.001	Benign	5.46	Benign	0.26	Tolerated	4.32	12	0.2240	0.4133		1	2	2.6	-18.03
c.1131G>T	M377I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus classify the change as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result and is therefore not considered evidence for pathogenicity. Overall, the evidence overwhelmingly supports a benign interpretation, 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	0.675549	Disordered	0.431183	Uncertain	0.324	0.884	0.625											-2.895	Likely Benign	0.212	Likely Benign	Likely Benign	0.76	Ambiguous	0.3	0.54	Ambiguous	0.65	Ambiguous	0.24	Likely Benign	0.227	Likely Benign	-0.41	Neutral	0.000	Benign	0.001	Benign	5.46	Benign	0.26	Tolerated	4.32	12	0.2240	0.4133		1	2	2.6	-18.03
c.1132G>A	G378S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G378S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as pathogenic, giving a mixed outcome. Because the predictions are evenly split and the high‑accuracy methods are contradictory, the variant’s functional impact is uncertain. Based on the available 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	0.767246	Disordered	0.432858	Uncertain	0.341	0.915	0.625											-5.331	Likely Benign	0.115	Likely Benign	Likely Benign	6.75	Destabilizing	2.2	7.81	Destabilizing	7.28	Destabilizing	0.12	Likely Benign	0.565	Likely Pathogenic	-0.63	Neutral	1.000	Probably Damaging	0.986	Probably Damaging	1.33	Pathogenic	0.08	Tolerated			0.3013	0.4724		1	0	-0.4	30.03
c.1132G>C	G378R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G378R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, and SIFT, while pathogenic predictions arise from REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also indicates pathogenicity. Overall, the preponderance of evidence points to a pathogenic impact for G378R. 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	C2	0.767246	Disordered	0.432858	Uncertain	0.341	0.915	0.625											-8.863	Likely Pathogenic	0.745	Likely Pathogenic	Likely Benign	12.27	Destabilizing	6.3	13.17	Destabilizing	12.72	Destabilizing	0.12	Likely Benign	0.653	Likely Pathogenic	-0.96	Neutral	1.000	Probably Damaging	0.996	Probably Damaging	1.32	Pathogenic	0.06	Tolerated			0.1343	0.4356		-3	-2	-4.1	99.14
c.1133G>A	G378D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G378D is not reported in ClinVar (ClinVar ID: None) but is present in gnomAD (ID 6‑33438038‑G‑A). Prediction tools that classify the variant as benign include premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. ESM1b is uncertain, and no other high‑accuracy predictions are available. Overall, the majority of evidence supports a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.767246	Disordered	0.432858	Uncertain	0.341	0.915	0.625								6-33438038-G-A	1	6.97e-7	-7.767	In-Between	0.576	Likely Pathogenic	Likely Benign	11.41	Destabilizing	5.0	11.84	Destabilizing	11.63	Destabilizing	0.50	Likely Benign	0.619	Likely Pathogenic	-0.63	Neutral	1.000	Probably Damaging	0.992	Probably Damaging	1.32	Pathogenic	0.08	Tolerated	4.32	12	0.2130	0.2035		-1	1	-3.1	58.04
c.1133G>C	G378A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G378A 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, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as “Likely Benign.” High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus confirms a benign likelihood, while Foldetta—combining FoldX‑MD and Rosetta outputs—predicts a pathogenic effect on protein folding stability. Overall, the majority of evidence points toward a benign impact, and this conclusion is consistent with the absence of ClinVar annotation and gnomAD data. 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.	Likely Benign	C2	0.767246	Disordered	0.432858	Uncertain	0.341	0.915	0.625											-6.450	Likely Benign	0.111	Likely Benign	Likely Benign	5.06	Destabilizing	1.3	6.00	Destabilizing	5.53	Destabilizing	-0.04	Likely Benign	0.497	Likely Benign	-0.55	Neutral	0.999	Probably Damaging	0.981	Probably Damaging	1.33	Pathogenic	0.18	Tolerated			0.4062	0.4576		1	0	2.2	14.03
c.1135T>A	S379T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are Rosetta, polyPhen‑2 HumDiv, and the Foldetta stability method. FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as pathogenic. Overall, the majority of evidence points to 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.	Likely Benign	C2	0.728858	Disordered	0.433206	Uncertain	0.327	0.931	0.625											-5.646	Likely Benign	0.092	Likely Benign	Likely Benign	1.42	Ambiguous	0.6	3.96	Destabilizing	2.69	Destabilizing	0.06	Likely Benign	0.230	Likely Benign	-0.50	Neutral	0.462	Possibly Damaging	0.084	Benign	3.87	Benign	0.16	Tolerated			0.2293	0.6248		1	1	0.1	14.03
c.1135T>C	S379P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, Rosetta, and Foldetta; FoldX is uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the majority of evidence—including the high‑accuracy benign predictions—suggests that the variant is most likely benign. 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 Benign	C2	0.728858	Disordered	0.433206	Uncertain	0.327	0.931	0.625											-5.007	Likely Benign	0.118	Likely Benign	Likely Benign	1.10	Ambiguous	0.8	2.92	Destabilizing	2.01	Destabilizing	0.17	Likely Benign	0.430	Likely Benign	-0.41	Neutral	0.808	Possibly Damaging	0.212	Benign	3.83	Benign	0.10	Tolerated			0.3035	0.6594		1	-1	-0.8	10.04
c.1135T>G	S379A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379A is reported in gnomAD (variant ID 6‑33438040‑T‑G) but has no entry in ClinVar. All available in‑silico predictors classify the change as benign: REVEL, FoldX, 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 are consistent: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote) indicates “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Consequently, 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	0.728858	Disordered	0.433206	Uncertain	0.327	0.931	0.625								6-33438040-T-G			-4.300	Likely Benign	0.077	Likely Benign	Likely Benign	-0.22	Likely Benign	0.3	1.03	Ambiguous	0.41	Likely Benign	0.10	Likely Benign	0.217	Likely Benign	-0.50	Neutral	0.012	Benign	0.002	Benign	3.91	Benign	0.21	Tolerated	4.32	11	0.5032	0.5555	Strenghten	1	1	2.6	-16.00
c.1139G>C	G380A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G380A 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, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FoldX predicts a pathogenic outcome, while Rosetta and Foldetta are benign or uncertain, respectively. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta as uncertain. Overall, the overwhelming majority of evidence points to a benign effect, with no conflict with ClinVar status (which has no entry for this variant). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.724957	Disordered	0.432982	Uncertain	0.316	0.939	0.750											-6.433	Likely Benign	0.107	Likely Benign	Likely Benign	3.11	Destabilizing	1.0	-0.15	Likely Benign	1.48	Ambiguous	-0.06	Likely Benign	0.422	Likely Benign	-0.53	Neutral	0.056	Benign	0.010	Benign	2.56	Benign	0.17	Tolerated			0.3915	0.4576		1	0	2.2	14.03
c.1141G>A	G381R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381R is not reported in ClinVar and is present in gnomAD (ID 6‑33438046‑G‑A). Prediction tools that classify it as benign include premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized indicates a benign outcome, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the majority of evidence points to a pathogenic impact for G381R, 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	0.724957	Disordered	0.431692	Uncertain	0.301	0.951	0.750								6-33438046-G-A			-8.990	Likely Pathogenic	0.652	Likely Pathogenic	Likely Benign	5.60	Destabilizing	0.9	2.80	Destabilizing	4.20	Destabilizing	0.20	Likely Benign	0.589	Likely Pathogenic	-0.82	Neutral	0.985	Probably Damaging	0.795	Possibly Damaging	1.32	Pathogenic	0.08	Tolerated	4.32	9	0.1339	0.3945		-2	-3	-4.1	99.14
c.1141G>C	G381R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G381R is catalogued in gnomAD (ID 6‑33438046‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from SGM‑Consensus, REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized reports a benign outcome, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the majority of evidence indicates a pathogenic impact for G381R, and this conclusion is not contradicted by ClinVar status, which currently lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.724957	Disordered	0.431692	Uncertain	0.301	0.951	0.750								6-33438046-G-C	2	1.25e-6	-8.990	Likely Pathogenic	0.652	Likely Pathogenic	Likely Benign	5.60	Destabilizing	0.9	2.80	Destabilizing	4.20	Destabilizing	0.20	Likely Benign	0.589	Likely Pathogenic	-0.82	Neutral	0.985	Probably Damaging	0.795	Possibly Damaging	1.32	Pathogenic	0.08	Tolerated	4.32	9	0.1339	0.3945		-2	-3	-4.1	99.14
c.1142G>A	G381E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381E is 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, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. 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) as pathogenic, and Foldetta as pathogenic. With seven pathogenic versus four benign predictions and two high‑accuracy tools supporting pathogenicity, 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.		C2	0.724957	Disordered	0.431692	Uncertain	0.301	0.951	0.750											-9.360	Likely Pathogenic	0.540	Ambiguous	Likely Benign	5.52	Destabilizing	1.1	0.53	Ambiguous	3.03	Destabilizing	0.24	Likely Benign	0.588	Likely Pathogenic	-0.71	Neutral	0.985	Probably Damaging	0.720	Possibly Damaging	1.32	Pathogenic	0.11	Tolerated			0.1554	0.3735		0	-2	-3.1	72.06
c.1142G>C	G381A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381A is reported in gnomAD (variant ID 6-33438047‑G‑C) but has no ClinVar entry. Functional prediction tools fall into two groups: benign predictions come from premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar; pathogenic predictions come from REVEL, FoldX, Rosetta, polyPhen‑2 HumDiv, FATHMM, and the SGM‑Consensus score. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, while Foldetta (combining FoldX‑MD and Rosetta stability outputs) indicates a pathogenic effect. No prediction or stability result is missing or inconclusive. Overall, the majority of tools suggest a benign effect, and the high‑accuracy consensus leans toward benign, though Foldetta’s pathogenic signal introduces uncertainty. The variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.724957	Disordered	0.431692	Uncertain	0.301	0.951	0.750								6-33438047-G-C	1	6.23e-7	-6.266	Likely Benign	0.103	Likely Benign	Likely Benign	3.97	Destabilizing	0.7	2.05	Destabilizing	3.01	Destabilizing	0.06	Likely Benign	0.507	Likely Pathogenic	-0.63	Neutral	0.718	Possibly Damaging	0.332	Benign	1.33	Pathogenic	0.52	Tolerated	4.32	9	0.3809	0.4770		0	1	2.2	14.03
c.1142G>T	G381V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381V is listed in ClinVar with an uncertain significance (ClinVar ID 1940172.0) and is present in the gnomAD database (6‑33438047‑G‑T). Functional prediction tools that report a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, FoldX, Rosetta, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a majority‑benign vote and is reported as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions lean toward a benign impact, and this 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	C2	0.724957	Disordered	0.431692	Uncertain	0.301	0.951	0.750					Uncertain		1	6-33438047-G-T	2	1.25e-6	-5.967	Likely Benign	0.146	Likely Benign	Likely Benign	7.16	Destabilizing	1.0	4.10	Destabilizing	5.63	Destabilizing	-0.32	Likely Benign	0.618	Likely Pathogenic	-0.95	Neutral	0.386	Benign	0.157	Benign	1.32	Pathogenic	0.10	Tolerated	4.32	9	0.1621	0.3902		-1	-3	4.6	42.08	214.6	-68.8	0.3	0.7	-0.5	0.3								Uncertain	Gly381 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Val381 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effects on Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn.
c.1145G>C	G382A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G382A 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, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the majority of predictions lean toward a benign effect, and this consensus does not contradict any ClinVar status (none available). Thus, based on the available computational evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.728858	Disordered	0.429690	Uncertain	0.315	0.951	0.750											-6.323	Likely Benign	0.109	Likely Benign	Likely Benign	2.90	Destabilizing	0.6	3.00	Destabilizing	2.95	Destabilizing	-0.03	Likely Benign	0.495	Likely Benign	-0.59	Neutral	0.953	Possibly Damaging	0.952	Probably Damaging	1.33	Pathogenic	0.12	Tolerated			0.4048	0.4576		1	0	2.2	14.03
c.1148G>C	G383A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383A 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 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as pathogenic. Thus, the majority of evidence points to a benign impact, with only a minority of high‑accuracy tools suggesting pathogenicity. The variant is most likely benign based on the overall predictions, and 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 Benign	C2	0.728858	Disordered	0.429104	Uncertain	0.296	0.949	0.750											-6.205	Likely Benign	0.105	Likely Benign	Likely Benign	3.17	Destabilizing	1.2	3.47	Destabilizing	3.32	Destabilizing	0.04	Likely Benign	0.178	Likely Benign	-0.64	Neutral	0.055	Benign	0.037	Benign	4.20	Benign	0.11	Tolerated			0.3880	0.4361		1	0	2.2	14.03
c.1153T>G	S385A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S385A is catalogued in gnomAD (variant ID 6‑33438058‑T‑G) but has no entry in ClinVar. All available in silico predictors report a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Consequently, the variant is most likely benign, 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	C2	0.733139	Disordered	0.425480	Uncertain	0.341	0.925	0.750								6-33438058-T-G			-4.412	Likely Benign	0.083	Likely Benign	Likely Benign	0.03	Likely Benign	0.1	0.19	Likely Benign	0.11	Likely Benign	0.07	Likely Benign	0.243	Likely Benign	-0.28	Neutral	0.140	Benign	0.355	Benign	4.65	Benign	0.13	Tolerated	4.32	3	0.4910	0.5366		1	1	2.6	-16.00
c.1159G>A	G387S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G387S missense variant is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (variant ID 6‑33438064‑G‑A). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX and FATHMM; Rosetta is uncertain. The high‑accuracy consensus (SGM‑Consensus) is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and is therefore likely benign. AlphaMissense‑Optimized itself predicts benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a pathogenic effect. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar classification (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.642678	Disordered	0.422910	Uncertain	0.293	0.861	0.750								6-33438064-G-A			-4.674	Likely Benign	0.089	Likely Benign	Likely Benign	2.37	Destabilizing	0.5	1.94	Ambiguous	2.16	Destabilizing	0.12	Likely Benign	0.359	Likely Benign	-0.12	Neutral	0.000	Benign	0.002	Benign	1.33	Pathogenic	0.13	Tolerated	4.32	3	0.3051	0.4724		0	1	-0.4	30.03
c.1160G>C	G387A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G387A is reported in gnomAD (variant ID 6‑33438065‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts it as pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive (treated as unavailable). No other tools provide decisive evidence. 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	C2	0.642678	Disordered	0.422910	Uncertain	0.293	0.861	0.750								6-33438065-G-C	3	1.87e-6	-6.313	Likely Benign	0.104	Likely Benign	Likely Benign	1.95	Ambiguous	0.1	1.68	Ambiguous	1.82	Ambiguous	-0.02	Likely Benign	0.300	Likely Benign	-0.29	Neutral	0.007	Benign	0.010	Benign	1.33	Pathogenic	0.06	Tolerated	4.32	3	0.4149	0.4576		0	1	2.2	14.03
c.1168G>A	G390R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G390R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the majority of tools and the high‑accuracy methods indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.626927	Disordered	0.413274	Uncertain	0.304	0.763	0.875											-9.242	Likely Pathogenic	0.686	Likely Pathogenic	Likely Benign	2.43	Destabilizing	0.9	4.85	Destabilizing	3.64	Destabilizing	0.16	Likely Benign	0.605	Likely Pathogenic	-0.92	Neutral	0.480	Possibly Damaging	0.163	Benign	1.32	Pathogenic	0.08	Tolerated			0.1190	0.4524		-3	-2	-4.1	99.14
c.1168G>C	G390R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G390R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the majority of tools and the high‑accuracy methods indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Pathogenic	C2	0.626927	Disordered	0.413274	Uncertain	0.304	0.763	0.875											-9.242	Likely Pathogenic	0.686	Likely Pathogenic	Likely Benign	2.43	Destabilizing	0.9	4.85	Destabilizing	3.64	Destabilizing	0.16	Likely Benign	0.605	Likely Pathogenic	-0.92	Neutral	0.480	Possibly Damaging	0.163	Benign	1.32	Pathogenic	0.08	Tolerated			0.1190	0.4524		-3	-2	-4.1	99.14
c.1171G>A	G391S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G391S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and FoldX. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also as likely benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact for G391S, 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	0.637480	Disordered	0.409509	Uncertain	0.279	0.741	0.750											-5.531	Likely Benign	0.096	Likely Benign	Likely Benign	2.14	Destabilizing	0.6	1.01	Ambiguous	1.58	Ambiguous	0.06	Likely Benign	0.462	Likely Benign	-0.54	Neutral	0.978	Probably Damaging	0.777	Possibly Damaging	1.33	Pathogenic	0.35	Tolerated			0.2820	0.5097		1	0	-0.4	30.03
c.1171G>C	G391R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G391R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include premPS, PROVEAN, and SIFT, whereas those that predict pathogenicity comprise REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further show AlphaMissense‑Optimized labeling the variant as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Overall, the majority of predictions lean toward pathogenicity, 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	0.637480	Disordered	0.409509	Uncertain	0.279	0.741	0.750											-9.115	Likely Pathogenic	0.709	Likely Pathogenic	Likely Benign	2.80	Destabilizing	1.3	3.86	Destabilizing	3.33	Destabilizing	0.32	Likely Benign	0.628	Likely Pathogenic	-0.95	Neutral	0.999	Probably Damaging	0.960	Probably Damaging	1.32	Pathogenic	0.17	Tolerated			0.1313	0.4124		-3	-2	-4.1	99.14
c.1172G>A	G391D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G391D is 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, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Two tools, Rosetta and Foldetta, return uncertain results. High‑accuracy methods give a benign call from AlphaMissense‑Optimized; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, six tools favor pathogenicity while five favor benignity, with two uncertain. Thus, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.		C2	0.637480	Disordered	0.409509	Uncertain	0.279	0.741	0.750											-4.651	Likely Benign	0.674	Likely Pathogenic	Likely Benign	2.59	Destabilizing	1.1	1.26	Ambiguous	1.93	Ambiguous	0.22	Likely Benign	0.562	Likely Pathogenic	-0.95	Neutral	0.999	Probably Damaging	0.960	Probably Damaging	1.32	Pathogenic	0.29	Tolerated			0.1900	0.1305		1	-1	-3.1	58.04
c.1172G>C	G391A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G391A 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 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are FoldX, polyPhen‑2 HumDiv, and FATHMM. Predictions that are inconclusive are Rosetta and Foldetta. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also likely benign, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.637480	Disordered	0.409509	Uncertain	0.279	0.741	0.750											-5.712	Likely Benign	0.120	Likely Benign	Likely Benign	2.02	Destabilizing	0.5	1.92	Ambiguous	1.97	Ambiguous	0.11	Likely Benign	0.442	Likely Benign	-0.76	Neutral	0.633	Possibly Damaging	0.219	Benign	1.33	Pathogenic	0.19	Tolerated			0.3828	0.4870		1	0	2.2	14.03
c.1172G>T	G391V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G391V is listed in ClinVar as Benign (ClinVar ID 1014488.0) and is present in gnomAD (variant ID 6‑33438077‑G‑T). Prediction tools that classify the variant as benign include premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. Tools that predict pathogenicity are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. With two high‑accuracy tools supporting benign and one supporting pathogenic, the overall prediction leans toward a benign effect. This conclusion aligns with the ClinVar benign classification, so there is no contradiction with the existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.637480	Disordered	0.409509	Uncertain	0.279	0.741	0.750					Likely Benign		1	6-33438077-G-T	3	1.86e-6	-6.642	Likely Benign	0.133	Likely Benign	Likely Benign	4.23	Destabilizing	1.3	4.81	Destabilizing	4.52	Destabilizing	-0.11	Likely Benign	0.595	Likely Pathogenic	-0.98	Neutral	0.994	Probably Damaging	0.887	Possibly Damaging	1.32	Pathogenic	0.10	Tolerated	3.69	8	0.1621	0.3821		-1	-3	4.6	42.08	228.6	-69.0	0.0	0.8	-0.5	0.3								Uncertain	Gly387 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. This loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play significant roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Val391 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. Since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn.
c.1174A>C	K392Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K392Q has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL and polyPhen‑2 HumDiv. 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 (combining FoldX‑MD and Rosetta outputs) as 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 is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.541878	Disordered	0.405672	Uncertain	0.319	0.702	0.750											-4.243	Likely Benign	0.377	Ambiguous	Likely Benign	0.13	Likely Benign	0.0	0.05	Likely Benign	0.09	Likely Benign	0.23	Likely Benign	0.525	Likely Pathogenic	-2.09	Neutral	0.652	Possibly Damaging	0.161	Benign	4.61	Benign	0.06	Tolerated			0.5612	0.2106	Weaken	1	1	0.4	-0.04
c.1175A>G	K392R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K392R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All available in silico predictors classify the change as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign effect. The high‑accuracy folding‑stability tool Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a benign impact. No tool predicts pathogenicity. Consequently, 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	C2	0.541878	Disordered	0.405672	Uncertain	0.319	0.702	0.750											-4.006	Likely Benign	0.091	Likely Benign	Likely Benign	-0.03	Likely Benign	0.0	0.44	Likely Benign	0.21	Likely Benign	0.23	Likely Benign	0.131	Likely Benign	-1.44	Neutral	0.436	Benign	0.112	Benign	7.12	Benign	0.08	Tolerated			0.5686	0.1875	Weaken	3	2	-0.6	28.01
c.1177G>A	G393S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G393S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, polyPhen‑2 HumDiv, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. No other tools provide decisive evidence. Overall, the majority of reliable predictors lean toward a benign effect, and this consensus does not conflict with the absence of ClinVar annotation. Therefore, G393S is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review.	Likely Benign	C2	0.538167	Disordered	0.402365	Uncertain	0.333	0.670	0.625											-5.207	Likely Benign	0.117	Likely Benign	Likely Benign	2.43	Destabilizing	0.7	-0.78	Ambiguous	0.83	Ambiguous	0.24	Likely Benign	0.466	Likely Benign	-1.76	Neutral	0.889	Possibly Damaging	0.444	Benign	1.33	Pathogenic	0.07	Tolerated			0.3011	0.5232		1	0	-0.4	30.03
c.1178G>A	G393D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G393D 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 SIFT, ESM1b, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default all indicate pathogenicity. High‑accuracy assessments further support this: AlphaMissense‑Optimized reports a benign outcome, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable. Overall, the preponderance of evidence points to a pathogenic effect for G393D, 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	0.538167	Disordered	0.402365	Uncertain	0.333	0.670	0.625											-5.247	Likely Benign	0.717	Likely Pathogenic	Likely Benign	3.30	Destabilizing	1.4	-1.00	Ambiguous	1.15	Ambiguous	0.57	Ambiguous	0.528	Likely Pathogenic	-2.60	Deleterious	0.991	Probably Damaging	0.831	Possibly Damaging	1.32	Pathogenic	0.19	Tolerated			0.2077	0.1645		1	-1	-3.1	58.04