Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain and Structure information: based on WT protein | Annotated databases | Deep learning-based pathogenicity predictions | Folding stability-based pathogenicity predictions | Sequence/structure-based pathogenicity predictions | Phase Separation | Evolutionary/physical properties | Molecular Dynamics-based analysis | DOI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Domain | IUPred2 | ANCHOR2 | AlphaFold | MobiDB | PhosphoSitePlus | ClinVar | gnomAD | ESM1b | AlphaMissense | FoldX | Rosetta | Foldetta | PremPS | REVEL | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PSMutPred | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | |||||||||||||||||||||||||||||||||||||||||||||
| Score | Prediction | Score | Prediction | pLDDT | disorder | disorder | LTP | HTP | KL | PTM | Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | IP RF | SP RF | Prediction | PAM250 | PAM120 | Hydropathy Δ | MW Δ | Average | Δ | Δ | StdDev | Δ | StdDev | Secondary | Tertiary bonds | Inside out | GAP-Ras interface | At membrane | No effect | MD Alert | Verdict | Description | |||||
| c.1342G>A | A448T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 A448T 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, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, 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. Taken together, the overwhelming majority of evidence indicates that A448T is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.192 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 3.06 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.73 | Destabilizing | 0.63 | Ambiguous | 0.558 | Likely Pathogenic | -3.95 | Deleterious | 0.996 | Probably Damaging | 0.973 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 0.1187 | 0.5050 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1342G>C | A448P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). 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 pathogenic effect, while only FATHMM predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized returns a pathogenic prediction; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a likely pathogenic result; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions or stability results are 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 | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -13.706 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.42 | Destabilizing | 0.0 | 8.74 | Destabilizing | 7.08 | Destabilizing | 1.16 | Destabilizing | 0.650 | Likely Pathogenic | -4.94 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.13 | Benign | 0.01 | Affected | 0.1758 | 0.3626 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1342G>T | A448S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 A448S missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict any ClinVar annotation because none exists. 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 | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.213 | Likely Pathogenic | 0.590 | Likely Pathogenic | Likely Benign | 1.18 | Ambiguous | 0.1 | 1.97 | Ambiguous | 1.58 | Ambiguous | 0.55 | Ambiguous | 0.310 | Likely Benign | -2.96 | Deleterious | 0.965 | Probably Damaging | 0.972 | Probably Damaging | 3.27 | Benign | 0.06 | Tolerated | 0.2420 | 0.3471 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1343C>A | A448D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448D 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 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: 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. No prediction or folding 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 annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -17.290 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 8.13 | Destabilizing | 0.2 | 4.35 | Destabilizing | 6.24 | Destabilizing | 1.40 | Destabilizing | 0.662 | Likely Pathogenic | -5.93 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | 0.1541 | 0.1741 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1343C>G | A448G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448G resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas those that predict pathogenicity are Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; FoldX is inconclusive. High‑accuracy assessments further clarify the impact: AlphaMissense‑Optimized reports a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a pathogenic effect. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.984 | Likely Pathogenic | 0.640 | Likely Pathogenic | Likely Benign | 1.76 | Ambiguous | 0.0 | 2.45 | Destabilizing | 2.11 | Destabilizing | 1.00 | Destabilizing | 0.378 | Likely Benign | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.980 | Probably Damaging | 3.15 | Benign | 0.06 | Tolerated | 0.2135 | 0.2936 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1343C>T | A448V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools (Rosetta and premPS) yield uncertain results. 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. Overall, the preponderance of evidence indicates that A448V is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -10.372 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 3.31 | Destabilizing | 0.2 | 1.80 | Ambiguous | 2.56 | Destabilizing | 0.66 | Ambiguous | 0.487 | Likely Benign | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.955 | Probably Damaging | 3.26 | Benign | 0.02 | Affected | 0.0950 | 0.4955 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.1345A>C | S449R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant S449R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, AlphaMissense‑Default, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifying it as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain stability change. No folding‑stability prediction is definitive. Overall, the majority of tools predict a benign outcome, and this 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. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -8.486 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | 0.145 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0.0762 | 0.3250 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1345A>G | S449G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449G is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (variant ID 6‑33438250‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta, Foldetta, and premPS 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, 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 | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | Uncertain | 1 | 6-33438250-A-G | 3 | 1.86e-6 | -5.936 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.47 | Likely Benign | 0.0 | 0.55 | Ambiguous | 0.51 | Ambiguous | 0.85 | Ambiguous | 0.116 | Likely Benign | -2.32 | Neutral | 0.948 | Possibly Damaging | 0.124 | Benign | 3.35 | Benign | 0.13 | Tolerated | 3.37 | 32 | 0.2600 | 0.3718 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||
| c.1345A>T | S449C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449C is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, FoldX, Rosetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Based on the unanimous benign predictions and lack of ClinVar evidence, 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 | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -2.207 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.48 | Likely Benign | 0.0 | -0.31 | Likely Benign | 0.09 | Likely Benign | -0.57 | Ambiguous | 0.067 | Likely Benign | 0.48 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.32 | Benign | 0.21 | Tolerated | 0.0864 | 0.5012 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.1346G>A | S449N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449N is not reported in ClinVar (ClinVar status: not listed) but is present in the gnomAD database (gnomAD ID: 6‑33438251‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from premPS (uncertain) and ESM1b (uncertain). High‑accuracy assessments reinforce the benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. 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 | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | 6-33438251-G-A | 1 | 6.19e-7 | -7.692 | In-Between | 0.210 | Likely Benign | Likely Benign | 0.38 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.18 | Likely Benign | 0.81 | Ambiguous | 0.070 | Likely Benign | -2.31 | Neutral | 0.372 | Benign | 0.026 | Benign | 3.37 | Benign | 0.18 | Tolerated | 3.37 | 32 | 0.1085 | 0.3767 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||
| c.1346G>C | S449T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449T is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the 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 predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on these predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -6.262 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.1 | -0.46 | Likely Benign | -0.05 | Likely Benign | -0.15 | Likely Benign | 0.039 | Likely Benign | -1.48 | Neutral | 0.038 | Benign | 0.008 | Benign | 3.42 | Benign | 0.33 | Tolerated | 0.1219 | 0.5077 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1346G>T | S449I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and ESM1b. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs. 2 pathogenic). Foldetta also remains uncertain. Overall, the majority of evidence (7 benign vs. 3 pathogenic) points to a benign 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. | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -9.549 | Likely Pathogenic | 0.310 | Likely Benign | Likely Benign | 0.04 | Likely Benign | 0.1 | -1.39 | Ambiguous | -0.68 | Ambiguous | 0.13 | Likely Benign | 0.105 | Likely Benign | -3.23 | Deleterious | 0.559 | Possibly Damaging | 0.044 | Benign | 3.40 | Benign | 0.14 | Tolerated | 0.0756 | 0.5006 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||
| c.1347T>A | S449R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, SIFT, FATHMM, and polyPhen‑2 HumVar, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments provide a mixed picture: AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an inconclusive result. FoldX and Rosetta predictions are also uncertain and are treated as unavailable. Overall, the evidence is balanced, with an equal number of benign and pathogenic calls, and the high‑accuracy tools do not converge on a single conclusion. Consequently, the variant is most likely pathogenic based on the preponderance of pathogenic 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 | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -8.486 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | 0.168 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0.0762 | 0.3250 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1347T>G | S449R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449R is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include REVEL, premPS, SIFT, FATHMM, and polyPhen‑2 HumVar. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicting a benign effect, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta’s stability prediction is uncertain and therefore treated as unavailable. Overall, the predictions are split, with an equal number of benign and pathogenic calls and conflicting high‑accuracy results. Consequently, the variant’s impact remains inconclusive, and there is no contradiction with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -8.486 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | 0.167 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0.0762 | 0.3250 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1348G>A | A450T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A450T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Because the majority of conventional tools lean toward benign and no ClinVar evidence contradicts this, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -9.149 | Likely Pathogenic | 0.380 | Ambiguous | Likely Benign | 0.50 | Ambiguous | 0.2 | 0.98 | Ambiguous | 0.74 | Ambiguous | 0.81 | Ambiguous | 0.233 | Likely Benign | -3.35 | Deleterious | 0.996 | Probably Damaging | 0.973 | Probably Damaging | 3.40 | Benign | 0.06 | Tolerated | 0.0943 | 0.5902 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.1348G>C | A450P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A450P missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, and FATHMM, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM Consensus score all classify the change as pathogenic. The high‑accuracy predictors give consistent pathogenic results: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. premPS remains uncertain. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which is consistent with the absence of a benign ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -15.378 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.75 | Destabilizing | 0.3 | 8.32 | Destabilizing | 5.54 | Destabilizing | 0.72 | Ambiguous | 0.459 | Likely Benign | -4.67 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.40 | Benign | 0.08 | Tolerated | 0.1494 | 0.4309 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1348G>T | A450S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A450S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining methods—FoldX, Rosetta, Foldetta, and premPS—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus unavailable; Foldetta is uncertain. Overall, the balance of evidence (five benign versus four pathogenic predictions, with three uncertain) suggests the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -9.257 | Likely Pathogenic | 0.274 | Likely Benign | Likely Benign | 0.81 | Ambiguous | 0.0 | 1.35 | Ambiguous | 1.08 | Ambiguous | 0.69 | Ambiguous | 0.268 | Likely Benign | -2.70 | Deleterious | 0.965 | Probably Damaging | 0.972 | Probably Damaging | 3.47 | Benign | 0.10 | Tolerated | 0.2003 | 0.4322 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1349C>A | A450E 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant A450E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include SIFT and FATHMM, whereas the majority of tools predict it to be pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No predictions are inconclusive. Overall, the evidence strongly favors a pathogenic impact for A450E, which 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 | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | Uncertain | 1 | -16.578 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 3.86 | Destabilizing | 0.2 | 5.23 | Destabilizing | 4.55 | Destabilizing | 1.59 | Destabilizing | 0.653 | Likely Pathogenic | -4.67 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.38 | Benign | 0.07 | Tolerated | 3.37 | 32 | 0.0823 | 0.1695 | 0 | -1 | -5.3 | 58.04 | 240.1 | -82.6 | 0.0 | 0.0 | 0.7 | 0.0 | X | X | Potentially Pathogenic | The methyl group of Ala450, located in an α helix (res. Asn440-Thr458), packs against hydrophobic residues in the inter-helix space (e.g., Leu692). In the variant simulations, the carboxylate group of the Glu450 side chain rotates outward, away from the hydrophobic niche, where it does not form any lasting salt bridges or H-bonds. Although the residue swap does not negatively affect the protein structure based on the simulations, it is possible that the introduction of the negatively charged residue adversely affects the folding process or tertiary assembly. | |||||||||||||||
| c.1349C>G | A450G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A450G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. The majority of other in silico predictors (SGM‑Consensus, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) classify the variant as pathogenic; FoldX is inconclusive. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized predicts benign, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenic. Overall, the preponderance of evidence indicates that A450G is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -11.090 | Likely Pathogenic | 0.695 | Likely Pathogenic | Likely Benign | 1.79 | Ambiguous | 0.0 | 2.29 | Destabilizing | 2.04 | Destabilizing | 1.23 | Destabilizing | 0.355 | Likely Benign | -3.82 | Deleterious | 0.998 | Probably Damaging | 0.980 | Probably Damaging | 3.40 | Benign | 0.04 | Affected | 0.1670 | 0.3078 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1349C>T | A450V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A450V is not reported in ClinVar and is present in gnomAD (ID 6‑33438254‑C‑T). Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give mixed results: 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) predicts benign. Overall, the majority of tools lean toward a benign effect, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign based on current predictions, with a single high‑accuracy tool suggesting pathogenicity but not overturning the overall benign consensus. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | 6-33438254-C-T | 1 | 6.20e-7 | -11.489 | Likely Pathogenic | 0.578 | Likely Pathogenic | Likely Benign | 0.04 | Likely Benign | 0.2 | 0.27 | Likely Benign | 0.16 | Likely Benign | 0.46 | Likely Benign | 0.306 | Likely Benign | -3.69 | Deleterious | 0.998 | Probably Damaging | 0.955 | Probably Damaging | 3.55 | Benign | 0.04 | Affected | 3.37 | 32 | 0.0792 | 0.5638 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||
| c.134A>C | N45T 2D  AIThe SynGAP1 missense variant N45T 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, and SIFT. 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 impact, 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 | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -2.425 | Likely Benign | 0.367 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -0.81 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.08 | Benign | 0.00 | Affected | 0.1642 | 0.8318 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||||||
| c.134A>G | N45S 2D  AIThe SynGAP1 missense variant N45S 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, and 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 the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -2.740 | Likely Benign | 0.217 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -0.38 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 4.14 | Benign | 0.00 | Affected | 0.3949 | 0.7617 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.134A>T | N45I 2D  AIThe SynGAP1 missense variant N45I is not reported in ClinVar and is absent from 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, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to 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. 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 Benign | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -4.063 | Likely Benign | 0.568 | Likely Pathogenic | Likely Benign | 0.147 | Likely Benign | -1.32 | Neutral | 0.943 | Possibly Damaging | 0.924 | Probably Damaging | 4.04 | Benign | 0.00 | Affected | 0.0861 | 0.7406 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.1351C>A | L451I 2D  AIThe SynGAP1 L451I 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, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results come from FoldX, Rosetta, premPS, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is also inconclusive. Overall, the majority of available predictions (five pathogenic versus four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar record. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -11.046 | Likely Pathogenic | 0.658 | Likely Pathogenic | Likely Benign | 1.43 | Ambiguous | 0.8 | 0.70 | Ambiguous | 1.07 | Ambiguous | 0.94 | Ambiguous | 0.284 | Likely Benign | -1.94 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.75 | Benign | 0.02 | Affected | 0.0681 | 0.2958 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1351C>G | L451V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451V is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain and does not contribute to the consensus. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic; and Foldetta predicts pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for L451V. 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 | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -10.732 | Likely Pathogenic | 0.635 | Likely Pathogenic | Likely Benign | 2.83 | Destabilizing | 0.1 | 1.81 | Ambiguous | 2.32 | Destabilizing | 1.39 | Destabilizing | 0.325 | Likely Benign | -2.90 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 2.54 | Benign | 0.01 | Affected | 0.1065 | 0.2856 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1352T>A | L451Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451Q is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: pathogenic predictions are returned by REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change 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 reports a 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 | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -15.426 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.91 | Destabilizing | 0.0 | 2.48 | Destabilizing | 2.70 | Destabilizing | 2.30 | Destabilizing | 0.708 | Likely Pathogenic | -5.79 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.0869 | 0.0558 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1352T>C | L451P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451P is reported in ClinVar as Pathogenic (ClinVar ID 3064222.0) and is not found 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 further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on these 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 | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | Likely Pathogenic | 1 | -14.549 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.92 | Destabilizing | 0.2 | 8.57 | Destabilizing | 7.75 | Destabilizing | 2.58 | Destabilizing | 0.750 | Likely Pathogenic | -6.81 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 3.37 | 34 | 0.2823 | 0.1221 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1352T>G | L451R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All available in‑silico predictors classify the substitution 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 (combining FoldX‑MD and Rosetta outputs) reports a pathogenic effect. Based on the unanimous pathogenic predictions and the absence of 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 | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -16.162 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.32 | Destabilizing | 0.1 | 3.76 | Destabilizing | 3.54 | Destabilizing | 2.25 | Destabilizing | 0.726 | Likely Pathogenic | -5.82 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.1130 | 0.0558 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1354G>A | V452I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V452I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and SIFT, while ESM1b also predicts pathogenicity. Uncertain predictions come from Rosetta 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 (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | Uncertain | 1 | -8.985 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | -0.08 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.22 | Likely Benign | 0.25 | Likely Benign | 0.218 | Likely Benign | -0.99 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.26 | Benign | 0.05 | Affected | 0.0630 | 0.3476 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||
| c.1354G>C | V452L 2D  3DClick to see structure in 3D Viewer AISynGAP1 V452L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. 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. Because the majority of tools (six) predict benign and the high‑accuracy Foldetta also supports benign, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -11.285 | Likely Pathogenic | 0.929 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.1 | -0.25 | Likely Benign | 0.02 | Likely Benign | 0.34 | Likely Benign | 0.316 | Likely Benign | -2.96 | Deleterious | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.54 | Benign | 0.11 | Tolerated | 0.0777 | 0.4061 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1354G>T | V452F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V452F variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect are Rosetta and FATHMM, whereas the remaining tools (REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized scores the variant as 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, also predicts pathogenicity. Based on the preponderance of evidence, the variant is most likely pathogenic, a conclusion that contradicts its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | Uncertain | 1 | -14.769 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 9.21 | Destabilizing | 0.1 | 0.37 | Likely Benign | 4.79 | Destabilizing | 0.61 | Ambiguous | 0.511 | Likely Pathogenic | -4.94 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | 3.37 | 34 | 0.0564 | 0.3451 | -1 | -1 | -1.4 | 48.04 | 249.4 | -35.7 | 0.0 | 0.0 | 0.4 | 0.1 | X | Potentially Pathogenic | The iso-propyl side chain of Val452, located in the middle of an α helix (res. Val441-Ser457), packs against hydrophobic residues in the inter-helix space at the intersection of three α helices (e.g., Leu500, His453, Leu465). In the variant simulations, the larger side chain of Phe452 cannot pack against the opposing α helix (res. Leu489-Glu519) as efficiently as valine. Due to space restrictions, the phenol ring adjusts to make room by rotating slightly sideways in the inter-helix space. Besides this small and local shift, no large-scale effects on the protein structure are seen based on the simulations. However, the size difference between the swapped residues could affect the protein folding process. | ||||||||||||||||
| c.1355T>A | V452D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V452D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods reinforce this consensus: 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 overwhelming agreement among both general and high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -15.793 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.92 | Destabilizing | 0.1 | 3.37 | Destabilizing | 3.65 | Destabilizing | 2.52 | Destabilizing | 0.630 | Likely Pathogenic | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.16 | Benign | 0.00 | Affected | 0.1320 | 0.0610 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||
| c.1355T>C | V452A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V452A is not reported in ClinVar and has no entry in gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta remains inconclusive. Overall, the consensus of the available tools points to a pathogenic effect for V452A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -10.423 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 2.21 | Destabilizing | 0.0 | 1.51 | Ambiguous | 1.86 | Ambiguous | 2.18 | Destabilizing | 0.505 | Likely Pathogenic | -3.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 0.2642 | 0.2521 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1355T>G | V452G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V452G 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—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. AlphaMissense‑Optimized is uncertain, providing no definitive direction. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. AlphaMissense‑Optimized remains uncertain. Overall, the preponderance of evidence indicates that V452G 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. | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -13.410 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 3.70 | Destabilizing | 0.1 | 3.37 | Destabilizing | 3.54 | Destabilizing | 2.46 | Destabilizing | 0.570 | Likely Pathogenic | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.17 | Benign | 0.00 | Affected | 0.1948 | 0.2567 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1357C>A | H453N 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant H453N is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. A third set of methods (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) yield 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, predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, the majority of evidence points toward a pathogenic effect for H453N. 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 | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -8.416 | Likely Pathogenic | 0.789 | Likely Pathogenic | Ambiguous | 0.93 | Ambiguous | 0.1 | 0.97 | Ambiguous | 0.95 | Ambiguous | 0.78 | Ambiguous | 0.347 | Likely Benign | -6.92 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.48 | Benign | 0.09 | Tolerated | 0.1435 | 0.2548 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| c.1357C>G | H453D 2D  3DClick to see structure in 3D Viewer AISynGAP1 H453D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are made by FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods reinforce a pathogenic interpretation: 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 indicates pathogenicity. premPS remains uncertain. Overall, the majority of evidence points to a pathogenic effect for H453D, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -15.256 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 3.33 | Destabilizing | 0.0 | 2.68 | Destabilizing | 3.01 | Destabilizing | 0.97 | Ambiguous | 0.443 | Likely Benign | -8.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.48 | Benign | 0.09 | Tolerated | 0.2225 | 0.1815 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.1357C>T | H453Y 2D  AIThe SynGAP1 missense variant H453Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign calls come from REVEL, premPS, FATHMM, and AlphaMissense‑Optimized; pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. Predictions from FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy methods provide a mixed picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts likely pathogenic, and Foldetta is inconclusive. Overall, the majority of evidence points toward a pathogenic effect, aligning with the SGM‑Consensus but opposing the benign predictions from several tools. Because ClinVar contains no entry for this variant, there is no conflict with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -12.060 | Likely Pathogenic | 0.753 | Likely Pathogenic | Likely Benign | -0.52 | Ambiguous | 0.7 | -0.68 | Ambiguous | -0.60 | Ambiguous | 0.09 | Likely Benign | 0.320 | Likely Benign | -5.93 | Deleterious | 0.995 | Probably Damaging | 0.961 | Probably Damaging | 3.41 | Benign | 0.04 | Affected | 0.0815 | 0.3843 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||
| c.1358A>C | H453P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H453P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM. The majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -15.704 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 3.29 | Destabilizing | 0.4 | 7.04 | Destabilizing | 5.17 | Destabilizing | 0.84 | Ambiguous | 0.488 | Likely Benign | -9.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.04 | Affected | 0.2115 | 0.3938 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.1358A>G | H453R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant H453R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an inconclusive result because FoldX is uncertain and Rosetta is benign. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -9.239 | Likely Pathogenic | 0.573 | Likely Pathogenic | Likely Benign | -0.52 | Ambiguous | 0.1 | 0.37 | Likely Benign | -0.08 | Likely Benign | 0.56 | Ambiguous | 0.396 | Likely Benign | -7.91 | Deleterious | 0.993 | Probably Damaging | 0.957 | Probably Damaging | 3.53 | Benign | 0.39 | Tolerated | 0.1646 | 0.2031 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||
| c.1358A>T | H453L 2D  3DClick to see structure in 3D Viewer AISynGAP1 H453L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, premPS, SIFT, FATHMM, and the protein‑folding stability method Foldetta; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments indicate that AlphaMissense‑Optimized is uncertain, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. Overall, the predictions are split, with a slight edge toward pathogenicity from the consensus and high‑accuracy tools, but the presence of several benign calls and the uncertainty of AlphaMissense‑Optimized temper this conclusion. Thus, 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 | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -10.438 | Likely Pathogenic | 0.834 | Likely Pathogenic | Ambiguous | -0.59 | Ambiguous | 0.1 | 0.04 | Likely Benign | -0.28 | Likely Benign | 0.31 | Likely Benign | 0.413 | Likely Benign | -10.87 | Deleterious | 0.998 | Probably Damaging | 0.973 | Probably Damaging | 3.45 | Benign | 0.11 | Tolerated | 0.0841 | 0.4964 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||
| c.1359C>A | H453Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H453Q 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, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results—FoldX, Rosetta, premPS, AlphaMissense‑Optimized, and Foldetta—are treated as unavailable for pathogenicity assessment. High‑accuracy methods specifically show SGM‑Consensus as Likely Pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the preponderance of evidence from consensus and high‑accuracy predictors indicates that H453Q is most likely pathogenic, and this assessment does not contradict the current ClinVar status, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -10.894 | Likely Pathogenic | 0.893 | Likely Pathogenic | Ambiguous | 0.90 | Ambiguous | 0.1 | 1.55 | Ambiguous | 1.23 | Ambiguous | 0.92 | Ambiguous | 0.259 | Likely Benign | -7.91 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.45 | Benign | 0.09 | Tolerated | 0.1223 | 0.3112 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.1359C>G | H453Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H453Q 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, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results—FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized—are treated as unavailable for pathogenicity assessment. High‑accuracy methods specifically show SGM‑Consensus as Likely Pathogenic, AlphaMissense‑Optimized as Uncertain, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for H453Q. 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 | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -10.894 | Likely Pathogenic | 0.893 | Likely Pathogenic | Ambiguous | 0.90 | Ambiguous | 0.1 | 1.55 | Ambiguous | 1.23 | Ambiguous | 0.92 | Ambiguous | 0.258 | Likely Benign | -7.91 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.45 | Benign | 0.09 | Tolerated | 0.1223 | 0.3112 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.135C>A | N45K 2D  AISynGAP1 missense variant N45K 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 score (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, while the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign outcome; Foldetta results are unavailable. Overall, the balance of evidence—five benign versus four pathogenic predictions, with two high‑accuracy tools supporting benign—suggests that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -1.711 | Likely Benign | 0.697 | Likely Pathogenic | Likely Benign | 0.082 | Likely Benign | -0.58 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 0.2409 | 0.6724 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.135C>G | N45K 2D AISynGAP1 missense variant N45K 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 score (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, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign outcome; Foldetta results are unavailable. Overall, the balance of evidence—five benign versus four pathogenic predictions, with two high‑accuracy tools supporting benign—suggests that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -1.711 | Likely Benign | 0.697 | Likely Pathogenic | Likely Benign | 0.082 | Likely Benign | -0.58 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 0.2409 | 0.6724 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.1360A>C | I454L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The remaining tools—FoldX, Rosetta, Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized—yield uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward benign, and Foldetta also uncertain. Overall, the majority of reliable predictors and the SGM Consensus favor a benign classification. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -7.852 | In-Between | 0.786 | Likely Pathogenic | Ambiguous | 0.57 | Ambiguous | 0.1 | 1.36 | Ambiguous | 0.97 | Ambiguous | 0.80 | Ambiguous | 0.246 | Likely Benign | -1.98 | Neutral | 0.908 | Possibly Damaging | 0.943 | Probably Damaging | 3.51 | Benign | 0.26 | Tolerated | 0.0653 | 0.2857 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1360A>G | I454V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454V 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as likely benign, and Foldetta as uncertain. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -4.719 | Likely Benign | 0.657 | Likely Pathogenic | Likely Benign | 1.47 | Ambiguous | 0.0 | 1.36 | Ambiguous | 1.42 | Ambiguous | 0.69 | Ambiguous | 0.132 | Likely Benign | -0.79 | Neutral | 0.935 | Possibly Damaging | 0.858 | Possibly Damaging | 3.40 | Benign | 0.18 | Tolerated | 0.0833 | 0.2959 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.1360A>T | I454F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. All other evaluated algorithms—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. premPS is uncertain and does not influence the overall assessment. Based on the preponderance of pathogenic predictions and the absence of benign evidence, the variant is most likely pathogenic, with no ClinVar status to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -12.468 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 4.15 | Destabilizing | 0.7 | 2.96 | Destabilizing | 3.56 | Destabilizing | 0.70 | Ambiguous | 0.464 | Likely Benign | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.973 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 0.0422 | 0.2560 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1361T>A | I454N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454N resides in the GAP domain. ClinVar has no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on benign impact are REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict pathogenicity. High‑accuracy methods further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta predicts a destabilizing, pathogenic change. Overall, the evidence strongly favors a pathogenic classification, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -14.246 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.24 | Destabilizing | 0.1 | 3.56 | Destabilizing | 3.90 | Destabilizing | 2.44 | Destabilizing | 0.497 | Likely Benign | -6.82 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.25 | Benign | 0.00 | Affected | 0.0750 | 0.0412 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1361T>C | I454T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -9.045 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.20 | Destabilizing | 0.0 | 2.83 | Destabilizing | 3.02 | Destabilizing | 2.02 | Destabilizing | 0.502 | Likely Pathogenic | -4.74 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.0877 | 0.0708 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.1361T>G | I454S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -13.025 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.50 | Destabilizing | 0.1 | 4.45 | Destabilizing | 4.48 | Destabilizing | 2.20 | Destabilizing | 0.574 | Likely Pathogenic | -5.83 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.2116 | 0.0800 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1362C>G | I454M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools (SGM‑Consensus, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Tools with inconclusive results are 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 I454M. 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 | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -8.437 | Likely Pathogenic | 0.871 | Likely Pathogenic | Ambiguous | 1.06 | Ambiguous | 0.1 | 2.32 | Destabilizing | 1.69 | Ambiguous | 1.08 | Destabilizing | 0.292 | Likely Benign | -2.86 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.27 | Benign | 0.01 | Affected | 0.0566 | 0.2524 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.1363C>A | L455M 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant L455M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. No folding‑stability method provides a definitive result. Consequently, the computational evidence does not favor either benign or pathogenic classification. The variant’s status is therefore inconclusive, and this lack of consensus does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -10.086 | Likely Pathogenic | 0.802 | Likely Pathogenic | Ambiguous | 0.88 | Ambiguous | 0.0 | 1.27 | Ambiguous | 1.08 | Ambiguous | 0.59 | Ambiguous | 0.147 | Likely Benign | -1.64 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.25 | Benign | 0.11 | Tolerated | 0.0606 | 0.3362 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1363C>G | L455V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL and FATHMM, whereas the remaining 11 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict pathogenicity. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is 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, also predicts pathogenicity. Taken together, the preponderance 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 | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -12.773 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 2.89 | Destabilizing | 0.1 | 2.38 | Destabilizing | 2.64 | Destabilizing | 1.41 | Destabilizing | 0.276 | Likely Benign | -2.83 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.29 | Benign | 0.02 | Affected | 0.1149 | 0.3056 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1364T>A | L455Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455Q 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 FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic 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 (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -13.075 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.84 | Destabilizing | 0.0 | 3.42 | Destabilizing | 3.13 | Destabilizing | 2.24 | Destabilizing | 0.655 | Likely Pathogenic | -5.66 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | 0.0871 | 0.0958 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1364T>C | L455P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455P 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 FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized 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 outputs, is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant 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 | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -14.150 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 7.45 | Destabilizing | 0.2 | 11.99 | Destabilizing | 9.72 | Destabilizing | 2.19 | Destabilizing | 0.695 | Likely Pathogenic | -6.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | 0.3211 | 0.1221 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1364T>G | L455R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455R resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM; 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 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 integrates FoldX‑MD and Rosetta stability outputs, also predicts 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 none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -16.347 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 6.36 | Destabilizing | 0.2 | 4.96 | Destabilizing | 5.66 | Destabilizing | 2.08 | Destabilizing | 0.648 | Likely Pathogenic | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0.1126 | 0.0600 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1366C>A | Q456K 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q456K is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; premPS and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of tools (six pathogenic vs five benign) and the SGM‑Consensus result point toward a pathogenic interpretation, while Foldetta suggests stability‑preserving benignity. 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 | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -13.768 | Likely Pathogenic | 0.806 | Likely Pathogenic | Ambiguous | 0.21 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.22 | Likely Benign | 0.78 | Ambiguous | 0.391 | Likely Benign | -3.75 | Deleterious | 0.969 | Probably Damaging | 0.875 | Possibly Damaging | 3.36 | Benign | 0.13 | Tolerated | 0.1321 | 0.2547 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.1366C>G | Q456E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remaining uncertain. Overall, the predictions are split, but the high‑accuracy consensus leans toward pathogenicity. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -12.982 | Likely Pathogenic | 0.503 | Ambiguous | Likely Benign | 0.71 | Ambiguous | 0.1 | 0.87 | Ambiguous | 0.79 | Ambiguous | 0.65 | Ambiguous | 0.233 | Likely Benign | -2.76 | Deleterious | 0.998 | Probably Damaging | 0.964 | Probably Damaging | 3.41 | Benign | 0.15 | Tolerated | 0.1191 | 0.1276 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.1367A>C | Q456P 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q456P is listed in ClinVar with an uncertain significance (ClinVar ID 2697090.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are made by FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. High‑accuracy methods specifically report pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are inconclusive. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, which contradicts the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | Uncertain | 1 | -15.250 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.68 | Destabilizing | 0.2 | 8.43 | Destabilizing | 6.06 | Destabilizing | 0.82 | Ambiguous | 0.469 | Likely Benign | -5.66 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.34 | Benign | 0.07 | Tolerated | 3.37 | 34 | 0.2256 | 0.3631 | -1 | 0 | 1.9 | -31.01 | |||||||||||||||||||||||||
| c.1367A>G | Q456R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain; the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta (a folding‑stability method combining FoldX‑MD and Rosetta outputs) predicts benign. No evidence from the data contradicts ClinVar status, which is currently unclassified. Based on the available predictions, the variant is most likely benign, though the evidence is conflicting and does not conflict with the lack of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -11.326 | Likely Pathogenic | 0.801 | Likely Pathogenic | Ambiguous | 0.21 | Likely Benign | 0.1 | 0.12 | Likely Benign | 0.17 | Likely Benign | 0.33 | Likely Benign | 0.295 | Likely Benign | -3.69 | Deleterious | 0.980 | Probably Damaging | 0.943 | Probably Damaging | 3.37 | Benign | 0.20 | Tolerated | 0.1241 | 0.1124 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1367A>T | Q456L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools with uncertain or inconclusive results are FoldX, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation, with no evidence of contradiction with the ClinVar 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. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -10.272 | Likely Pathogenic | 0.492 | Ambiguous | Likely Benign | -0.88 | Ambiguous | 0.1 | -0.30 | Likely Benign | -0.59 | Ambiguous | 0.28 | Likely Benign | 0.347 | Likely Benign | -6.65 | Deleterious | 0.987 | Probably Damaging | 0.914 | Probably Damaging | 3.49 | Benign | 0.36 | Tolerated | 0.0554 | 0.4317 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||
| c.1368G>C | Q456H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions lean toward a benign impact, and this does not contradict the lack of ClinVar annotation. Thus, based on the available computational evidence, the variant is most likely benign, though a high‑accuracy consensus suggests a possible pathogenic effect that warrants further investigation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -7.993 | In-Between | 0.598 | Likely Pathogenic | Likely Benign | 0.74 | Ambiguous | 0.1 | 0.39 | Likely Benign | 0.57 | Ambiguous | 0.32 | Likely Benign | 0.214 | Likely Benign | -4.07 | Deleterious | 0.996 | Probably Damaging | 0.974 | Probably Damaging | 3.37 | Benign | 0.19 | Tolerated | 0.0987 | 0.2358 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1368G>T | Q456H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions lean toward a benign impact, and this does not contradict the lack of ClinVar annotation. Thus, based on the available computational evidence, the variant is most likely benign, though a high‑accuracy consensus suggests a possible pathogenic effect that warrants further investigation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -7.993 | In-Between | 0.598 | Likely Pathogenic | Likely Benign | 0.74 | Ambiguous | 0.1 | 0.39 | Likely Benign | 0.57 | Ambiguous | 0.32 | Likely Benign | 0.214 | Likely Benign | -4.07 | Deleterious | 0.996 | Probably Damaging | 0.974 | Probably Damaging | 3.37 | Benign | 0.19 | Tolerated | 0.0987 | 0.2358 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1369A>C | S457R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from REVEL, Rosetta, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenic, whereas Foldetta’s stability analysis is uncertain. Overall, the majority of evidence points toward a pathogenic impact. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -10.882 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | 0.468 | Likely Benign | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0.0781 | 0.3426 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1369A>G | S457G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S457G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for S457G. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -9.154 | Likely Pathogenic | 0.811 | Likely Pathogenic | Ambiguous | 0.86 | Ambiguous | 0.0 | 0.87 | Ambiguous | 0.87 | Ambiguous | 0.65 | Ambiguous | 0.382 | Likely Benign | -3.82 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 3.35 | Benign | 0.13 | Tolerated | 0.2735 | 0.4074 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.1369A>T | S457C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S457C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, Foldetta, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give mixed results: AlphaMissense‑Optimized is inconclusive and therefore not used as evidence; the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign effect. Overall, the majority of individual predictors lean toward pathogenicity, while the high‑accuracy Foldetta result suggests benign stability. Given the predominance of pathogenic calls and the lack of ClinVar evidence, the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -8.152 | Likely Pathogenic | 0.815 | Likely Pathogenic | Ambiguous | -0.12 | Likely Benign | 0.0 | -0.79 | Ambiguous | -0.46 | Likely Benign | 0.56 | Ambiguous | 0.497 | Likely Benign | -4.81 | Deleterious | 0.999 | Probably Damaging | 0.987 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 0.0865 | 0.6284 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.136C>A | P46T 2D  AIThe SynGAP1 missense variant P46T is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, all of which classify the change as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic impact. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy methods give a consistent benign signal: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign,” and Foldetta data are missing. Overall, the majority of reliable predictors and the consensus analysis indicate that P46T is most likely benign, and this conclusion does not contradict the ClinVar status, which contains no pathogenic assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.390993 | Structured | 0.433588 | Uncertain | 0.549 | 0.741 | 0.375 | -4.329 | Likely Benign | 0.383 | Ambiguous | Likely Benign | 0.092 | Likely Benign | -0.68 | Neutral | 0.909 | Possibly Damaging | 0.901 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 0.2194 | 0.6400 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.136C>G | P46A 2D  AIThe SynGAP1 missense variant P46A 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 P46A, 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 | 0.390993 | Structured | 0.433588 | Uncertain | 0.549 | 0.741 | 0.375 | -4.811 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.68 | Neutral | 0.805 | Possibly Damaging | 0.857 | Possibly Damaging | 4.16 | Benign | 0.00 | Affected | 0.3987 | 0.5696 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.136C>T | P46S 2D  AIThe SynGAP1 missense variant P46S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from 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 (majority vote) also indicates benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence—including high‑accuracy tools—points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.390993 | Structured | 0.433588 | Uncertain | 0.549 | 0.741 | 0.375 | Uncertain | 1 | -3.338 | Likely Benign | 0.302 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.60 | Neutral | 0.909 | Possibly Damaging | 0.901 | Possibly Damaging | 4.15 | Benign | 0.00 | Affected | 0.3904 | 0.5771 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||
| c.1370G>A | S457N 2D AIThe SynGAP1 missense variant S457N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, SIFT, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus methods give a mixed picture: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the majority of individual predictors lean toward pathogenicity, but the high‑accuracy Foldetta result suggests a benign impact. Thus, the variant is most likely pathogenic based on the preponderance of predictions, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | Uncertain | 1 | -10.221 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 0.19 | Likely Benign | 0.0 | -0.22 | Likely Benign | -0.02 | Likely Benign | 0.67 | Ambiguous | 0.241 | Likely Benign | -2.76 | Deleterious | 0.940 | Possibly Damaging | 0.843 | Possibly Damaging | 3.28 | Benign | 0.06 | Tolerated | 0.1015 | 0.4980 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||
| c.1370G>C | S457T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457T has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. FoldX and Rosetta provide uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicting likely pathogenic, and Foldetta predicting benign. Overall, the majority of high‑confidence tools lean toward a benign effect, and there is no conflict with the ClinVar status, which is currently unreported. 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. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -8.772 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 0.82 | Ambiguous | 0.1 | -0.57 | Ambiguous | 0.13 | Likely Benign | 0.38 | Likely Benign | 0.273 | Likely Benign | -2.83 | Deleterious | 0.866 | Possibly Damaging | 0.780 | Possibly Damaging | 3.34 | Benign | 0.09 | Tolerated | 0.1154 | 0.6487 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1370G>T | S457I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457I lies within the GAP domain. ClinVar has no entry for this change, and it is absent from gnomAD. Prediction tools that report a benign effect include FoldX and FATHMM, whereas the majority of other in silico predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized—classify it as pathogenic. Uncertain results come from Rosetta, Foldetta and premPS. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN) is Likely Pathogenic, and Foldetta remains inconclusive. Based on the preponderance of pathogenic predictions, 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 | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -13.170 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | -0.26 | Likely Benign | 0.3 | -0.96 | Ambiguous | -0.61 | Ambiguous | 0.65 | Ambiguous | 0.557 | Likely Pathogenic | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.34 | Benign | 0.02 | Affected | 0.0779 | 0.6095 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.1371T>A | S457R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457R is 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 FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, SGM‑Consensus confirms a likely pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence from multiple independent predictors indicates that S457R is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -10.882 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | 0.343 | Likely Benign | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0.0781 | 0.3426 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1371T>G | S457R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457R is 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 FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, SGM‑Consensus confirms a likely pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence from multiple independent predictors indicates that S457R is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -10.882 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | 0.343 | Likely Benign | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0.0781 | 0.3426 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1372A>C | T458P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T458P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are SIFT and FATHMM, while the remaining tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, ESM1b, and the SGM‑Consensus) all predict a pathogenic impact; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a pathogenic effect. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of pathogenic 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 | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -13.547 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 3.05 | Destabilizing | 0.2 | 5.36 | Destabilizing | 4.21 | Destabilizing | 0.78 | Ambiguous | 0.557 | Likely Pathogenic | -5.33 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.35 | Benign | 0.06 | Tolerated | 0.2098 | 0.5395 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1372A>G | T458A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 T458A missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign. Overall, the majority of reliable predictors (six pathogenic vs. five benign) indicate a pathogenic effect. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -10.734 | Likely Pathogenic | 0.924 | Likely Pathogenic | Ambiguous | 0.36 | Likely Benign | 0.0 | 0.31 | Likely Benign | 0.34 | Likely Benign | 0.56 | Ambiguous | 0.358 | Likely Benign | -4.27 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.40 | Benign | 0.15 | Tolerated | 0.4137 | 0.4257 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1372A>T | T458S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 T458S missense variant has no ClinVar entry and is not present in gnomAD. Functional prediction tools cluster into two groups: benign calls from REVEL, FoldX, Rosetta, SIFT, and FATHMM; pathogenic calls from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments further split the signal: AlphaMissense‑Optimized remains uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Because the majority of standard predictors are evenly divided and the high‑accuracy methods disagree, the variant’s effect cannot be confidently classified as benign or pathogenic. Thus, the variant is of uncertain significance, and this uncertainty 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 | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -8.465 | Likely Pathogenic | 0.915 | Likely Pathogenic | Ambiguous | 0.44 | Likely Benign | 0.1 | 0.35 | Likely Benign | 0.40 | Likely Benign | 0.55 | Ambiguous | 0.260 | Likely Benign | -3.49 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.48 | Benign | 0.13 | Tolerated | 0.3525 | 0.4349 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1373C>A | T458K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T458K 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, SIFT, and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results from FoldX and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting pathogenicity, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicting pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting benign stability. Overall, the majority of evidence points 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. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -13.734 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | -0.59 | Ambiguous | 0.1 | -0.26 | Likely Benign | -0.43 | Likely Benign | 0.80 | Ambiguous | 0.373 | Likely Benign | -5.23 | Deleterious | 0.999 | Probably Damaging | 0.973 | Probably Damaging | 3.40 | Benign | 0.14 | Tolerated | 0.1153 | 0.3326 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||
| c.1373C>G | T458R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant T458R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, SIFT, and FATHMM, whereas a larger set—SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict pathogenicity. Uncertain results come from FoldX and premPS. 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) as benign. Overall, the majority of evidence points to 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. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -12.984 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | -0.81 | Ambiguous | 0.1 | -0.11 | Likely Benign | -0.46 | Likely Benign | 0.61 | Ambiguous | 0.390 | Likely Benign | -5.26 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.52 | Benign | 0.20 | Tolerated | 0.1016 | 0.3013 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||
| c.1373C>T | T458I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 T458I missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM. Those that predict a pathogenic impact are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools (seven versus six) and the two high‑accuracy pathogenic predictions suggest the variant is most likely pathogenic. 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 | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -9.436 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | -0.40 | Likely Benign | 0.1 | 0.29 | Likely Benign | -0.06 | Likely Benign | 0.50 | Likely Benign | 0.337 | Likely Benign | -4.76 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.40 | Benign | 0.09 | Tolerated | 0.0724 | 0.6128 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1375G>A | G459S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G459S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from REVEL and FATHMM, while pathogenic predictions are made by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic 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 Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -10.979 | Likely Pathogenic | 0.873 | Likely Pathogenic | Ambiguous | 2.34 | Destabilizing | 0.1 | 0.77 | Ambiguous | 1.56 | Ambiguous | 0.60 | Ambiguous | 0.414 | Likely Benign | -5.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.09 | Benign | 0.05 | Affected | 0.2340 | 0.5197 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.1375G>C | G459R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant G459R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM Consensus score (Likely Pathogenic) all indicate a pathogenic impact. Stability‑based methods (FoldX, Rosetta, premPS) are inconclusive, and Foldetta likewise reports an uncertain effect. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as Likely Pathogenic, and Foldetta as unavailable. Taken together, the consensus of the majority of tools points to a pathogenic effect for G459R. This prediction is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -12.958 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.84 | Ambiguous | 0.2 | 0.79 | Ambiguous | 1.32 | Ambiguous | 0.79 | Ambiguous | 0.486 | Likely Benign | -7.41 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 0.0903 | 0.4248 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1375G>T | G459C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G459C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the majority of algorithms (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence points to a pathogenic effect for G459C, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -12.109 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 2.46 | Destabilizing | 0.2 | 1.49 | Ambiguous | 1.98 | Ambiguous | 0.65 | Ambiguous | 0.586 | Likely Pathogenic | -8.46 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | 0.0960 | 0.4103 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.1376G>A | G459D 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant G459D is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate benign effects include REVEL and FATHMM, while the majority of tools predict pathogenicity: FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta, Foldetta, 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 as inconclusive. Overall, the evidence points to a pathogenic effect for G459D, 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 | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -11.258 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 2.21 | Destabilizing | 0.1 | 0.56 | Ambiguous | 1.39 | Ambiguous | 0.93 | Ambiguous | 0.454 | Likely Benign | -6.18 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.07 | Benign | 0.05 | Affected | 0.1466 | 0.1905 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.1376G>C | G459A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 G459A missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions labeled Uncertain (Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is Uncertain and therefore not considered evidence. Overall, the majority of reliable tools indicate a pathogenic impact, 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 | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -11.684 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 2.44 | Destabilizing | 0.1 | 0.90 | Ambiguous | 1.67 | Ambiguous | 0.72 | Ambiguous | 0.469 | Likely Benign | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.06 | Benign | 0.01 | Affected | 0.3529 | 0.5161 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1376G>T | G459V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G459V is not reported in ClinVar and is absent from gnomAD. 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, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; premPS is inconclusive and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the consensus of these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for G459V. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -13.606 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.79 | Destabilizing | 0.1 | 5.01 | Destabilizing | 4.40 | Destabilizing | 0.71 | Ambiguous | 0.605 | Likely Pathogenic | -8.46 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.99 | Benign | 0.00 | Affected | 0.0997 | 0.4240 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1378A>C | K460Q 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant K460Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, SIFT, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive include FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments give a pathogenic consensus from the SGM method (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and an uncertain result from AlphaMissense‑Optimized; Foldetta likewise reports no definitive stability change. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -9.404 | Likely Pathogenic | 0.793 | Likely Pathogenic | Ambiguous | 0.71 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.79 | Ambiguous | 0.86 | Ambiguous | 0.312 | Likely Benign | -3.15 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 3.35 | Benign | 0.14 | Tolerated | 0.4523 | 0.1454 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1378A>G | K460E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K460E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. In contrast, a majority of tools predict a pathogenic impact: AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 (HumDiv and HumVar), Rosetta, and premPS all indicate pathogenicity, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No prediction or folding‑stability result is missing or inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for K460E, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -13.304 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 1.68 | Ambiguous | 0.0 | 2.02 | Destabilizing | 1.85 | Ambiguous | 1.05 | Destabilizing | 0.398 | Likely Benign | -3.40 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.34 | Benign | 0.09 | Tolerated | 0.3966 | 0.1022 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1379A>C | K460T 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant K460T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Stability‑based methods (FoldX, Rosetta, premPS, Foldetta) yield uncertain or inconclusive results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta’s combined FoldX‑MD/Rosetta analysis remains inconclusive. Overall, the majority of evidence points to a pathogenic impact for K460T, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -11.187 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 1.23 | Ambiguous | 0.1 | 1.16 | Ambiguous | 1.20 | Ambiguous | 0.77 | Ambiguous | 0.208 | Likely Benign | -5.02 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.35 | Benign | 0.07 | Tolerated | 0.1858 | 0.3848 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1379A>G | K460R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K460R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity, while Rosetta and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Taken together, the overwhelming majority of evidence 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 | GAP | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -5.349 | Likely Benign | 0.175 | Likely Benign | Likely Benign | -0.41 | Likely Benign | 0.0 | 0.63 | Ambiguous | 0.11 | Likely Benign | 0.55 | Ambiguous | 0.103 | Likely Benign | -1.52 | Neutral | 0.991 | Probably Damaging | 0.962 | Probably Damaging | 3.46 | Benign | 0.63 | Tolerated | 0.5093 | 0.1169 | Weaken | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||
| c.1379A>T | K460M 2D  3DClick to see structure in 3D Viewer AISynGAP1 K460M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic calls arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: FoldX and AlphaMissense‑Optimized. When high‑accuracy methods are considered separately, AlphaMissense‑Optimized remains inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of predictions lean toward pathogenicity, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -10.351 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 0.61 | Ambiguous | 0.0 | 0.18 | Likely Benign | 0.40 | Likely Benign | 0.20 | Likely Benign | 0.252 | Likely Benign | -4.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.29 | Benign | 0.02 | Affected | 0.1148 | 0.4522 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.137C>A | P46H 2D  AIThe SynGAP1 missense variant P46H is evaluated by multiple in silico tools. Consensus from SGM‑Consensus indicates a likely benign effect, and the variant is not reported in ClinVar or gnomAD. Functional predictors that agree on a benign outcome include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Predictors that flag a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports likely benign, while Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for P46H, and this conclusion is not contradicted by any ClinVar annotation. The variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.390993 | Structured | 0.433588 | Uncertain | 0.549 | 0.741 | 0.375 | -4.022 | Likely Benign | 0.428 | Ambiguous | Likely Benign | 0.097 | Likely Benign | -0.43 | Neutral | 0.992 | Probably Damaging | 0.977 | Probably Damaging | 4.10 | Benign | 0.00 | Affected | 0.2360 | 0.5229 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.137C>G | P46R 2D  AIThe SynGAP1 missense variant P46R is catalogued in gnomAD (ID 6‑33423546‑C‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (FoldX‑MD/Rosetta stability assessment) has no available result. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data is missing. 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 | 0.390993 | Structured | 0.433588 | Uncertain | 0.549 | 0.741 | 0.375 | 6-33423546-C-G | 1 | 6.20e-7 | -0.520 | Likely Benign | 0.385 | Ambiguous | Likely Benign | 0.155 | Likely Benign | 0.39 | Neutral | 0.972 | Probably Damaging | 0.954 | Probably Damaging | 4.39 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1669 | 0.4543 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||
| c.137C>T | P46L 2D  AIThe SynGAP1 missense variant P46L 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 and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for P46L, 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 | 0.390993 | Structured | 0.433588 | Uncertain | 0.549 | 0.741 | 0.375 | -5.135 | Likely Benign | 0.594 | Likely Pathogenic | Likely Benign | 0.076 | Likely Benign | -1.14 | Neutral | 0.909 | Possibly Damaging | 0.927 | Probably Damaging | 4.12 | Benign | 0.00 | Affected | 0.2469 | 0.6633 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.1380G>C | K460N 2D  AIThe SynGAP1 missense variant K460N 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, SIFT, and FATHMM, whereas those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic signal: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic; and the protein‑folding stability method Foldetta, which integrates FoldX‑MD and Rosetta outputs, indicates a benign effect. Overall, the balance of evidence—six pathogenic versus five benign predictions, a pathogenic SGM Consensus, and a pathogenic AlphaMissense‑Optimized—suggests that K460N is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant is not currently catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -11.988 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.5 | 0.45 | Likely Benign | 0.35 | Likely Benign | 0.89 | Ambiguous | 0.202 | Likely Benign | -4.13 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.29 | Benign | 0.06 | Tolerated | 0.3669 | 0.1599 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1380G>T | K460N 2D AIThe SynGAP1 K460N missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods further support a pathogenic interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; whereas Foldetta, which integrates FoldX‑MD and Rosetta outputs, indicates a benign effect. Overall, the majority of evidence—including the high‑accuracy tools—points to a pathogenic impact for K460N. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -11.988 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.5 | 0.45 | Likely Benign | 0.35 | Likely Benign | 0.89 | Ambiguous | 0.202 | Likely Benign | -4.13 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.29 | Benign | 0.06 | Tolerated | 0.3669 | 0.1599 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1381G>A | A461T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A461T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta is also inconclusive. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -10.885 | Likely Pathogenic | 0.323 | Likely Benign | Likely Benign | 1.21 | Ambiguous | 0.2 | 0.51 | Ambiguous | 0.86 | Ambiguous | 0.65 | Ambiguous | 0.214 | Likely Benign | -3.27 | Deleterious | 0.508 | Possibly Damaging | 0.042 | Benign | 3.40 | Benign | 0.13 | Tolerated | 0.1083 | 0.5930 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.1381G>C | A461P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and FATHMM, whereas the majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS remains uncertain. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is pathogenic. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -13.869 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | -0.35 | Likely Benign | 0.1 | 5.09 | Destabilizing | 2.37 | Destabilizing | 0.84 | Ambiguous | 0.451 | Likely Benign | -4.52 | Deleterious | 0.999 | Probably Damaging | 0.849 | Possibly Damaging | 3.32 | Benign | 0.03 | Affected | 0.1748 | 0.3949 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1381G>T | A461S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 (HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv), SIFT, and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta’s stability analysis is also unavailable. Overall, the balance of evidence leans toward a benign effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -10.663 | Likely Pathogenic | 0.309 | Likely Benign | Likely Benign | 0.87 | Ambiguous | 0.0 | 1.18 | Ambiguous | 1.03 | Ambiguous | 0.63 | Ambiguous | 0.236 | Likely Benign | -2.74 | Deleterious | 0.600 | Possibly Damaging | 0.289 | Benign | 3.36 | Benign | 0.02 | Affected | 0.2401 | 0.4551 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1382C>A | A461D 2D AIThe SynGAP1 missense variant A461D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. 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). FoldX and Foldetta are inconclusive, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that A461D is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -14.918 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.89 | Ambiguous | 1.1 | 2.18 | Destabilizing | 1.54 | Ambiguous | 1.09 | Destabilizing | 0.477 | Likely Benign | -5.47 | Deleterious | 0.997 | Probably Damaging | 0.792 | Possibly Damaging | 3.32 | Benign | 0.01 | Affected | 0.1533 | 0.2016 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1382C>G | A461G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461G has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into three groups: benign predictions come from REVEL, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; the remaining tools (FoldX, premPS, AlphaMissense‑Default, Foldetta) 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 pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect, with no ClinVar record 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. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -11.360 | Likely Pathogenic | 0.556 | Ambiguous | Likely Benign | 1.46 | Ambiguous | 0.1 | 2.06 | Destabilizing | 1.76 | Ambiguous | 0.83 | Ambiguous | 0.276 | Likely Benign | -3.79 | Deleterious | 0.991 | Probably Damaging | 0.628 | Possibly Damaging | 3.32 | Benign | 0.00 | Affected | 0.1988 | 0.3317 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.1382C>T | A461V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Because the majority of standard predictors (nine benign vs. three pathogenic) favor a benign outcome, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -9.968 | Likely Pathogenic | 0.436 | Ambiguous | Likely Benign | -0.08 | Likely Benign | 0.3 | 0.34 | Likely Benign | 0.13 | Likely Benign | 0.02 | Likely Benign | 0.141 | Likely Benign | -3.05 | Deleterious | 0.983 | Probably Damaging | 0.273 | Benign | 3.43 | Benign | 0.66 | Tolerated | 0.0819 | 0.5078 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.1384A>C | K462Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K462Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, 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) as benign. Overall, the majority of tools and the protein‑stability analysis favor a benign effect, while the consensus pathogenic score introduces uncertainty. Thus, the variant is most likely benign; this assessment does not contradict ClinVar status, which has no entry for K462Q. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | -12.144 | Likely Pathogenic | 0.809 | Likely Pathogenic | Ambiguous | 0.12 | Likely Benign | 0.1 | 0.34 | Likely Benign | 0.23 | Likely Benign | 0.48 | Likely Benign | 0.384 | Likely Benign | -3.85 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 3.40 | Benign | 0.15 | Tolerated | 0.4639 | 0.1286 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1384A>G | K462E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K462E is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta and Foldetta are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta is uncertain. Overall, the majority of predictions (7 pathogenic vs. 5 benign) and the high‑accuracy tools support a pathogenic classification. Thus, 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 | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | -14.696 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.34 | Likely Benign | 0.0 | 1.56 | Ambiguous | 0.95 | Ambiguous | 0.33 | Likely Benign | 0.433 | Likely Benign | -3.88 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 3.49 | Benign | 0.15 | Tolerated | 0.4145 | 0.1022 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1385A>C | K462T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K462T missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect. 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 | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | -11.586 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.55 | Ambiguous | 0.0 | 1.08 | Ambiguous | 0.82 | Ambiguous | 0.30 | Likely Benign | 0.414 | Likely Benign | -5.82 | Deleterious | 0.999 | Probably Damaging | 1.000 | Probably Damaging | 3.47 | Benign | 0.08 | Tolerated | 0.2095 | 0.3257 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1385A>G | K462R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K462R is catalogued in gnomAD (ID 6‑33438290‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Three tools (Rosetta, Foldetta, premPS) yield uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic) and Foldetta is uncertain, so neither provides decisive evidence. Overall, the majority of reliable predictors lean toward a benign effect. This consensus does not contradict ClinVar status, which is currently absent. Thus, based on available predictions, K462R is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | 6-33438290-A-G | 1 | 6.20e-7 | -9.980 | Likely Pathogenic | 0.184 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.90 | Ambiguous | 0.52 | Ambiguous | 0.84 | Ambiguous | 0.246 | Likely Benign | -2.75 | Deleterious | 0.983 | Probably Damaging | 0.962 | Probably Damaging | 3.43 | Benign | 0.09 | Tolerated | 3.37 | 34 | 0.4995 | 0.1201 | 2 | 3 | -0.6 | 28.01 | |||||||||||||||||||||||||
| c.1385A>T | K462M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K462M 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, FATHMM, premPS, and the protein‑folding stability method Foldetta; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. Rosetta’s output is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also pathogenic, while Foldetta indicates a benign effect on protein stability. No evidence from ClinVar contradicts these findings. Overall, the majority of predictive tools and the consensus score support a pathogenic classification, suggesting that K462M is most likely pathogenic rather than benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | -12.837 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | -0.23 | Likely Benign | 0.1 | 0.86 | Ambiguous | 0.32 | Likely Benign | 0.17 | Likely Benign | 0.475 | Likely Benign | -5.82 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.02 | Affected | 0.1282 | 0.3932 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1386G>C | K462N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K462N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are returned by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, and the SGM Consensus also indicates Likely Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result, providing no definitive evidence. Overall, the majority of high‑confidence predictors lean toward pathogenicity, contradicting the absence of a ClinVar classification. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | -12.823 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.69 | Ambiguous | 0.1 | 1.67 | Ambiguous | 1.18 | Ambiguous | 0.90 | Ambiguous | 0.304 | Likely Benign | -4.83 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.07 | Tolerated | 3.37 | 34 | 0.3967 | 0.1242 | 0 | 1 | 0.4 | -14.07 | |||||||||||||||||||||||||||
| c.1386G>T | K462N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K462N is reported in gnomAD (ID 6‑33438291‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑based methods (FoldX, Rosetta, premPS) and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, while Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for K462N. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | 6-33438291-G-T | 1 | 6.20e-7 | -12.823 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.69 | Ambiguous | 0.1 | 1.67 | Ambiguous | 1.18 | Ambiguous | 0.90 | Ambiguous | 0.303 | Likely Benign | -4.83 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.07 | Tolerated | 3.37 | 34 | 0.3967 | 0.1242 | 0 | 1 | 0.4 | -14.07 | ||||||||||||||||||||||||
| c.1387G>A | D463N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D463N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic impact are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Predictions that are uncertain (Foldetta, AlphaMissense‑Optimized, Rosetta) are treated as unavailable and do not influence the overall assessment. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; Foldetta is uncertain. Overall, the majority of available predictions lean toward a benign effect, and this conclusion does not contradict any ClinVar status (none reported). 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. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -11.428 | Likely Pathogenic | 0.812 | Likely Pathogenic | Ambiguous | 0.10 | Likely Benign | 0.1 | 1.19 | Ambiguous | 0.65 | Ambiguous | 0.40 | Likely Benign | 0.217 | Likely Benign | -4.37 | Deleterious | 0.880 | Possibly Damaging | 0.430 | Benign | 3.33 | Benign | 0.10 | Tolerated | 0.1152 | 0.5531 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1387G>C | D463H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant D463H is not reported in ClinVar and is absent from gnomAD. Consensus from standard prediction algorithms shows a split: benign predictions come from REVEL, FoldX, SIFT, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, SGM Consensus confirms Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains Uncertain. No evidence from ClinVar contradicts these findings. Overall, the preponderance of computational evidence indicates that D463H is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -13.151 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.20 | Likely Benign | 0.1 | 0.85 | Ambiguous | 0.53 | Ambiguous | 0.57 | Ambiguous | 0.356 | Likely Benign | -5.96 | Deleterious | 0.996 | Probably Damaging | 0.852 | Possibly Damaging | 3.35 | Benign | 0.11 | Tolerated | 0.1341 | 0.6156 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1387G>T | D463Y 2D  3DClick to see structure in 3D Viewer AIClinVar reports no entry for this SynGAP1 D463Y variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results come from AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of conventional tools lean toward pathogenicity, while the high‑accuracy Foldetta suggests benign. Thus, the variant is most likely pathogenic based on the prevailing 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 | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -14.387 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | -0.14 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.32 | Likely Benign | 0.07 | Likely Benign | 0.399 | Likely Benign | -7.95 | Deleterious | 0.998 | Probably Damaging | 0.904 | Possibly Damaging | 3.35 | Benign | 0.14 | Tolerated | 0.0540 | 0.6213 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1388A>C | D463A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D463A missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, premPS, SIFT, FATHMM, and the folding‑stability method Foldetta. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as likely pathogenic, and Foldetta predicts a benign effect on protein stability. Overall, the majority of tools and the consensus high‑accuracy prediction lean toward pathogenicity, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -8.607 | Likely Pathogenic | 0.894 | Likely Pathogenic | Ambiguous | -0.04 | Likely Benign | 0.1 | 0.96 | Ambiguous | 0.46 | Likely Benign | 0.43 | Likely Benign | 0.425 | Likely Benign | -6.96 | Deleterious | 0.978 | Probably Damaging | 0.602 | Possibly Damaging | 3.33 | Benign | 0.29 | Tolerated | 0.3591 | 0.5169 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1388A>G | D463G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D463G missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Five tools favor pathogenicity versus three favor benign, with the remaining five (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) yielding uncertain results. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive; 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 outputs, also remains inconclusive. Overall, the preponderance of evidence points to a pathogenic effect, and 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 | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -10.713 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 0.66 | Ambiguous | 0.1 | 1.93 | Ambiguous | 1.30 | Ambiguous | 0.54 | Ambiguous | 0.422 | Likely Benign | -6.36 | Deleterious | 0.994 | Probably Damaging | 0.824 | Possibly Damaging | 3.32 | Benign | 0.09 | Tolerated | 0.3751 | 0.4898 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1388A>T | D463V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D463V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain predictions come from Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points toward a pathogenic impact for D463V, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -12.374 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 0.23 | Likely Benign | 0.1 | 0.98 | Ambiguous | 0.61 | Ambiguous | 0.33 | Likely Benign | 0.521 | Likely Pathogenic | -7.95 | Deleterious | 0.973 | Probably Damaging | 0.658 | Possibly Damaging | 3.31 | Benign | 0.09 | Tolerated | 0.0713 | 0.5526 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1389C>A | D463E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D463E 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and premPS. Only PROVEAN predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that 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. | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -5.170 | Likely Benign | 0.527 | Ambiguous | Likely Benign | -0.42 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.04 | Likely Benign | 0.47 | Likely Benign | 0.162 | Likely Benign | -2.58 | Deleterious | 0.012 | Benign | 0.003 | Benign | 3.47 | Benign | 0.29 | Tolerated | 0.1330 | 0.5177 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.1389C>G | D463E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D463E 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and premPS. Only PROVEAN predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) resolves to benign, and Foldetta also indicates benign stability. No prediction or stability result is missing or inconclusive. Overall, the variant is most likely benign based on the collective 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. | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -5.170 | Likely Benign | 0.527 | Ambiguous | Likely Benign | -0.42 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.04 | Likely Benign | 0.47 | Likely Benign | 0.162 | Likely Benign | -2.58 | Deleterious | 0.012 | Benign | 0.003 | Benign | 3.47 | Benign | 0.29 | Tolerated | 0.1330 | 0.5177 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.1390T>A | F464I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464I 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 limited to FATHMM, while all other evaluated algorithms—including SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -11.210 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 4.77 | Destabilizing | 0.2 | 4.35 | Destabilizing | 4.56 | Destabilizing | 1.23 | Destabilizing | 0.539 | Likely Pathogenic | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | 0.1439 | 0.2002 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1390T>C | F464L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability assessments. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta’s combined FoldX‑MD and Rosetta output is uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not conflict with any ClinVar annotation because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -10.482 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.63 | Ambiguous | 0.3 | 0.95 | Ambiguous | 1.29 | Ambiguous | 1.12 | Destabilizing | 0.435 | Likely Benign | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 3.93 | Benign | 0.22 | Tolerated | 0.1664 | 0.2883 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1390T>G | F464V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 F464V variant is listed in ClinVar with an “Uncertain” status (ClinVar ID 1716596.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective predictions, the variant is most likely pathogenic, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | Uncertain | 1 | -12.254 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.61 | Destabilizing | 0.1 | 2.89 | Destabilizing | 3.25 | Destabilizing | 1.40 | Destabilizing | 0.592 | Likely Pathogenic | -6.96 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 3.36 | Benign | 0.04 | Affected | 3.37 | 34 | 0.1587 | 0.2219 | -1 | -1 | 1.4 | -48.04 | 210.1 | 40.5 | -0.1 | 0.0 | -0.9 | 0.3 | X | Potentially Pathogenic | The phenyl ring of Phe464, located in the middle of an α helix (res. Ala461–Phe476), packs against hydrophobic residues (e.g., Met468, Leu451, Leu455, and Tyr428) in the inter-helix space formed with two other α helices (res. Asn440-Lys460 and res. Pro413-Glu436). The iso-propyl side chain of Val464 is similarly hydrophobic but considerably smaller than the original phenyl ring of Phe464. To compensate for the size difference, neighboring residues need to fill in the gap in the variant simulations.The phenolic side chain of Tyr428, located at the middle bend of an α helix (res. Glu436-Pro413), assumes a new position in the inter-helix space or rotates inward next to the third α helix (res. Asn440-Lys460) when the stable H-bond between Tyr428 and Asp467 seen in the WT simulations breaks. The residue swap also leads to the loss of the methionine-aromatic interaction between the Met468 and Phe464 side chains, which could weaken the integrity of the parent α helix (res. Ala461-Phe476). Although the simulations likely underestimate the full adverse effect of the introduced mutation during folding, the two opposing α helices (res. Ala461–Phe476 and res. Glu436-Pro413) move substantially closer to each other in the variant simulations. | ||||||||||||||||
| c.1391T>A | F464Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464Y is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, while AlphaMissense‑Optimized and Foldetta provide uncertain results and are treated as unavailable evidence. Overall, the balance of evidence points to a pathogenic effect for F464Y, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -10.056 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 1.35 | Ambiguous | 0.1 | 0.24 | Likely Benign | 0.80 | Ambiguous | 1.31 | Destabilizing | 0.387 | Likely Benign | -2.98 | Deleterious | 0.979 | Probably Damaging | 0.953 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.1081 | 0.1523 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1391T>C | F464S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -13.361 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.84 | Destabilizing | 0.0 | 4.90 | Destabilizing | 4.87 | Destabilizing | 2.52 | Destabilizing | 0.748 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.27 | Benign | 0.00 | Affected | 0.3700 | 0.0358 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1391T>G | F464C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -13.011 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.18 | Destabilizing | 0.0 | 4.31 | Destabilizing | 4.25 | Destabilizing | 2.20 | Destabilizing | 0.740 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.2298 | 0.1219 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1392C>A | F464L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability assessments. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta’s combined FoldX‑MD and Rosetta output is uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not conflict with any ClinVar annotation because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -10.482 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.63 | Ambiguous | 0.3 | 0.95 | Ambiguous | 1.29 | Ambiguous | 1.12 | Destabilizing | 0.279 | Likely Benign | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 3.93 | Benign | 0.22 | Tolerated | 0.1664 | 0.2883 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1392C>G | F464L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability assessments. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta’s combined FoldX‑MD and Rosetta output is uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not conflict with any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -10.482 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.63 | Ambiguous | 0.3 | 0.95 | Ambiguous | 1.29 | Ambiguous | 1.12 | Destabilizing | 0.279 | Likely Benign | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 3.93 | Benign | 0.22 | Tolerated | 0.1664 | 0.2883 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1393C>A | L465I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L465I missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score classifies the variant as benign, whereas the Foldetta stability assessment is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive due to a 2‑to‑2 split. Overall, the evidence is mixed; the balance of predictions leans toward a benign interpretation, and this does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | -9.672 | Likely Pathogenic | 0.770 | Likely Pathogenic | Likely Benign | 1.21 | Ambiguous | 0.1 | 1.27 | Ambiguous | 1.24 | Ambiguous | 0.78 | Ambiguous | 0.258 | Likely Benign | -1.99 | Neutral | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 2.54 | Benign | 0.08 | Tolerated | 0.0967 | 0.3539 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1393C>G | L465V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and SIFT, while the remaining tools—FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default—indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports likely pathogenic; and Foldetta, which combines FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Overall, the majority of evidence points to a pathogenic impact, 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 | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | Uncertain | 1 | -9.893 | Likely Pathogenic | 0.838 | Likely Pathogenic | Ambiguous | 2.46 | Destabilizing | 0.1 | 2.66 | Destabilizing | 2.56 | Destabilizing | 1.21 | Destabilizing | 0.276 | Likely Benign | -2.98 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.44 | Pathogenic | 0.10 | Tolerated | 3.37 | 34 | 0.1493 | 0.3378 | 2 | 1 | 0.4 | -14.03 | 204.3 | 30.9 | 0.0 | 0.0 | -0.4 | 0.6 | X | Potentially Benign | The iso-butyl side chain of Leu465, located in the middle of an α helix (res. Ala461–Phe476), packs with hydrophobic residues (e.g., Phe464, Met468, Tyr497, Ile494) in an inter-helix space formed with two other α helices (res. Ala461–Phe476 and res. Thr488-Gly502). In the variant simulations, the iso-propyl side chain of Val465 is equally sized and similarly hydrophobic as the original side chain of Leu465. Hence, the mutation does not exert any negative effects on the protein structure based on the variant simulations. | ||||||||||||||||
| c.1393C>T | L465F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465F is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL and Rosetta, whereas the majority of tools predict a pathogenic impact: FoldX, 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). Two tools (Foldetta and premPS) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus also pathogenic, and Foldetta remains uncertain. Overall, the consensus of high‑confidence predictors points to a pathogenic effect for L465F. 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 | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | -12.626 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 3.11 | Destabilizing | 0.7 | 0.05 | Likely Benign | 1.58 | Ambiguous | 0.52 | Ambiguous | 0.432 | Likely Benign | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.0771 | 0.2759 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1394T>A | L465H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465H 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, predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | -16.751 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.15 | Destabilizing | 0.4 | 2.29 | Destabilizing | 2.72 | Destabilizing | 2.54 | Destabilizing | 0.764 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 0.1289 | 0.1089 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.1394T>C | L465P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465P is listed in ClinVar as Pathogenic (ClinVar ID 1067821.0) 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 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. 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 | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | Likely Pathogenic | 1 | -14.824 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 7.18 | Destabilizing | 0.3 | 10.85 | Destabilizing | 9.02 | Destabilizing | 2.73 | Destabilizing | 0.778 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 3.37 | 34 | 0.3387 | 0.1582 | -3 | -3 | -5.4 | -16.04 | 211.1 | 65.9 | 0.1 | 0.0 | -0.2 | 0.0 | X | Potentially Pathogenic | The iso-butyl side chain of Leu465, located in the middle of an α helix (res. Ala461–Phe476), packs with hydrophobic residues (e.g., Phe464, Met468, Tyr497, Ile494) in an inter-helix space formed with two other α helices (res. Ala461–Phe476 and res. Thr488-Gly502). In the variant simulations, the cyclic five-membered pyrrolidine ring of Pro465 is not as optimal as the side chain of Leu465 for filling the three α helix hydrophobic niche. Although the residue swap does not cause a large-scale conformational shift during the simulations, the H-bond between the backbone amide group of Leu465 and the backbone carbonyl group of Ala461 is lost. This, in turn, breaks the continuity of the α helix secondary structure element. | ||||||||||||||||
| c.1394T>G | L465R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: 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) reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No inconclusive or missing results are present. Based on the consensus of all available predictions, 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 | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | -17.976 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.52 | Destabilizing | 0.7 | 4.44 | Destabilizing | 4.48 | Destabilizing | 2.41 | Destabilizing | 0.761 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 0.1597 | 0.0963 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1396T>A | S466T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S466T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain results come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Taken together, the majority of evidence points to a benign impact. Therefore, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -5.488 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.2 | -1.02 | Ambiguous | -0.36 | Likely Benign | -0.65 | Ambiguous | 0.414 | Likely Benign | 1.05 | Neutral | 0.740 | Possibly Damaging | 0.872 | Possibly Damaging | -1.51 | Pathogenic | 1.00 | Tolerated | 0.0928 | 0.5152 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1396T>C | S466P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S466P is not reported in ClinVar (ClinVar status: 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the only inconclusive result is from premPS (Uncertain). High‑accuracy methods reinforce this view: 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. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -13.107 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.67 | Destabilizing | 0.2 | 2.83 | Destabilizing | 2.75 | Destabilizing | 0.95 | Ambiguous | 0.811 | Likely Pathogenic | -3.02 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | -1.55 | Pathogenic | 0.04 | Affected | 0.1617 | 0.4915 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1396T>G | S466A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S466A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: pathogenic scores are given by REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas benign predictions come from SIFT, PROVEAN, premPS, ESM1b, Rosetta, Foldetta, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, the SGM‑Consensus itself is Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports Benign. FoldX alone is Uncertain, but this does not alter the overall consensus. Taken together, the majority of evidence indicates the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -6.928 | Likely Benign | 0.228 | Likely Benign | Likely Benign | -0.50 | Ambiguous | 0.1 | 0.06 | Likely Benign | -0.22 | Likely Benign | 0.37 | Likely Benign | 0.537 | Likely Pathogenic | -1.46 | Neutral | 0.909 | Possibly Damaging | 0.987 | Probably Damaging | -1.51 | Pathogenic | 0.10 | Tolerated | 0.4245 | 0.3996 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1397C>T | S466L 2D  AIThe SynGAP1 missense variant S466L 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, while the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. Tools with uncertain or inconclusive results are AlphaMissense‑Optimized, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for S466L. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -9.417 | Likely Pathogenic | 0.806 | Likely Pathogenic | Ambiguous | -0.36 | Likely Benign | 1.6 | -1.60 | Ambiguous | -0.98 | Ambiguous | -0.52 | Ambiguous | 0.768 | Likely Pathogenic | -3.05 | Deleterious | 0.995 | Probably Damaging | 0.991 | Probably Damaging | -1.56 | Pathogenic | 0.03 | Affected | 0.0666 | 0.4884 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||
| c.1399G>A | D467N 2D 3DClick to see structure in 3D Viewer AISynGAP1 D467N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a predominance of pathogenic calls: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of the four high‑accuracy predictors) all predict a deleterious effect. Benign predictions come from FoldX, premPS, and SIFT. Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy methods specifically give an uncertain result for AlphaMissense‑Optimized, a pathogenic verdict for the SGM‑Consensus, and an uncertain outcome for Foldetta. Overall, the balance of evidence favors a pathogenic impact for D467N, 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 | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -11.881 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.43 | Likely Benign | 0.1 | 1.63 | Ambiguous | 1.03 | Ambiguous | 0.38 | Likely Benign | 0.673 | Likely Pathogenic | -4.82 | Deleterious | 0.987 | Probably Damaging | 0.990 | Probably Damaging | -1.22 | Pathogenic | 0.06 | Tolerated | 0.0936 | 0.4879 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1399G>C | D467H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D467H 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 premPS, whereas the remaining evaluated algorithms uniformly predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta yield uncertain results and are treated as unavailable. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; Foldetta remains uncertain. Overall, the variant is most likely pathogenic based on the consensus of the available predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -13.348 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.05 | Ambiguous | 0.1 | 0.59 | Ambiguous | 0.82 | Ambiguous | 0.32 | Likely Benign | 0.851 | Likely Pathogenic | -6.71 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.31 | Pathogenic | 0.02 | Affected | 0.1074 | 0.5564 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1399G>T | D467Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D467Y is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Foldetta, premPS, and SIFT, whereas pathogenic calls are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy methods give a clearer picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No evidence from Rosetta is available due to its uncertain status. Overall, the majority of high‑confidence predictions lean toward pathogenicity, and this does not contradict any ClinVar annotation because none exists. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -14.373 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.36 | Likely Benign | 0.1 | -0.60 | Ambiguous | -0.12 | Likely Benign | 0.07 | Likely Benign | 0.846 | Likely Pathogenic | -8.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.28 | Pathogenic | 0.07 | Tolerated | 0.0517 | 0.5521 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.139C>G | R47G 2D  AIThe SynGAP1 missense variant R47G 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 the majority vote of 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 benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence points to a benign impact for R47G, 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 | 0.318242 | Structured | 0.436559 | Uncertain | 0.520 | 0.719 | 0.125 | -6.670 | Likely Benign | 0.616 | Likely Pathogenic | Likely Benign | 0.169 | Likely Benign | -1.79 | Neutral | 0.686 | Possibly Damaging | 0.630 | Possibly Damaging | 4.04 | Benign | 0.00 | Affected | 0.3471 | 0.3758 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.139C>T | R47W 2D  AIThe SynGAP1 missense variant R47W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33423548‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect 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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split; Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs four benign) indicate 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. | 0.318242 | Structured | 0.436559 | Uncertain | 0.520 | 0.719 | 0.125 | 6-33423548-C-T | 1 | 6.20e-7 | -9.201 | Likely Pathogenic | 0.752 | Likely Pathogenic | Likely Benign | 0.201 | Likely Benign | -2.17 | Neutral | 0.994 | Probably Damaging | 0.919 | Probably Damaging | 4.00 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1101 | 0.4158 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.13C>G | R5G 2D AIThe SynGAP1 missense variant R5G is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as 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 | 0.595080 | Disordered | 0.547847 | Binding | 0.363 | 0.920 | 0.750 | Uncertain | 1 | -3.639 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.169 | Likely Benign | -0.16 | Neutral | 0.013 | Benign | 0.003 | Benign | 4.12 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3760 | 0.4332 | -2 | -3 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.1400A>C | D467A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D467A 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 and SIFT, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results—FoldX, Rosetta, and Foldetta—do not provide decisive evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is 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 current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -12.499 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.83 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.81 | Ambiguous | 0.23 | Likely Benign | 0.790 | Likely Pathogenic | -7.71 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.19 | Pathogenic | 0.07 | Tolerated | 0.3134 | 0.5117 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1400A>G | D467G 2D AISynGAP1 missense variant D467G is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from premPS, while all other evaluated algorithms—including SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. No prediction is inconclusive. Consequently, 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 | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -12.973 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.87 | Ambiguous | 0.8 | 2.55 | Destabilizing | 2.21 | Destabilizing | 0.23 | Likely Benign | 0.910 | Likely Pathogenic | -6.81 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | -1.32 | Pathogenic | 0.03 | Affected | 0.3455 | 0.4908 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1400A>T | D467V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D467V missense variant is not reported in ClinVar or gnomAD. Prediction tools cluster into two groups: benign predictions come from Rosetta and premPS, while the majority—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label the change as pathogenic. Two tools, FoldX and Foldetta, give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta remains uncertain. Overall, the consensus of high‑confidence predictors points to a pathogenic effect, and this conclusion is consistent with the absence of any ClinVar annotation or gnomAD observation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -15.041 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.24 | Ambiguous | 0.1 | 0.08 | Likely Benign | 0.66 | Ambiguous | 0.02 | Likely Benign | 0.893 | Likely Pathogenic | -8.70 | Deleterious | 0.997 | Probably Damaging | 0.997 | Probably Damaging | -1.28 | Pathogenic | 0.02 | Affected | 0.0644 | 0.5274 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1401C>A | D467E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D467E is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (gnomAD ID: 6‑33438433‑C‑A). Prediction tools that agree on a benign effect include only FoldX. Tools that agree on a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). Uncertain or inconclusive predictions come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized and are treated as unavailable. 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 indicate 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. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | 6-33438433-C-A | 2 | 1.24e-6 | -9.774 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.36 | Likely Benign | 0.1 | 0.87 | Ambiguous | 0.62 | Ambiguous | 0.60 | Ambiguous | 0.576 | Likely Pathogenic | -3.63 | Deleterious | 0.887 | Possibly Damaging | 0.938 | Probably Damaging | -1.08 | Pathogenic | 0.04 | Affected | 3.37 | 31 | 0.1061 | 0.4564 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||
| c.1401C>G | D467E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D467E missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive predictions 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 Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -9.774 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.36 | Likely Benign | 0.1 | 0.87 | Ambiguous | 0.62 | Ambiguous | 0.60 | Ambiguous | 0.576 | Likely Pathogenic | -3.63 | Deleterious | 0.887 | Possibly Damaging | 0.938 | Probably Damaging | -1.08 | Pathogenic | 0.04 | Affected | 3.37 | 31 | 0.1061 | 0.4564 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||
| c.1402A>C | M468L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar and FATHMM. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments—all available—show benign predictions: AlphaMissense‑Optimized (Benign), SGM‑Consensus (Likely Benign), and Foldetta (Benign). Based on the overall consensus of the majority of tools and the high‑accuracy 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 | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -6.886 | Likely Benign | 0.290 | Likely Benign | Likely Benign | 0.43 | Likely Benign | 0.1 | -0.38 | Likely Benign | 0.03 | Likely Benign | -0.35 | Likely Benign | 0.412 | Likely Benign | 0.19 | Neutral | 0.359 | Benign | 0.654 | Possibly Damaging | -0.73 | Pathogenic | 1.00 | Tolerated | 0.1564 | 0.4408 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1402A>G | M468V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468V 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 PROVEAN, SIFT, and AlphaMissense‑Optimized, while pathogenic predictions are made by REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools, premPS and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments further clarify the variant’s impact: AlphaMissense‑Optimized predicts a benign effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also classifies the variant as pathogenic. Overall, the preponderance of evidence points to a pathogenic 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. | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | Uncertain | 1 | -9.461 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | 2.69 | Destabilizing | 0.1 | 2.20 | Destabilizing | 2.45 | Destabilizing | 0.89 | Ambiguous | 0.570 | Likely Pathogenic | -1.66 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.21 | Pathogenic | 0.08 | Tolerated | 3.37 | 31 | 0.3309 | 0.3845 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||
| c.1402A>T | M468L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar and FATHMM. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta (combining FoldX‑MD and Rosetta outputs)—all indicate a benign outcome. 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 | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -6.886 | Likely Benign | 0.290 | Likely Benign | Likely Benign | 0.43 | Likely Benign | 0.1 | -0.38 | Likely Benign | 0.03 | Likely Benign | -0.35 | Likely Benign | 0.412 | Likely Benign | 0.19 | Neutral | 0.359 | Benign | 0.654 | Possibly Damaging | -0.73 | Pathogenic | 1.00 | Tolerated | 0.1564 | 0.4408 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1403T>A | M468K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468K is listed in ClinVar (ID 642691.0) as Pathogenic and is not reported in gnomAD. All available in silico predictors 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 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 | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | Likely Pathogenic | 1 | -16.982 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 3.21 | Destabilizing | 0.1 | 3.30 | Destabilizing | 3.26 | Destabilizing | 2.57 | Destabilizing | 0.828 | Likely Pathogenic | -4.61 | Deleterious | 0.878 | Possibly Damaging | 0.922 | Probably Damaging | -1.34 | Pathogenic | 0.04 | Affected | 3.37 | 31 | 0.1576 | 0.0456 | 0 | -1 | -5.8 | -3.02 | 188.7 | 69.3 | 0.0 | 0.0 | -0.1 | 0.2 | X | X | Potentially Pathogenic | The thioether group of Met468, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Phe464, Leu465, Leu489) in an inter-helix space formed by two other α helices (res. Ala461–Phe476, res. Thr488–Gly502). In the variant simulations, the positively charged side chain of Lys468 rotates outward to escape the hydrophobic niche, forming an H-bond with the hydroxyl group of the Ser471 side chain and a salt bridge with the carboxylate group of the Glu472 side chain. This residue swap also disrupts the methionine-aromatic stacking with the phenyl ring of the Phe464 side chain. Although no large-scale structural changes are observed during the variant simulations, the importance of hydrophobic packing suggests that the effects could be more pronounced during protein folding. | |||||||||||||||
| c.1403T>C | M468T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468T is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database. Prediction tools that are available all converge on a pathogenic interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool reports a benign outcome. High‑accuracy assessments are consistent: AlphaMissense‑Optimized is “Uncertain,” SGM Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. **Based on the aggregate predictions, 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 | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | Uncertain | 2 | 6-33438435-T-C | 1 | 6.20e-7 | -12.399 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 3.47 | Destabilizing | 0.1 | 3.10 | Destabilizing | 3.29 | Destabilizing | 1.84 | Destabilizing | 0.801 | Likely Pathogenic | -3.85 | Deleterious | 0.994 | Probably Damaging | 0.985 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 3.37 | 31 | 0.2094 | 0.1950 | -1 | -1 | -2.6 | -30.09 | 214.6 | 47.1 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | The thioether group of Met468, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Phe464, Leu465, Leu489) in an inter-helix space formed by two other α helices (res. Ala461–Phe476, res. Thr488–Gly502). In the variant simulations, the hydrophilic side chain of Thr468 does not pack favorably in the hydrophobic niche, and the methionine-aromatic stacking is lost. Although the hydroxyl group of Thr468 forms an H-bond with the backbone carbonyl group of Phe464, the integrity of the α helix is not affected in the simulations. No large-scale structural changes are observed during the variant simulations; however, due to the importance of hydrophobic packing, the effects could be more pronounced during protein folding. | |||||||||||||
| c.1403T>G | M468R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468R is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution 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 indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Consequently, the variant is most likely pathogenic based on the consensus of predictive tools, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -16.180 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 2.66 | Destabilizing | 0.2 | 2.23 | Destabilizing | 2.45 | Destabilizing | 2.43 | Destabilizing | 0.837 | Likely Pathogenic | -4.64 | Deleterious | 0.939 | Possibly Damaging | 0.943 | Probably Damaging | -1.34 | Pathogenic | 0.00 | Affected | 0.1717 | 0.0637 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||
| c.1404G>A | M468I 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant M468I is listed in ClinVar with an uncertain significance (ClinVar ID 3657719.0) and is present in gnomAD (6‑33438436‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, and SIFT, while pathogenic predictions arise from REVEL, FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools report uncertainty: AlphaMissense‑Optimized and Rosetta. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Overall, the preponderance of evidence indicates a pathogenic impact for M468I, which does not contradict the ClinVar uncertain status but suggests a likely pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | Uncertain | 1 | 6-33438436-G-A | 1 | 6.20e-7 | -8.583 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 2.53 | Destabilizing | 0.2 | 1.89 | Ambiguous | 2.21 | Destabilizing | 0.37 | Likely Benign | 0.508 | Likely Pathogenic | -1.06 | Neutral | 0.748 | Possibly Damaging | 0.886 | Possibly Damaging | -1.10 | Pathogenic | 0.07 | Tolerated | 3.37 | 31 | 0.1369 | 0.3354 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||
| c.1404G>C | M468I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468I is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, and SIFT, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default—classify the change as pathogenic. Two methods report uncertainty: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious outcome: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also indicates a pathogenic effect. AlphaMissense‑Optimized remains inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for M468I, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -8.583 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 2.53 | Destabilizing | 0.2 | 1.89 | Ambiguous | 2.21 | Destabilizing | 0.37 | Likely Benign | 0.508 | Likely Pathogenic | -1.06 | Neutral | 0.748 | Possibly Damaging | 0.886 | Possibly Damaging | -1.10 | Pathogenic | 0.07 | Tolerated | 3.37 | 31 | 0.1369 | 0.3354 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1404G>T | M468I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468I is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, and SIFT, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default—classify the change as pathogenic. Two methods report uncertainty: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious outcome: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also indicates a pathogenic effect; AlphaMissense‑Optimized remains inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for M468I, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -8.583 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 2.53 | Destabilizing | 0.2 | 1.89 | Ambiguous | 2.21 | Destabilizing | 0.37 | Likely Benign | 0.510 | Likely Pathogenic | -1.06 | Neutral | 0.748 | Possibly Damaging | 0.886 | Possibly Damaging | -1.10 | Pathogenic | 0.07 | Tolerated | 3.37 | 31 | 0.1369 | 0.3354 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1405G>A | A469T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A469T 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 premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and the Foldetta stability assessment (combining FoldX‑MD and Rosetta). The high‑accuracy subset shows AlphaMissense‑Optimized as benign, whereas SGM Consensus and Foldetta both predict pathogenic. Overall, the majority of evidence supports a pathogenic effect, and this conclusion does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | Uncertain | 1 | -9.540 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 2.26 | Destabilizing | 0.1 | 1.90 | Ambiguous | 2.08 | Destabilizing | 0.34 | Likely Benign | 0.527 | Likely Pathogenic | -1.46 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | -1.21 | Pathogenic | 0.42 | Tolerated | 0.1005 | 0.5884 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||
| c.1405G>C | A469P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only SIFT, whereas all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Based on the overwhelming consensus of these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -16.072 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.06 | Destabilizing | 0.3 | 8.83 | Destabilizing | 6.95 | Destabilizing | 1.02 | Destabilizing | 0.774 | Likely Pathogenic | -2.69 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.33 | Pathogenic | 0.21 | Tolerated | 0.1606 | 0.4092 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1405G>T | A469S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are SGM‑Consensus, REVEL, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Foldetta, and premPS give uncertain or inconclusive results. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts a benign change; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -9.051 | Likely Pathogenic | 0.627 | Likely Pathogenic | Likely Benign | 0.86 | Ambiguous | 0.0 | 2.10 | Destabilizing | 1.48 | Ambiguous | 0.81 | Ambiguous | 0.558 | Likely Pathogenic | -1.53 | Neutral | 0.953 | Possibly Damaging | 0.985 | Probably Damaging | -1.30 | Pathogenic | 0.41 | Tolerated | 0.2113 | 0.4505 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1406C>A | A469D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469D is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: the single benign prediction from SIFT, and a consensus of pathogenic predictions from the remaining 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus). High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. Taken together, the overwhelming majority of evidence points to a pathogenic effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | Uncertain | 1 | -14.643 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.09 | Destabilizing | 0.2 | 4.16 | Destabilizing | 4.63 | Destabilizing | 1.68 | Destabilizing | 0.738 | Likely Pathogenic | -3.48 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.34 | Pathogenic | 0.21 | Tolerated | 3.37 | 34 | 0.1372 | 0.1583 | 0 | -2 | -5.3 | 44.01 | 237.0 | -58.2 | -0.2 | 0.1 | 0.8 | 0.1 | X | X | Potentially Pathogenic | The methyl group of Ala469, located in an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Trp572, Leu588, Met470) in an inter-helix space formed by two other α helices (res. Glu582–Ser604, res. Arg563–Gly580). In the variant simulations, Asp469 introduces a negatively charged and bulky side chain into the hydrophobic niche. Consequently, the side chain of Asp469 rotates outward, allowing the carboxylate group to form a salt bridge with the guanidinium group of Arg575 on the protein surface. This interaction affects the continuity of the parent α helix (Ala461–Phe476). Due to the importance of hydrophobic packing, the structural effects could be more pronounced during actual protein folding. | |||||||||||||||
| c.1406C>G | A469G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise REVEL, Rosetta, Foldetta, premPS, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy methods give mixed results: AlphaMissense‑Optimized indicates benign, Foldetta indicates pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of tools (12 vs. 4) predict pathogenicity, and there is no ClinVar entry 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. | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -4.438 | Likely Benign | 0.733 | Likely Pathogenic | Likely Benign | 1.99 | Ambiguous | 0.1 | 2.22 | Destabilizing | 2.11 | Destabilizing | 1.01 | Destabilizing | 0.569 | Likely Pathogenic | -2.42 | Neutral | 0.997 | Probably Damaging | 0.990 | Probably Damaging | -1.32 | Pathogenic | 0.37 | Tolerated | 0.1797 | 0.3078 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.1406C>T | A469V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A469V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect comprise FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and Foldetta; premPS and AlphaMissense‑Default 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 predicts pathogenic. With seven tools supporting pathogenicity versus four supporting benignity, 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. | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -8.858 | Likely Pathogenic | 0.459 | Ambiguous | Likely Benign | 2.30 | Destabilizing | 0.4 | 2.66 | Destabilizing | 2.48 | Destabilizing | -0.77 | Ambiguous | 0.426 | Likely Benign | 0.26 | Neutral | 0.997 | Probably Damaging | 0.976 | Probably Damaging | -1.20 | Pathogenic | 0.60 | Tolerated | 0.0827 | 0.5421 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.1408A>C | M470L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M470L is listed in ClinVar as benign (ClinVar ID 536996.0) and is present in gnomAD (variant ID 6‑33438440‑A‑C). Functional prediction tools cluster into two groups: benign predictions come from SIFT and AlphaMissense‑Optimized, while pathogenic predictions are made by REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No definitive folding‑stability change is reported by FoldX or Rosetta individually. Overall, the majority of predictive algorithms favor a pathogenic effect, directly contradicting the benign classification in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | Likely Benign | 1 | 6-33438440-A-C | 1 | 6.20e-7 | -8.993 | Likely Pathogenic | 0.406 | Ambiguous | Likely Benign | 0.73 | Ambiguous | 0.1 | 0.84 | Ambiguous | 0.79 | Ambiguous | 1.04 | Destabilizing | 0.678 | Likely Pathogenic | -2.72 | Deleterious | 0.484 | Possibly Damaging | 0.654 | Possibly Damaging | -1.22 | Pathogenic | 0.16 | Tolerated | 3.37 | 34 | 0.1192 | 0.4071 | 4 | 2 | 1.9 | -18.03 | 225.3 | 17.9 | 0.0 | 0.0 | -0.8 | 0.5 | X | Potentially Benign | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, Met470 also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the iso-butyl side chain of Leu470 packs similarly with the hydrophobic residues as methionine, resulting in no negative effects on the protein structure during the simulation. | |||||||||||||
| c.1408A>G | M470V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M470V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Consensus from most in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM all score it as deleterious. Only two tools—SIFT and AlphaMissense‑Optimized—classify it as benign, while Rosetta and AlphaMissense‑Default remain inconclusive. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized reports a benign outcome, but the SGM‑Consensus (derived from a majority of pathogenic calls among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining pathogenic FoldX with uncertain Rosetta) both predict pathogenicity. Overall, the preponderance of evidence supports a likely pathogenic classification, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | Uncertain | 1 | -8.856 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 2.73 | Destabilizing | 0.1 | 1.88 | Ambiguous | 2.31 | Destabilizing | 1.31 | Destabilizing | 0.770 | Likely Pathogenic | -3.58 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.20 | Pathogenic | 0.15 | Tolerated | 3.37 | 34 | 0.2710 | 0.3256 | 1 | 2 | 2.3 | -32.06 | |||||||||||||||||||||||||
| c.1408A>T | M470L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M470L is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on benign effect include SIFT and AlphaMissense‑Optimized. Tools that agree on pathogenic effect include SGM Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. AlphaMissense‑Default, FoldX, Rosetta, and Foldetta are inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, whereas the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the majority of evidence points to a pathogenic effect, 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 | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -8.993 | Likely Pathogenic | 0.406 | Ambiguous | Likely Benign | 0.73 | Ambiguous | 0.1 | 0.84 | Ambiguous | 0.79 | Ambiguous | 1.04 | Destabilizing | 0.678 | Likely Pathogenic | -2.72 | Deleterious | 0.484 | Possibly Damaging | 0.654 | Possibly Damaging | -1.22 | Pathogenic | 0.16 | Tolerated | 3.37 | 34 | 0.1192 | 0.4071 | 4 | 2 | 1.9 | -18.03 | 225.3 | 17.9 | 0.0 | 0.0 | -0.8 | 0.5 | X | Potentially Benign | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, Met470 also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the iso-butyl side chain of Leu470 packs similarly with the hydrophobic residues as methionine, resulting in no negative effects on the protein structure during the simulation. | ||||||||||||||||||
| c.1409T>A | M470K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M470K is not reported in ClinVar (status: None) and is absent from gnomAD. Prediction tools cluster into two groups: the single benign call comes from SIFT, while all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—label the change as pathogenic or likely pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports pathogenic. Thus, the variant is most likely pathogenic based on the consensus of available predictions, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -14.327 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.77 | Destabilizing | 0.1 | 2.67 | Destabilizing | 2.72 | Destabilizing | 1.55 | Destabilizing | 0.823 | Likely Pathogenic | -5.42 | Deleterious | 0.923 | Possibly Damaging | 0.922 | Probably Damaging | -1.06 | Pathogenic | 0.20 | Tolerated | 0.1157 | 0.0656 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.1409T>C | M470T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M470T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is 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, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | Uncertain | 1 | -8.104 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 3.19 | Destabilizing | 0.1 | 2.68 | Destabilizing | 2.94 | Destabilizing | 1.49 | Destabilizing | 0.763 | Likely Pathogenic | -5.30 | Deleterious | 0.996 | Probably Damaging | 0.985 | Probably Damaging | -1.08 | Pathogenic | 0.24 | Tolerated | 3.37 | 34 | 0.1782 | 0.1950 | -1 | -1 | -2.6 | -30.09 | 213.8 | 46.5 | 0.0 | 0.0 | -0.2 | 0.2 | X | X | Potentially Pathogenic | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558, Cys576, Trp572) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, the Met470 side chain also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the hydroxyl group of the Thr470 side chain forms an H-bond with the backbone carbonyl group of Ser466 in the α helix, potentially lowering its structural integrity. Importantly, the hydroxyl group of Thr470 also forms an H-bond with the guanidinium group of Arg575, which helps it form a more permanent salt bridge with Asp467. | |||||||||||||||
| c.1409T>G | M470R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M470R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only SIFT, whereas all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -13.161 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.75 | Destabilizing | 0.1 | 2.75 | Destabilizing | 2.75 | Destabilizing | 1.57 | Destabilizing | 0.823 | Likely Pathogenic | -5.47 | Deleterious | 0.963 | Probably Damaging | 0.943 | Probably Damaging | -1.19 | Pathogenic | 0.17 | Tolerated | 0.1399 | 0.0757 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||
| c.140G>A | R47Q 2D  AIThe SynGAP1 missense variant R47Q is listed in ClinVar (ID 436920.0) as Benign and is present in gnomAD (6‑33423549‑G‑A). 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 is uncertain, and Foldetta results are unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Benign, and no Foldetta data to influence the conclusion. Overall, the majority of evidence points to a benign impact, consistent with the ClinVar classification; there is no contradiction with the reported ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.318242 | Structured | 0.436559 | Uncertain | 0.520 | 0.719 | 0.125 | Likely Benign | 1 | 6-33423549-G-A | 4 | 2.48e-6 | -4.989 | Likely Benign | 0.347 | Ambiguous | Likely Benign | 0.096 | Likely Benign | -0.57 | Neutral | 0.829 | Possibly Damaging | 0.614 | Possibly Damaging | 4.12 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3326 | 0.2591 | 1 | 1 | 1.0 | -28.06 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.140G>C | R47P 2D  AIThe SynGAP1 missense variant R47P is 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign) and therefore unavailable as evidence. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant and is likewise unavailable. High‑accuracy tools specifically indicate a benign prediction from AlphaMissense‑Optimized, while the other high‑accuracy methods (SGM Consensus, Foldetta) provide no definitive assessment. Overall, the balance of evidence (five pathogenic vs. four benign predictions) suggests 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. | 0.318242 | Structured | 0.436559 | Uncertain | 0.520 | 0.719 | 0.125 | -10.316 | Likely Pathogenic | 0.746 | Likely Pathogenic | Likely Benign | 0.195 | Likely Benign | -1.63 | Neutral | 0.841 | Possibly Damaging | 0.809 | Possibly Damaging | 4.02 | Benign | 0.00 | Affected | 0.2050 | 0.4956 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.140G>T | R47L 2D  AIThe SynGAP1 missense variant R47L 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, 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 of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R47L. 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 Benign | 0.318242 | Structured | 0.436559 | Uncertain | 0.520 | 0.719 | 0.125 | -5.758 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.130 | Likely Benign | -1.76 | Neutral | 0.686 | Possibly Damaging | 0.630 | Possibly Damaging | 4.04 | Benign | 0.00 | Affected | 0.1904 | 0.5206 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.1410G>A | M470I 2D AIThe SynGAP1 missense variant M470I is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic impact. Predictions marked as uncertain (AlphaMissense‑Optimized, FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta are uncertain. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -9.474 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 1.53 | Ambiguous | 0.7 | 1.34 | Ambiguous | 1.44 | Ambiguous | 0.84 | Ambiguous | 0.747 | Likely Pathogenic | -3.55 | Deleterious | 0.833 | Possibly Damaging | 0.886 | Possibly Damaging | -1.26 | Pathogenic | 0.07 | Tolerated | 0.1061 | 0.2827 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1410G>C | M470I 2D AIThe SynGAP1 missense variant M470I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include only SIFT, whereas the remaining evidence—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict pathogenicity. Results from high‑accuracy methods are mixed: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta is uncertain. Overall, the preponderance of predictions supports a pathogenic effect for M470I, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -9.474 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 1.53 | Ambiguous | 0.7 | 1.34 | Ambiguous | 1.44 | Ambiguous | 0.84 | Ambiguous | 0.747 | Likely Pathogenic | -3.55 | Deleterious | 0.833 | Possibly Damaging | 0.886 | Possibly Damaging | -1.26 | Pathogenic | 0.07 | Tolerated | 0.1061 | 0.2827 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1410G>T | M470I 2D AIThe SynGAP1 missense variant M470I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include only SIFT, whereas the remaining evidence—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict pathogenicity. Results from high‑accuracy methods are mixed: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta is uncertain. Overall, the preponderance of predictions supports a pathogenic effect for M470I, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -9.474 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 1.53 | Ambiguous | 0.7 | 1.34 | Ambiguous | 1.44 | Ambiguous | 0.84 | Ambiguous | 0.747 | Likely Pathogenic | -3.55 | Deleterious | 0.833 | Possibly Damaging | 0.886 | Possibly Damaging | -1.26 | Pathogenic | 0.07 | Tolerated | 0.1061 | 0.2827 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1411T>A | S471T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (3 benign vs. 1 pathogenic) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. No prediction or stability result is inconclusive. Overall, the evidence overwhelmingly supports a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -5.780 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.59 | Ambiguous | 0.2 | -0.47 | Likely Benign | 0.06 | Likely Benign | 0.20 | Likely Benign | 0.257 | Likely Benign | -1.96 | Neutral | 0.000 | Benign | 0.000 | Benign | -1.18 | Pathogenic | 0.09 | Tolerated | 0.1307 | 0.5046 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1411T>C | S471P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only polyPhen‑2 HumVar, whereas the remaining evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic or likely pathogenic outcome. 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) is 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 does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -12.379 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 3.65 | Destabilizing | 0.2 | 9.24 | Destabilizing | 6.45 | Destabilizing | 0.84 | Ambiguous | 0.530 | Likely Pathogenic | -4.03 | Deleterious | 0.552 | Possibly Damaging | 0.141 | Benign | -1.31 | Pathogenic | 0.05 | Affected | 0.2007 | 0.4769 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1411T>G | S471A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471A is not reported in ClinVar and is absent from gnomAD. Across the spectrum of in‑silico predictors, the majority (REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) classify the change as benign, whereas only FATHMM predicts it as pathogenic; Rosetta is inconclusive. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. No evidence suggests pathogenicity, and the predictions do not contradict the absence of ClinVar annotation. Therefore, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -5.516 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.11 | Likely Benign | 0.1 | -0.61 | Ambiguous | -0.25 | Likely Benign | 0.23 | Likely Benign | 0.252 | Likely Benign | -1.93 | Neutral | 0.010 | Benign | 0.037 | Benign | -1.22 | Pathogenic | 0.29 | Tolerated | 0.4439 | 0.3691 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1412C>A | S471Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, premPS, and AlphaMissense‑Optimized; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The high‑accuracy AlphaMissense‑Optimized scores 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, returns an uncertain stability change. No evidence from ClinVar contradicts these computational assessments. Overall, the preponderance of pathogenic predictions and the SGM Consensus suggest the variant is most likely pathogenic, consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -11.257 | Likely Pathogenic | 0.493 | Ambiguous | Likely Benign | -0.33 | Likely Benign | 0.1 | -1.31 | Ambiguous | -0.82 | Ambiguous | 0.19 | Likely Benign | 0.446 | Likely Benign | -4.79 | Deleterious | 0.980 | Probably Damaging | 0.584 | Possibly Damaging | -1.27 | Pathogenic | 0.03 | Affected | 0.0607 | 0.4417 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.1412C>G | S471C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471C is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33438444‑C‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of predictions (10 benign vs. 3 pathogenic) indicate that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no reported pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | 6-33438444-C-G | 1 | 6.20e-7 | -3.454 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.0 | -0.05 | Likely Benign | 0.16 | Likely Benign | 0.07 | Likely Benign | 0.273 | Likely Benign | -2.90 | Deleterious | 0.000 | Benign | 0.001 | Benign | -1.32 | Pathogenic | 0.01 | Affected | 3.37 | 34 | 0.1048 | 0.4913 | -1 | 0 | 3.3 | 16.06 | |||||||||||||||||||||||||
| c.1412C>T | S471F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and AlphaMissense‑Optimized, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The remaining tools—AlphaMissense‑Default, FoldX, Rosetta, and Foldetta—return uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Taken together, the majority of evidence points toward a pathogenic impact for S471F, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -10.777 | Likely Pathogenic | 0.492 | Ambiguous | Likely Benign | -0.54 | Ambiguous | 0.1 | -1.51 | Ambiguous | -1.03 | Ambiguous | 0.12 | Likely Benign | 0.423 | Likely Benign | -4.75 | Deleterious | 0.942 | Possibly Damaging | 0.487 | Possibly Damaging | -1.26 | Pathogenic | 0.02 | Affected | 0.0553 | 0.4691 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.1414G>A | E472K 2D  AIThe SynGAP1 missense variant E472K is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the only inconclusive result is from premPS, which is listed as uncertain. High‑accuracy methods reinforce this view: 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, predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -15.214 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.01 | Destabilizing | 1.2 | 3.23 | Destabilizing | 2.62 | Destabilizing | 0.78 | Ambiguous | 0.670 | Likely Pathogenic | -3.95 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | 2.33 | Pathogenic | 0.03 | Affected | 0.3077 | 0.5651 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1414G>C | E472Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472Q 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 Foldetta, which classifies the variant as benign. Tools that predict a pathogenic effect are 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). Uncertain or inconclusive predictions come from FoldX, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact for E472Q, 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 | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -13.760 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 1.34 | Ambiguous | 0.3 | -0.67 | Ambiguous | 0.34 | Likely Benign | 0.89 | Ambiguous | 0.555 | Likely Pathogenic | -2.95 | Deleterious | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 2.39 | Pathogenic | 0.01 | Affected | 0.1388 | 0.5726 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1415A>C | E472A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472A is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; all these methods uniformly classify the change as deleterious. Tools that are inconclusive or uncertain for this variant are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a pathogenic outcome, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity, while Foldetta’s stability analysis remains uncertain. Taken together, the overwhelming majority of evidence points to a pathogenic effect for E472A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -15.356 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 1.81 | Ambiguous | 0.3 | 0.67 | Ambiguous | 1.24 | Ambiguous | 0.69 | Ambiguous | 0.732 | Likely Pathogenic | -5.90 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.32 | Pathogenic | 0.01 | Affected | 0.4639 | 0.6315 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1415A>G | E472G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472G is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic or likely pathogenic. Only premPS predicts a benign effect. High‑accuracy methods reinforce this consensus: 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 predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -15.239 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.06 | Destabilizing | 0.2 | 2.86 | Destabilizing | 2.96 | Destabilizing | 0.24 | Likely Benign | 0.744 | Likely Pathogenic | -6.83 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.30 | Pathogenic | 0.00 | Affected | 0.3343 | 0.4950 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1415A>T | E472V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E472V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include Foldetta and premPS, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. No prediction or folding‑stability result is missing or inconclusive; uncertain outputs from FoldX and Rosetta are treated as unavailable. Overall, the majority of evidence points to a pathogenic effect, 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 | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -14.957 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.05 | Ambiguous | 0.3 | -0.64 | Ambiguous | 0.21 | Likely Benign | 0.37 | Likely Benign | 0.733 | Likely Pathogenic | -6.90 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 0.0881 | 0.6347 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1416G>C | E472D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472D is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL and SIFT, whereas the majority of tools—SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict pathogenicity. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability estimates. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (derived from the four high‑confidence predictors) is pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E472D, 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 | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -9.798 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.27 | Ambiguous | 0.3 | 1.99 | Ambiguous | 1.63 | Ambiguous | 1.00 | Destabilizing | 0.304 | Likely Benign | -2.75 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 2.43 | Pathogenic | 0.06 | Tolerated | 0.1975 | 0.3918 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1416G>T | E472D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and SIFT, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), FATHMM, ESM1b, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, premPS, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑based methods (FoldX, Rosetta, Foldetta) yield uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -9.798 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.27 | Ambiguous | 0.3 | 1.99 | Ambiguous | 1.63 | Ambiguous | 1.00 | Destabilizing | 0.303 | Likely Benign | -2.75 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 2.43 | Pathogenic | 0.06 | Tolerated | 0.1975 | 0.3918 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1417G>A | V473I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438449‑G‑A). Functional prediction tools that agree on benign impact include REVEL, FoldX, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Pathogenic predictions are provided by both polyPhen‑2 HumDiv and HumVar. Predictions that are inconclusive are AlphaMissense‑Default, ESM1b, Foldetta, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to no majority, and Foldetta is uncertain. Overall, the balance of evidence favors a benign effect for V473I, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | Uncertain | 1 | 6-33438449-G-A | 1 | 6.20e-7 | -7.481 | In-Between | 0.418 | Ambiguous | Likely Benign | -0.12 | Likely Benign | 0.0 | 1.20 | Ambiguous | 0.54 | Ambiguous | -0.06 | Likely Benign | 0.203 | Likely Benign | -0.91 | Neutral | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.74 | Benign | 0.18 | Tolerated | 3.37 | 34 | 0.0568 | 0.3335 | 3 | 4 | 0.3 | 14.03 | |||||||||||||||||||||||
| c.1417G>C | V473L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473L is 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, and Foldetta, while those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. 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. Overall, the majority of tools (seven pathogenic vs. six benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, 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 | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -9.073 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | -0.29 | Likely Benign | 0.1 | -0.52 | Ambiguous | -0.41 | Likely Benign | 0.35 | Likely Benign | 0.336 | Likely Benign | -2.85 | Deleterious | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.43 | Benign | 0.21 | Tolerated | 0.0708 | 0.3921 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1417G>T | V473L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473L is 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, and Foldetta, while those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. 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. Overall, the majority of tools (seven pathogenic vs. six benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, 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 | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -9.073 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | -0.29 | Likely Benign | 0.1 | -0.52 | Ambiguous | -0.41 | Likely Benign | 0.35 | Likely Benign | 0.335 | Likely Benign | -2.85 | Deleterious | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.43 | Benign | 0.21 | Tolerated | 0.0708 | 0.3921 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1418T>A | V473E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a deleterious effect: all evaluated algorithms except FATHMM predict pathogenicity, while FATHMM alone predicts benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the consensus of the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -15.296 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 3.20 | Destabilizing | 0.2 | 2.24 | Destabilizing | 2.72 | Destabilizing | 2.22 | Destabilizing | 0.664 | Likely Pathogenic | -5.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | 0.0903 | 0.1396 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.1418T>C | V473A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V473A missense variant is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are all uncertain or unavailable, providing no decisive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions support a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation (no contradiction). 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. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -10.867 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 1.88 | Ambiguous | 0.0 | 1.76 | Ambiguous | 1.82 | Ambiguous | 2.17 | Destabilizing | 0.485 | Likely Benign | -3.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 0.2529 | 0.2521 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1418T>G | V473G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473G has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the remaining eleven tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) votes pathogenic, and Foldetta also predicts pathogenic. No predictions are missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective evidence, and this conclusion does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -14.782 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 3.45 | Destabilizing | 0.0 | 3.40 | Destabilizing | 3.43 | Destabilizing | 2.69 | Destabilizing | 0.683 | Likely Pathogenic | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | 0.1885 | 0.2567 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1420G>A | D474N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D474N missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from FoldX, Rosetta, Foldetta, premPS, and SIFT, whereas pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further indicate that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. AlphaMissense‑Optimized is inconclusive and therefore not considered evidence. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -10.696 | Likely Pathogenic | 0.879 | Likely Pathogenic | Ambiguous | 0.13 | Likely Benign | 0.0 | 0.31 | Likely Benign | 0.22 | Likely Benign | 0.06 | Likely Benign | 0.542 | Likely Pathogenic | -4.21 | Deleterious | 0.992 | Probably Damaging | 0.990 | Probably Damaging | -1.18 | Pathogenic | 0.08 | Tolerated | 0.1047 | 0.4135 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1420G>C | D474H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D474H is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta, Foldetta, and premPS, whereas the majority of tools predict it to be pathogenic: 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 methods give mixed results: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. Overall, the preponderance of evidence points to a pathogenic effect for D474H, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -13.610 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.66 | Ambiguous | 0.0 | 0.00 | Likely Benign | 0.33 | Likely Benign | 0.27 | Likely Benign | 0.739 | Likely Pathogenic | -5.93 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.02 | Affected | 0.1398 | 0.4619 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1420G>T | D474Y 2D AIThe SynGAP1 missense variant D474Y is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include FoldX, Foldetta, 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 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 preponderance of evidence points to a pathogenic effect for D474Y. This conclusion does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -14.647 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.27 | Likely Benign | 0.5 | -0.74 | Ambiguous | -0.24 | Likely Benign | 0.20 | Likely Benign | 0.864 | Likely Pathogenic | -7.72 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.30 | Pathogenic | 0.01 | Affected | 0.0493 | 0.4237 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1421A>C | D474A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D474A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, premPS, and SIFT, while pathogenic predictions arise from REVEL, 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 show AlphaMissense‑Optimized as Pathogenic, SGM Consensus as Likely Pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) as 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 | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -11.082 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.08 | Likely Benign | 0.0 | 0.15 | Likely Benign | 0.12 | Likely Benign | 0.17 | Likely Benign | 0.757 | Likely Pathogenic | -6.73 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.22 | Pathogenic | 0.22 | Tolerated | 0.3265 | 0.4354 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1421A>G | D474G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D474G is not reported in ClinVar and is present in gnomAD (ID 6‑33438453‑A‑G). Functional prediction tools show a split: benign calls come from FoldX, Foldetta, premPS, and SIFT, while pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta remains uncertain. High‑accuracy assessments give a pathogenic verdict from AlphaMissense‑Optimized and a pathogenic consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign stability. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | 6-33438453-A-G | 1 | 6.20e-7 | -11.215 | Likely Pathogenic | 0.959 | Likely Pathogenic | Likely Pathogenic | -0.38 | Likely Benign | 0.0 | 0.82 | Ambiguous | 0.22 | Likely Benign | 0.44 | Likely Benign | 0.823 | Likely Pathogenic | -6.13 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.28 | Pathogenic | 0.07 | Tolerated | 3.37 | 34 | 0.3245 | 0.4933 | -1 | 1 | 3.1 | -58.04 | ||||||||||||||||||||||||
| c.1421A>T | D474V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D474V missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, Foldetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -12.999 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.77 | Ambiguous | 0.0 | 0.18 | Likely Benign | 0.48 | Likely Benign | 0.18 | Likely Benign | 0.866 | Likely Pathogenic | -7.69 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | -1.30 | Pathogenic | 0.04 | Affected | 0.0694 | 0.4510 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1422C>A | D474E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D474E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, and SIFT, whereas a separate group predicts pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Two tools are uncertain: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, AlphaMissense‑Optimized as Uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of predictions lean toward pathogenicity, but the high‑accuracy tools provide conflicting evidence. Thus, the variant is most likely pathogenic based on the current computational predictions, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -7.079 | In-Between | 0.874 | Likely Pathogenic | Ambiguous | -0.35 | Likely Benign | 0.1 | 0.05 | Likely Benign | -0.15 | Likely Benign | 0.10 | Likely Benign | 0.408 | Likely Benign | -3.01 | Deleterious | 0.929 | Possibly Damaging | 0.938 | Probably Damaging | -1.11 | Pathogenic | 0.20 | Tolerated | 0.1233 | 0.4287 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1422C>G | D474E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D474E is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, and SIFT, while those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. Two tools—AlphaMissense‑Optimized and ESM1b—return uncertain results. High‑accuracy assessments show SGM‑Consensus predicting a likely pathogenic outcome, AlphaMissense‑Optimized remaining uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign effect. Overall, the majority of consensus tools lean toward pathogenicity, 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 | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -7.079 | In-Between | 0.874 | Likely Pathogenic | Ambiguous | -0.35 | Likely Benign | 0.1 | 0.05 | Likely Benign | -0.15 | Likely Benign | 0.10 | Likely Benign | 0.408 | Likely Benign | -3.01 | Deleterious | 0.929 | Possibly Damaging | 0.938 | Probably Damaging | -1.11 | Pathogenic | 0.20 | Tolerated | 0.1233 | 0.4287 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1423C>G | R475G 2D AIThe SynGAP1 missense variant R475G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict pathogenicity. Only Rosetta and AlphaMissense‑Optimized return uncertain results, and no tool predicts a benign outcome. High‑accuracy methods provide a consistent view: AlphaMissense‑Optimized is uncertain, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. Taken together, the overwhelming majority of evidence supports a pathogenic classification for R475G, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | -14.466 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 2.39 | Destabilizing | 1.0 | 1.64 | Ambiguous | 2.02 | Destabilizing | 1.11 | Destabilizing | 0.697 | Likely Pathogenic | -6.53 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.41 | Pathogenic | 0.00 | Affected | 0.2779 | 0.2310 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1423C>T | R475W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475W is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438455‑C‑T). Prediction tools that agree on a benign effect include only Foldetta, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) uniformly predict a pathogenic impact; FoldX, Rosetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar “Uncertain” classification but suggests that the variant is more likely pathogenic rather than benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | Uncertain | 1 | 6-33438455-C-T | 1 | 6.20e-7 | -13.235 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 1.44 | Ambiguous | 0.4 | -0.92 | Ambiguous | 0.26 | Likely Benign | 0.56 | Ambiguous | 0.725 | Likely Pathogenic | -7.56 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.45 | Pathogenic | 0.00 | Affected | 3.39 | 28 | 0.1231 | 0.2785 | 2 | -3 | 3.6 | 30.03 | 266.9 | 39.6 | 0.0 | 0.0 | 0.0 | 0.1 | X | X | X | Potentially Pathogenic | In the WT simulations, the guanidinium group of Arg475, located near the end of an α-helix (res. Ala461-Phe476), stacks with the phenyl ring of Phe476 and forms a salt bridge with Glu472. Additionally, Arg475 occasionally forms another salt bridge with the carboxylate group of Glu486 on the α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. Therefore, Arg475 potentially plays a key role in positioning the loop by interacting with Glu486, which is necessary for the positioning of the “arginine finger” (Arg485) and, ultimately, for RasGTPase activation.In the variant simulations, Trp475 moves and stacks with Arg479 on the proceeding α-α loop, disrupting the terminal end of the α-helix. Lastly, the potential effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||
| c.1424G>A | R475Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475Q is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438456‑G‑A). Prediction tools that indicate a benign effect include AlphaMissense‑Optimized, Foldetta, and Rosetta. Those that predict a pathogenic effect comprise SGM Consensus, SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points toward a pathogenic impact, 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 | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | Uncertain | 2 | 6-33438456-G-A | 5 | 3.10e-6 | -12.087 | Likely Pathogenic | 0.721 | Likely Pathogenic | Likely Benign | 0.71 | Ambiguous | 0.1 | 0.12 | Likely Benign | 0.42 | Likely Benign | 0.82 | Ambiguous | 0.632 | Likely Pathogenic | -3.65 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.39 | 28 | 0.2190 | 0.1926 | 1 | 1 | 1.0 | -28.06 | 253.6 | 52.7 | 0.0 | 0.0 | -0.8 | 0.0 | X | X | X | Potentially Pathogenic | In the WT simulations, the guanidinium group of Arg475, located near the end of an α-helix (res. Ala461-Phe476), stacks with the phenyl ring of Phe476 and forms a salt bridge with Glu472. Additionally, Arg475 occasionally forms another salt bridge with the carboxylate group of Glu486 on the α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. Therefore, Arg475 potentially plays a key role in positioning the loop by interacting with Glu486, which is necessary for the positioning of the “arginine finger” (Arg485) and, ultimately, for RasGTPase activation. In the variant simulations, Asn475 forms a hydrogen bond with Arg479 on the proceeding α-α loop. The absence of Phe476/Arg475 stacking and the Arg475-Glu472 salt bridge weakens the integrity of the terminal end of the α-helix during the variant simulations. Lastly, the potential effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||
| c.1424G>C | R475P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: benign‑predicting algorithms are not present, while pathogenic‑predicting tools—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—all classify the substitution as pathogenic. High‑accuracy assessments corroborate this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. Consequently, the variant is most likely pathogenic based on the available computational evidence, 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. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | -16.637 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.93 | Destabilizing | 0.4 | 5.40 | Destabilizing | 4.17 | Destabilizing | 1.02 | Destabilizing | 0.835 | Likely Pathogenic | -6.53 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.43 | Pathogenic | 0.00 | Affected | 0.1943 | 0.3295 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1424G>T | R475L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R475L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score, whereas only Rosetta predicts a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. With the preponderance of pathogenic calls and no conflicting evidence from ClinVar or population databases, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | -13.074 | Likely Pathogenic | 0.928 | Likely Pathogenic | Ambiguous | 1.49 | Ambiguous | 0.4 | -0.47 | Likely Benign | 0.51 | Ambiguous | 0.55 | Ambiguous | 0.806 | Likely Pathogenic | -6.40 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.40 | Pathogenic | 0.00 | Affected | 0.1580 | 0.3428 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1426T>A | F476I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F476I has no ClinVar entry and is not reported in gnomAD. Functional prediction tools fall into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, and FATHMM; pathogenic predictions come from FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—remains inconclusive and is treated as unavailable. With seven tools indicating pathogenicity versus five indicating benign, and two high‑accuracy tools supporting pathogenicity, the evidence points to a likely pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no record for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -12.617 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 3.90 | Destabilizing | 0.1 | 3.09 | Destabilizing | 3.50 | Destabilizing | 0.39 | Likely Benign | 0.239 | Likely Benign | -1.23 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 3.50 | Benign | 0.37 | Tolerated | 0.1383 | 0.2202 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||
| c.1426T>C | F476L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. No other tools provide definitive evidence. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -10.109 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 1.04 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | 0.196 | Likely Benign | -1.10 | Neutral | 0.997 | Probably Damaging | 0.978 | Probably Damaging | 3.53 | Benign | 0.60 | Tolerated | 3.40 | 22 | 0.1653 | 0.2916 | 2 | 0 | 1.0 | -34.02 | 235.9 | 16.1 | 0.0 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | In the WT simulations, the phenyl ring of Phe476, located at the end of an α-helix (res. Ala461-Phe476), packs with the hydrophobic side chains of Leu482 and Ile483. Additionally, Phe476 stacks with the Arg475 side chain on the preceding α-α loop connecting the two α-helices (res. Ala461-Phe476 and res. Leu489-Glu519) near the GAP-Ras interface.In the variant simulations, Leu476 can maintain hydrophobic packing with neighboring residues, although not as efficiently as the phenylalanine in the WT system. The absence of Phe476/Arg475 stacking weakens the integrity of the α-helix end in the variant simulations. Nonetheless, no large-scale adverse effects are observed in the simulations. Lastly, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||||||||||
| c.1426T>G | F476V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F476V variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Those that agree on a pathogenic effect are FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and Foldetta. Tools with uncertain or mixed outputs are Rosetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a pathogenic impact. Overall, the majority of evidence points toward a pathogenic effect. The variant is most likely pathogenic 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. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -12.329 | Likely Pathogenic | 0.918 | Likely Pathogenic | Ambiguous | 3.01 | Destabilizing | 0.2 | 1.90 | Ambiguous | 2.46 | Destabilizing | 0.64 | Ambiguous | 0.353 | Likely Benign | -1.63 | Neutral | 0.996 | Probably Damaging | 0.993 | Probably Damaging | 3.49 | Benign | 0.53 | Tolerated | 0.1478 | 0.2251 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||
| c.1427T>A | F476Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; FoldX is uncertain and therefore not counted. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta predicts a benign outcome. Overall, the balance of evidence leans toward a benign impact for F476Y, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -9.707 | Likely Pathogenic | 0.576 | Likely Pathogenic | Likely Benign | 0.50 | Ambiguous | 0.2 | 0.30 | Likely Benign | 0.40 | Likely Benign | 1.10 | Destabilizing | 0.169 | Likely Benign | -1.10 | Neutral | 0.965 | Probably Damaging | 0.919 | Probably Damaging | 3.46 | Benign | 0.90 | Tolerated | 0.1109 | 0.1568 | 7 | 3 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||
| c.1427T>C | F476S 2D AIThe SynGAP1 missense variant F476S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields an equal split of pathogenic and benign signals. Overall, the balance of evidence favors a pathogenic effect for F476S, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -12.675 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 3.02 | Destabilizing | 0.9 | 4.07 | Destabilizing | 3.55 | Destabilizing | 1.23 | Destabilizing | 0.278 | Likely Benign | -2.33 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.56 | Benign | 0.44 | Tolerated | 0.3387 | 0.0558 | -3 | -2 | -3.6 | -60.10 | ||||||||||||||||||||||||||||||
| c.1427T>G | F476C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476C is catalogued in gnomAD (ID 6‑33438459‑T‑G) but has no ClinVar entry. Functional prediction tools split in two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, seven tools predict pathogenicity versus six predicting benign, with no ClinVar evidence to contradict this assessment. Thus, the variant is most likely pathogenic based on the current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | 6-33438459-T-G | -9.270 | Likely Pathogenic | 0.745 | Likely Pathogenic | Likely Benign | 2.05 | Destabilizing | 0.1 | 2.62 | Destabilizing | 2.34 | Destabilizing | -0.30 | Likely Benign | 0.280 | Likely Benign | 2.69 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.46 | Benign | 0.83 | Tolerated | 3.40 | 22 | 0.2051 | 0.1251 | -2 | -4 | -0.3 | -44.04 | |||||||||||||||||||||||||||
| c.1428C>A | F476L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. No other tools provide definitive evidence. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -10.109 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 1.04 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | 0.180 | Likely Benign | -1.10 | Neutral | 0.997 | Probably Damaging | 0.978 | Probably Damaging | 3.53 | Benign | 0.60 | Tolerated | 3.40 | 22 | 0.1653 | 0.2916 | 2 | 0 | 1.0 | -34.02 | 235.9 | 16.1 | 0.0 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | In the WT simulations, the phenyl ring of Phe476, located at the end of an α-helix (res. Ala461-Phe476), packs with the hydrophobic side chains of Leu482 and Ile483. Additionally, Phe476 stacks with the Arg475 side chain on the preceding α-α loop connecting the two α-helices (res. Ala461-Phe476 and res. Leu489-Glu519) near the GAP-Ras interface.In the variant simulations, Leu476 can maintain hydrophobic packing with neighboring residues, although not as efficiently as the phenylalanine in the WT system. The absence of Phe476/Arg475 stacking weakens the integrity of the α-helix end in the variant simulations. Nonetheless, no large-scale adverse effects are observed in the simulations. Lastly, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||||||||||
| c.1428C>G | F476L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438460‑C‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that returned uncertain results—FoldX, Rosetta, Foldetta, and premPS—do not contribute to the assessment. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, with two pathogenic and two benign calls; Foldetta also reports an uncertain stability change. Overall, the balance of evidence favors a pathogenic effect for F476L, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | Uncertain | 2 | 6-33438460-C-G | 4 | 2.48e-6 | -10.109 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 1.04 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | 0.180 | Likely Benign | -1.10 | Neutral | 0.997 | Probably Damaging | 0.978 | Probably Damaging | 3.53 | Benign | 0.60 | Tolerated | 3.40 | 22 | 0.1653 | 0.2916 | 2 | 0 | 1.0 | -34.02 | 235.9 | 16.1 | 0.0 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | In the WT simulations, the phenyl ring of Phe476, located at the end of an α-helix (res. Ala461-Phe476), packs with the hydrophobic side chains of Leu482 and Ile483. Additionally, Phe476 stacks with the Arg475 side chain on the preceding α-α loop connecting the two α-helices (res. Ala461-Phe476 and res. Leu489-Glu519) near the GAP-Ras interface.In the variant simulations, Leu476 can maintain hydrophobic packing with neighboring residues, although not as efficiently as the phenylalanine in the WT system. The absence of Phe476/Arg475 stacking weakens the integrity of the α-helix end in the variant simulations. Nonetheless, no large-scale adverse effects are observed in the simulations. Lastly, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||||||
| c.1429A>C | M477L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome; premPS is uncertain and therefore not counted as evidence. High‑accuracy assessments are consistent: AlphaMissense‑Optimized reports Benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. Overall, the preponderance of evidence supports a benign classification for M477L, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -4.772 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.0 | 0.19 | Likely Benign | 0.15 | Likely Benign | 0.58 | Ambiguous | 0.236 | Likely Benign | -1.25 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.18 | Pathogenic | 0.17 | Tolerated | 0.1586 | 0.4220 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1429A>G | M477V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477V is listed in ClinVar with no submitted interpretation and is present in the gnomAD database (variant ID 6‑33438461‑A‑G). Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict benign or likely benign. Only two tools predict a pathogenic outcome: polyPhen2_HumDiv and FATHMM. Predictions from FoldX and Foldetta are uncertain. High‑accuracy methods reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, while Foldetta remains inconclusive. Taken together, the majority of evidence supports a benign classification for M477V, and this assessment does not contradict the ClinVar status, which currently has no pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | 6-33438461-A-G | 1 | 6.20e-7 | -3.995 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 1.64 | Ambiguous | 0.3 | 0.42 | Likely Benign | 1.03 | Ambiguous | 0.24 | Likely Benign | 0.209 | Likely Benign | -1.04 | Neutral | 0.716 | Possibly Damaging | 0.204 | Benign | -1.19 | Pathogenic | 0.22 | Tolerated | 3.37 | 34 | 0.3093 | 0.3445 | 1 | 2 | 2.3 | -32.06 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||
| c.1429A>T | M477L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477L 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, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The high‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all uniformly indicate a benign effect. No prediction or folding‑stability result is missing or inconclusive. Based on the consensus of 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 | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -4.772 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.0 | 0.19 | Likely Benign | 0.15 | Likely Benign | 0.58 | Ambiguous | 0.236 | Likely Benign | -1.25 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.18 | Pathogenic | 0.17 | Tolerated | 0.1586 | 0.4220 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.142T>A | F48I 2D AIThe SynGAP1 missense variant F48I is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while SIFT and AlphaMissense‑Default predict a pathogenic impact. Two tools—ESM1b and AlphaMissense‑Optimized—return uncertain results. High‑accuracy assessments further clarify the variant’s likely benign nature: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors benign; AlphaMissense‑Optimized remains uncertain, and Foldetta (which would evaluate protein‑folding stability) is unavailable. Overall, the balance of evidence points to a benign classification, 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. | 0.298791 | Structured | 0.440452 | Uncertain | 0.558 | 0.707 | 0.125 | -7.994 | In-Between | 0.808 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | -1.67 | Neutral | 0.092 | Benign | 0.050 | Benign | 3.99 | Benign | 0.00 | Affected | 0.2561 | 0.2301 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.142T>C | F48L 2D AIThe SynGAP1 missense variant F48L 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, and FATHMM. Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions lean toward a benign impact, but the high‑accuracy tools provide conflicting evidence and no Foldetta data is available. Thus, the variant is most likely benign based on the consensus of available predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.298791 | Structured | 0.440452 | Uncertain | 0.558 | 0.707 | 0.125 | -4.955 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.108 | Likely Benign | -1.56 | Neutral | 0.022 | Benign | 0.016 | Benign | 4.16 | Benign | 0.00 | Affected | 0.2641 | 0.3082 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.142T>G | F48V 2D AIThe SynGAP1 missense variant F48V is not reported in ClinVar and is absent from gnomAD. Consensus from routine in silico predictors shows six tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) classifying the change as benign, while two (SIFT, AlphaMissense‑Default) predict pathogenicity; ESM1b remains uncertain. High‑accuracy assessment further supports a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority vote, and Foldetta data are unavailable. Consequently, the overall evidence points to a benign effect for F48V, 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. | 0.298791 | Structured | 0.440452 | Uncertain | 0.558 | 0.707 | 0.125 | -7.591 | In-Between | 0.756 | Likely Pathogenic | Likely Benign | 0.144 | Likely Benign | -1.87 | Neutral | 0.092 | Benign | 0.037 | Benign | 4.00 | Benign | 0.00 | Affected | 0.2533 | 0.2300 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||||||
| c.1430T>A | M477K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477K is 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 (HumDiv and HumVar), SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS and FATHMM. Predictions that are uncertain or inconclusive are FoldX, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to mixed or uncertain inputs. 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, which contains no report of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -7.519 | In-Between | 0.553 | Ambiguous | Likely Benign | 0.54 | Ambiguous | 0.1 | 0.37 | Likely Benign | 0.46 | Likely Benign | 1.12 | Destabilizing | 0.371 | Likely Benign | -1.32 | Neutral | 0.254 | Benign | 0.122 | Benign | -1.15 | Pathogenic | 0.14 | Tolerated | 0.1817 | 0.0847 | 0 | -1 | -5.8 | -3.02 | ||||||||||||||||||||||||||||||
| c.1430T>C | M477T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477T has no ClinVar entry and is present in gnomAD (ID 6‑33438462‑T‑C). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Default) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign (2 benign vs. 1 pathogenic votes); Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | 6-33438462-T-C | 2 | 1.24e-6 | -2.509 | Likely Benign | 0.373 | Ambiguous | Likely Benign | 1.62 | Ambiguous | 0.2 | 0.16 | Likely Benign | 0.89 | Ambiguous | 0.51 | Ambiguous | 0.273 | Likely Benign | -1.33 | Neutral | 0.765 | Possibly Damaging | 0.363 | Benign | -1.10 | Pathogenic | 0.40 | Tolerated | 3.37 | 34 | 0.2177 | 0.1950 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||
| c.1430T>G | M477R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477R is 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, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, and FATHMM. Tools with uncertain or inconclusive results are Rosetta, Foldetta, 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, while Foldetta remains uncertain and is not taken as evidence. Overall, the majority of reliable predictors indicate a benign 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. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -6.786 | Likely Benign | 0.552 | Ambiguous | Likely Benign | 0.48 | Likely Benign | 0.2 | 0.77 | Ambiguous | 0.63 | Ambiguous | 1.24 | Destabilizing | 0.442 | Likely Benign | -1.12 | Neutral | 0.720 | Possibly Damaging | 0.242 | Benign | -1.22 | Pathogenic | 0.11 | Tolerated | 0.1901 | 0.0828 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||
| c.1431G>A | M477I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477I is 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, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, indicating no contradiction with existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -2.662 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.72 | Ambiguous | 0.1 | 0.36 | Likely Benign | 0.54 | Ambiguous | 0.45 | Likely Benign | 0.291 | Likely Benign | -1.57 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.21 | Pathogenic | 0.09 | Tolerated | 0.1368 | 0.3176 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1431G>C | M477I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta remains uncertain. Overall, the majority of evidence supports a benign 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. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -2.662 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.72 | Ambiguous | 0.1 | 0.36 | Likely Benign | 0.54 | Ambiguous | 0.45 | Likely Benign | 0.290 | Likely Benign | -1.57 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.21 | Pathogenic | 0.09 | Tolerated | 0.1368 | 0.3176 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1431G>T | M477I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta remains uncertain. Overall, the majority of evidence supports a benign 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. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -2.662 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.72 | Ambiguous | 0.1 | 0.36 | Likely Benign | 0.54 | Ambiguous | 0.45 | Likely Benign | 0.291 | Likely Benign | -1.57 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.21 | Pathogenic | 0.09 | Tolerated | 0.1368 | 0.3176 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1432G>A | E478K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E478K 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, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as benign. Overall, the majority of evidence (eight benign versus five pathogenic predictions) points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -12.654 | Likely Pathogenic | 0.899 | Likely Pathogenic | Ambiguous | 0.23 | Likely Benign | 0.0 | 0.12 | Likely Benign | 0.18 | Likely Benign | -0.02 | Likely Benign | 0.309 | Likely Benign | -3.45 | Deleterious | 0.320 | Benign | 0.117 | Benign | 3.49 | Benign | 0.05 | Affected | 0.2066 | 0.6192 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1432G>C | E478Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E478Q is listed in gnomAD (ID 6‑33438464‑G‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and Foldetta as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑vs‑2 split. Overall, the majority of evidence (nine benign vs three pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | 6-33438464-G-C | 1 | 6.20e-7 | -9.881 | Likely Pathogenic | 0.603 | Likely Pathogenic | Likely Benign | -0.04 | Likely Benign | 0.0 | 0.31 | Likely Benign | 0.14 | Likely Benign | 0.07 | Likely Benign | 0.222 | Likely Benign | -2.49 | Neutral | 0.623 | Possibly Damaging | 0.199 | Benign | 3.40 | Benign | 0.14 | Tolerated | 3.37 | 34 | 0.1027 | 0.5867 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1433A>C | E478A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E478A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No predictions are missing or inconclusive. Overall, the majority of high‑confidence tools lean toward a benign classification, and this does not contradict the lack of ClinVar annotation. 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 | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -8.499 | Likely Pathogenic | 0.612 | Likely Pathogenic | Likely Benign | 0.46 | Likely Benign | 0.0 | 0.45 | Likely Benign | 0.46 | Likely Benign | 0.02 | Likely Benign | 0.342 | Likely Benign | -4.74 | Deleterious | 0.585 | Possibly Damaging | 0.505 | Possibly Damaging | 3.42 | Benign | 0.05 | Affected | 0.3516 | 0.5847 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1433A>G | E478G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E478G 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. Uncertain predictions come from Rosetta, ESM1b, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to equal benign and pathogenic signals and two uncertain calls; Foldetta likewise yields an uncertain result. Overall, the majority of evaluated tools (seven benign vs. two pathogenic) support a benign classification. This consensus does not contradict any ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -7.897 | In-Between | 0.418 | Ambiguous | Likely Benign | 0.40 | Likely Benign | 0.0 | 0.73 | Ambiguous | 0.57 | Ambiguous | 0.02 | Likely Benign | 0.306 | Likely Benign | -4.91 | Deleterious | 0.923 | Possibly Damaging | 0.427 | Benign | 3.41 | Benign | 0.15 | Tolerated | 0.2758 | 0.5572 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||
| c.1433A>T | E478V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E478V missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, Rosetta, polyPhen‑2 (HumDiv and HumVar), FATHMM, and premPS; pathogenic predictions from SGM‑Consensus, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Two tools give inconclusive results: FoldX (uncertain) and AlphaMissense‑Optimized (uncertain). High‑accuracy assessments further split the signal: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. With six benign versus five pathogenic calls and no ClinVar evidence, the overall evidence slightly favors a benign interpretation, and there is no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -10.322 | Likely Pathogenic | 0.831 | Likely Pathogenic | Ambiguous | 0.55 | Ambiguous | 0.0 | 0.33 | Likely Benign | 0.44 | Likely Benign | 0.04 | Likely Benign | 0.385 | Likely Benign | -5.84 | Deleterious | 0.434 | Benign | 0.199 | Benign | 3.35 | Benign | 0.01 | Affected | 0.0586 | 0.6604 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1434A>C | E478D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E478D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -1.004 | Likely Benign | 0.085 | Likely Benign | Likely Benign | -0.04 | Likely Benign | 0.0 | -0.65 | Ambiguous | -0.35 | Likely Benign | -0.28 | Likely Benign | 0.175 | Likely Benign | 0.55 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.53 | Benign | 0.70 | Tolerated | 0.1768 | 0.3315 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1434A>T | E478D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E478D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -1.004 | Likely Benign | 0.085 | Likely Benign | Likely Benign | -0.04 | Likely Benign | 0.0 | -0.65 | Ambiguous | -0.35 | Likely Benign | -0.28 | Likely Benign | 0.175 | Likely Benign | 0.55 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.53 | Benign | 0.70 | Tolerated | 0.1768 | 0.3315 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1435C>G | R479G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R479G is reported in gnomAD (ID 6-33438467-C-G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise AlphaMissense‑Default, ESM1b, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, Rosetta, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX and Foldetta, which assess protein‑folding stability, returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta as inconclusive. Overall, the majority of computational evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Therefore, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | 6-33438467-C-G | 1 | 6.20e-7 | -8.600 | Likely Pathogenic | 0.624 | Likely Pathogenic | Likely Benign | 0.97 | Ambiguous | 0.0 | 2.51 | Destabilizing | 1.74 | Ambiguous | 0.71 | Ambiguous | 0.228 | Likely Benign | -2.82 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.42 | Tolerated | 3.39 | 32 | 0.2911 | 0.2707 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||
| c.1435C>T | R479W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R479W is not reported in ClinVar and is present in gnomAD (ID 6‑33438467‑C‑T). Functional prediction tools show a split opinion: benign calls come from REVEL, premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely pathogenic; Foldetta remains inconclusive. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | 6-33438467-C-T | 6 | 3.72e-6 | -11.356 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 0.60 | Ambiguous | 0.1 | 0.72 | Ambiguous | 0.66 | Ambiguous | 0.42 | Likely Benign | 0.249 | Likely Benign | -4.75 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 3.35 | Benign | 0.02 | Affected | 3.39 | 32 | 0.1046 | 0.2933 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||
| c.1436G>A | R479Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R479Q is listed in ClinVar with an “Uncertain” significance and is present in gnomAD (variant ID 6‑33438468‑G‑A). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv and HumVar both predict a pathogenic impact. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and ESM1b. 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 effect, and this consensus does not contradict the ClinVar “Uncertain” status; thus the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | Uncertain | 1 | 6-33438468-G-A | 7 | 4.34e-6 | -7.109 | In-Between | 0.259 | Likely Benign | Likely Benign | 0.54 | Ambiguous | 0.1 | 0.57 | Ambiguous | 0.56 | Ambiguous | 0.49 | Likely Benign | 0.191 | Likely Benign | -1.16 | Neutral | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.42 | Benign | 0.31 | Tolerated | 3.39 | 32 | 0.2448 | 0.1812 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||
| c.1436G>C | R479P 2D 3DClick to see structure in 3D Viewer AIClinVar lists the SynGAP1 R479P variant as Uncertain, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. Those that predict a pathogenic effect are FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive are AlphaMissense‑Optimized and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as pathogenic. Overall, the majority of tools and the high‑accuracy methods support a pathogenic classification, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | Uncertain | 1 | -11.795 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 2.86 | Destabilizing | 0.2 | 3.88 | Destabilizing | 3.37 | Destabilizing | 0.81 | Ambiguous | 0.277 | Likely Benign | -3.52 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.41 | Benign | 0.18 | Tolerated | 0.1993 | 0.3747 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||
| c.1436G>T | R479L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R479L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM) and pathogenic predictions (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). AlphaMissense‑Optimized is uncertain. High‑accuracy assessments give mixed results: AlphaMissense‑Optimized remains uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. No single metric dominates, and the overall evidence is balanced. Therefore, the variant’s pathogenicity is inconclusive; it is not contradicted by ClinVar status, which has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | -11.118 | Likely Pathogenic | 0.832 | Likely Pathogenic | Ambiguous | 0.45 | Likely Benign | 0.1 | 0.12 | Likely Benign | 0.29 | Likely Benign | 0.39 | Likely Benign | 0.265 | Likely Benign | -4.21 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.38 | Benign | 0.15 | Tolerated | 0.1326 | 0.3624 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1438G>A | E480K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E480K is catalogued in gnomAD (ID 6‑33438470‑G‑A) but has no entry in ClinVar. Functional prediction tools cluster into two groups: benign predictions come from FoldX and SIFT, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results are reported by Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that E480K is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | 6-33438470-G-A | 1 | 6.20e-7 | -14.059 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 1.08 | Ambiguous | 0.74 | Ambiguous | 0.83 | Ambiguous | 0.768 | Likely Pathogenic | -3.45 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | -1.26 | Pathogenic | 0.11 | Tolerated | 3.37 | 34 | 0.1828 | 0.6813 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.1438G>C | E480Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 E480Q is not reported in ClinVar (no ClinVar ID) and is present in gnomAD (ID 6‑33438470‑G‑C). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, and the protein‑folding stability method Foldetta. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). AlphaMissense‑Optimized is uncertain and therefore not used as evidence. High‑accuracy assessments show Foldetta predicts benign stability change, SGM Consensus predicts pathogenic, and AlphaMissense‑Optimized is inconclusive. Overall, the predictions are split, but the presence of a benign prediction from a high‑accuracy folding method and the lack of a ClinVar pathogenic claim suggest 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 Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | 6-33438470-G-C | 2 | 1.24e-6 | -12.336 | Likely Pathogenic | 0.845 | Likely Pathogenic | Ambiguous | 0.43 | Likely Benign | 0.0 | -0.01 | Likely Benign | 0.21 | Likely Benign | 0.75 | Ambiguous | 0.480 | Likely Benign | -2.29 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | -1.29 | Pathogenic | 0.11 | Tolerated | 3.37 | 34 | 0.0854 | 0.6870 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||
| c.1439A>C | E480A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E480A 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 SIFT, whereas a majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from the four pathogenic‑predicted tools above) as likely pathogenic, and Foldetta as uncertain. Because most evidence points to a deleterious effect, the variant is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -13.192 | Likely Pathogenic | 0.931 | Likely Pathogenic | Ambiguous | 0.91 | Ambiguous | 0.1 | 1.15 | Ambiguous | 1.03 | Ambiguous | 0.55 | Ambiguous | 0.694 | Likely Pathogenic | -5.04 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.25 | Pathogenic | 0.09 | Tolerated | 0.3468 | 0.6635 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1439A>G | E480G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E480G missense variant is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in‑silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify it as pathogenic. Predictions that are uncertain—FoldX, premPS, and AlphaMissense‑Optimized—do not provide evidence for benignity. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic, and AlphaMissense‑Optimized remains uncertain. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -11.651 | Likely Pathogenic | 0.839 | Likely Pathogenic | Ambiguous | 1.83 | Ambiguous | 0.1 | 2.34 | Destabilizing | 2.09 | Destabilizing | 0.65 | Ambiguous | 0.778 | Likely Pathogenic | -5.44 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.03 | Affected | 0.2806 | 0.6172 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1439A>T | E480V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E480V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only premPS. All other evaluated algorithms—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)—classify the variant as pathogenic or likely pathogenic. 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. Taken together, the overwhelming majority of predictions support a pathogenic effect for E480V. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -12.347 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.94 | Ambiguous | 0.1 | 0.74 | Ambiguous | 0.84 | Ambiguous | 0.31 | Likely Benign | 0.797 | Likely Pathogenic | -6.07 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | -1.24 | Pathogenic | 0.02 | Affected | 0.0496 | 0.7192 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.143T>A | F48Y 2D AIThe SynGAP1 missense variant F48Y 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 further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence indicates that F48Y is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.298791 | Structured | 0.440452 | Uncertain | 0.558 | 0.707 | 0.125 | -1.983 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -0.20 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.26 | Benign | 0.00 | Affected | 0.1657 | 0.2778 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.143T>C | F48S 2D AIThe SynGAP1 missense variant F48S has no ClinVar assertion and is not reported in gnomAD. High‑accuracy predictors: AlphaMissense‑Optimized returned an uncertain classification; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect; Foldetta predictions are unavailable. Among the remaining tools, six predict benign (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM) while two predict pathogenic (SIFT, AlphaMissense‑Default). Based on the aggregate predictions, the variant is most likely benign; 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 | 0.298791 | Structured | 0.440452 | Uncertain | 0.558 | 0.707 | 0.125 | -6.382 | Likely Benign | 0.916 | Likely Pathogenic | Ambiguous | 0.214 | Likely Benign | -2.25 | Neutral | 0.334 | Benign | 0.099 | Benign | 3.95 | Benign | 0.00 | Affected | 0.4577 | 0.0901 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||||||||||||
| c.143T>G | F48C 2D AIThe SynGAP1 missense variant F48C 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, 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 the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (3 benign vs. 1 pathogenic). 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 any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.298791 | Structured | 0.440452 | Uncertain | 0.558 | 0.707 | 0.125 | -5.950 | Likely Benign | 0.676 | Likely Pathogenic | Likely Benign | 0.153 | Likely Benign | -2.31 | Neutral | 0.953 | Possibly Damaging | 0.431 | Benign | 3.93 | Benign | 0.00 | Affected | 0.2657 | 0.1962 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||||||
| c.1440G>C | E480D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E480D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, whereas polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. The remaining tools—FoldX, Rosetta, premPS, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority, and Foldetta remains uncertain. Overall, the balance of evidence favors a benign classification for E480D, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -3.001 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.62 | Ambiguous | 0.2 | 1.39 | Ambiguous | 1.01 | Ambiguous | 0.61 | Ambiguous | 0.405 | Likely Benign | -0.77 | Neutral | 0.989 | Probably Damaging | 0.979 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 0.1526 | 0.4130 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1440G>T | E480D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E480D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic outcome. The remaining tools—FoldX, Rosetta, premPS, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward benign, and Foldetta providing no definitive stability change. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -3.001 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.62 | Ambiguous | 0.2 | 1.39 | Ambiguous | 1.01 | Ambiguous | 0.61 | Ambiguous | 0.405 | Likely Benign | -0.77 | Neutral | 0.989 | Probably Damaging | 0.979 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 0.1526 | 0.4130 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1441C>A | H481N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H481N 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, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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. 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 predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -8.229 | Likely Pathogenic | 0.381 | Ambiguous | Likely Benign | 0.16 | Likely Benign | 0.1 | 0.54 | Ambiguous | 0.35 | Likely Benign | 0.09 | Likely Benign | 0.205 | Likely Benign | -4.11 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.68 | Benign | 0.57 | Tolerated | 0.1205 | 0.1631 | 2 | 1 | -0.3 | -23.04 | ||||||||||||||||||||||||||||||
| c.1441C>G | H481D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H481D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, FoldX, SIFT, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a pathogenic signal: the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Uncertain results from AlphaMissense‑Optimized, Foldetta, premPS, and Rosetta are treated as unavailable. Overall, the preponderance of evidence points to a pathogenic effect for H481D, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -11.822 | Likely Pathogenic | 0.812 | Likely Pathogenic | Ambiguous | -0.09 | Likely Benign | 0.1 | 0.54 | Ambiguous | 0.23 | Likely Benign | 0.70 | Ambiguous | 0.273 | Likely Benign | -5.41 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.48 | Benign | 0.50 | Tolerated | 0.2109 | 0.1058 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.1441C>T | H481Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H481Y is listed in ClinVar as benign (ClinVar ID 1543764.0) and is present in the gnomAD database (gnomAD ID 6‑33438473‑C‑T). Prediction tools that classify the variant as benign include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta report uncertain stability effects. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Taking all available evidence together, the variant is most likely benign, which is consistent with its ClinVar benign annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | Likely Benign | 1 | 6-33438473-C-T | 16 | 9.91e-6 | -10.910 | Likely Pathogenic | 0.565 | Likely Pathogenic | Likely Benign | -0.53 | Ambiguous | 0.1 | -0.46 | Likely Benign | -0.50 | Ambiguous | 0.20 | Likely Benign | 0.256 | Likely Benign | -3.32 | Deleterious | 0.988 | Probably Damaging | 0.979 | Probably Damaging | 3.40 | Benign | 0.59 | Tolerated | 3.37 | 33 | 0.0610 | 0.3558 | 0 | 2 | 1.9 | 26.03 | 256.5 | -44.4 | 0.0 | 0.0 | 0.2 | 0.2 | X | X | Uncertain | The imidazole ring of the His481 side chain is located in a short helical structure (res. Glu480-Leu482) within an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. In the WT simulations, His481 alternately stacks against Arg485, Arg587, and Glu480 without a definite role. In the variant simulations, Tyr481 also alternately stacks with nearby arginine residues, including Arg485, Arg587, and Arg479. The interaction between Tyr481 and Arg479 affects the α-α loop, causing it to fold into a distorted helical structure, an effect that might be more pronounced during protein folding. Finally, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||||
| c.1442A>C | H481P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H481P is 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. Those that predict a pathogenic effect comprise SGM Consensus (Likely Pathogenic), PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and PROVEAN. Tools with inconclusive results are Foldetta (Uncertain) and premPS (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta remains uncertain. Overall, the majority of predictions lean toward pathogenicity, 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 | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -10.205 | Likely Pathogenic | 0.630 | Likely Pathogenic | Likely Benign | -0.48 | Likely Benign | 0.3 | 3.69 | Destabilizing | 1.61 | Ambiguous | 0.67 | Ambiguous | 0.385 | Likely Benign | -5.84 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.26 | Tolerated | 0.1979 | 0.3553 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.1442A>G | H481R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H481R is not listed in ClinVar and has no reported allele in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by AlphaMissense‑Optimized, premPS, and Rosetta. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized is inconclusive; the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; and Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion is not contradicted by the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -11.753 | Likely Pathogenic | 0.823 | Likely Pathogenic | Ambiguous | -0.45 | Likely Benign | 0.1 | 0.68 | Ambiguous | 0.12 | Likely Benign | 0.59 | Ambiguous | 0.252 | Likely Benign | -4.48 | Deleterious | 0.983 | Probably Damaging | 0.977 | Probably Damaging | 3.47 | Benign | 0.53 | Tolerated | 0.1515 | 0.1690 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||
| c.1442A>T | H481L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H481L missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; FoldX is uncertain and therefore not counted. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or stability result is missing or inconclusive. Overall, the majority of tools (seven benign vs five pathogenic) lean toward a benign interpretation, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign, though a subset of high‑accuracy predictors suggest pathogenicity, indicating some uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -9.097 | Likely Pathogenic | 0.587 | Likely Pathogenic | Likely Benign | -0.58 | Ambiguous | 0.1 | 0.15 | Likely Benign | -0.22 | Likely Benign | 0.29 | Likely Benign | 0.349 | Likely Benign | -5.91 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 3.41 | Benign | 0.48 | Tolerated | 0.0661 | 0.4678 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||
| c.1443C>A | H481Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 H481Q 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, and FATHMM; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized classifies the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the balance of evidence leans toward a benign effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -8.524 | Likely Pathogenic | 0.663 | Likely Pathogenic | Likely Benign | -0.41 | Likely Benign | 0.1 | 0.31 | Likely Benign | -0.05 | Likely Benign | 0.32 | Likely Benign | 0.243 | Likely Benign | -4.11 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.55 | Benign | 0.51 | Tolerated | 0.1052 | 0.2797 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.1443C>G | H481Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 H481Q 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, and FATHMM; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized classifies the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the balance of evidence leans toward a benign effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -8.524 | Likely Pathogenic | 0.663 | Likely Pathogenic | Likely Benign | -0.41 | Likely Benign | 0.1 | 0.31 | Likely Benign | -0.05 | Likely Benign | 0.32 | Likely Benign | 0.243 | Likely Benign | -4.11 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.55 | Benign | 0.51 | Tolerated | 0.1052 | 0.2797 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.1444C>A | L482I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from PROVEAN and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (REVEL, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) indicate pathogenicity. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments give a consistent picture: AlphaMissense‑Optimized predicts a benign effect, 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 stability calculations, yields an uncertain outcome. Overall, the preponderance of pathogenic predictions suggests that the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -11.116 | Likely Pathogenic | 0.760 | Likely Pathogenic | Likely Benign | 1.29 | Ambiguous | 0.1 | 1.90 | Ambiguous | 1.60 | Ambiguous | 0.71 | Ambiguous | 0.600 | Likely Pathogenic | -1.97 | Neutral | 0.994 | Probably Damaging | 0.994 | Probably Damaging | -1.31 | Pathogenic | 0.05 | Affected | 0.0677 | 0.2368 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.1444C>G | L482V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482V has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—indicates pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for the variant, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -11.676 | Likely Pathogenic | 0.734 | Likely Pathogenic | Likely Benign | 1.97 | Ambiguous | 0.1 | 1.52 | Ambiguous | 1.75 | Ambiguous | 0.76 | Ambiguous | 0.709 | Likely Pathogenic | -2.95 | Deleterious | 0.989 | Probably Damaging | 0.984 | Probably Damaging | -1.30 | Pathogenic | 0.10 | Tolerated | 0.1074 | 0.2027 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1444C>T | L482F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX and premPS, while pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further reveal AlphaMissense‑Optimized as Uncertain, SGM Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for L482F. 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 | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -11.257 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.48 | Likely Benign | 0.0 | 1.09 | Ambiguous | 0.79 | Ambiguous | 0.43 | Likely Benign | 0.724 | Likely Pathogenic | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | -1.22 | Pathogenic | 0.01 | Affected | 0.0457 | 0.1814 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1445T>A | L482H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482H is not reported in ClinVar (ClinVar status: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are absent; all available pathogenic predictors (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus vote (Likely Pathogenic) uniformly indicate a deleterious impact. Uncertain predictions come from FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. No evidence suggests a benign outcome. Consequently, the variant is most likely pathogenic based on the consensus of pathogenic predictions, 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 | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -13.825 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 1.49 | Ambiguous | 0.0 | 1.44 | Ambiguous | 1.47 | Ambiguous | 1.64 | Destabilizing | 0.886 | Likely Pathogenic | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.28 | Pathogenic | 0.00 | Affected | 0.1000 | 0.0879 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.1445T>C | L482P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482P is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the substitution 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 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 outputs, predicts a pathogenic impact. Based on the unanimous computational evidence, 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 | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -12.866 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.59 | Destabilizing | 0.1 | 10.87 | Destabilizing | 7.23 | Destabilizing | 1.55 | Destabilizing | 0.896 | Likely Pathogenic | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.30 | Pathogenic | 0.01 | Affected | 0.2756 | 0.0825 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1445T>G | L482R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, while FoldX, Rosetta, and Foldetta return uncertain results. In a consensus framework, the SGM‑Consensus score is “Likely Pathogenic,” reflecting the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus is Likely Pathogenic, and Foldetta remains inconclusive. Taken together, the overwhelming majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -14.684 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.74 | Ambiguous | 0.1 | 1.31 | Ambiguous | 1.03 | Ambiguous | 1.53 | Destabilizing | 0.878 | Likely Pathogenic | -5.92 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | -1.27 | Pathogenic | 0.01 | Affected | 0.1255 | 0.0679 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1447A>C | I483L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign.” In contrast, polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic impact, and premPS remains uncertain. High‑accuracy assessments are uniformly benign: AlphaMissense‑Optimized is benign, the SGM‑Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Taken together, the majority of evidence, including the high‑accuracy tools, supports a benign classification for I483L. This conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -10.258 | Likely Pathogenic | 0.332 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.35 | Likely Benign | 0.67 | Ambiguous | 0.341 | Likely Benign | -1.86 | Neutral | 0.879 | Possibly Damaging | 0.970 | Probably Damaging | 4.09 | Benign | 0.31 | Tolerated | 0.0664 | 0.2461 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.1447A>G | I483V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions are reported by premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions marked as uncertain include FoldX, Foldetta, 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) also yields benign, whereas Foldetta remains uncertain. Overall, the balance of evidence from both general and high‑accuracy tools leans toward 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. | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | Conflicting | 2 | -10.121 | Likely Pathogenic | 0.523 | Ambiguous | Likely Benign | 1.00 | Ambiguous | 0.0 | 0.27 | Likely Benign | 0.64 | Ambiguous | 1.02 | Destabilizing | 0.228 | Likely Benign | -0.86 | Neutral | 0.914 | Possibly Damaging | 0.921 | Probably Damaging | 3.23 | Benign | 0.03 | Affected | 3.37 | 32 | 0.0876 | 0.2691 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||||
| c.1447A>T | I483L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign.” In contrast, polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic impact, and premPS remains uncertain. High‑accuracy assessments are uniformly benign: AlphaMissense‑Optimized is benign, the SGM‑Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Taken together, the majority of evidence, including the high‑accuracy tools, supports a benign classification for I483L. This conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -10.258 | Likely Pathogenic | 0.332 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.35 | Likely Benign | 0.67 | Ambiguous | 0.342 | Likely Benign | -1.86 | Neutral | 0.879 | Possibly Damaging | 0.970 | Probably Damaging | 4.09 | Benign | 0.31 | Tolerated | 0.0664 | 0.2461 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.1448T>A | I483K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -18.260 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.53 | Destabilizing | 0.1 | 5.15 | Destabilizing | 4.34 | Destabilizing | 2.01 | Destabilizing | 0.585 | Likely Pathogenic | -6.50 | Deleterious | 0.962 | Probably Damaging | 0.991 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | 0.0868 | 0.0670 | -2 | -3 | -8.4 | 15.01 | |||||||||||||||||||||||||||||
| c.1448T>C | I483T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483T 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 and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote 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 preponderance of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -10.692 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.32 | Destabilizing | 0.0 | 2.05 | Destabilizing | 2.19 | Destabilizing | 1.77 | Destabilizing | 0.474 | Likely Benign | -4.24 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.15 | Benign | 0.05 | Affected | 0.0888 | 0.0840 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.1448T>G | I483R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -17.066 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 5.14 | Destabilizing | 0.4 | 4.09 | Destabilizing | 4.62 | Destabilizing | 1.97 | Destabilizing | 0.595 | Likely Pathogenic | -6.50 | Deleterious | 0.997 | Probably Damaging | 0.991 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | 0.1120 | 0.0870 | -2 | -3 | -9.0 | 43.03 | |||||||||||||||||||||||||||||
| c.1449A>G | I483M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I483M missense variant is not reported in ClinVar (ClinVar status: not present) but is catalogued in gnomAD (gnomAD ID: 6‑33438481‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta as benign. No conclusive folding‑stability result is available from Rosetta. Overall, the majority of high‑accuracy tools (two benign, one pathogenic) lean toward a benign interpretation, and this assessment is not contradicted by any 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. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | 6-33438481-A-G | 1 | 6.20e-7 | -8.839 | Likely Pathogenic | 0.777 | Likely Pathogenic | Likely Benign | 0.02 | Likely Benign | 0.0 | 0.73 | Ambiguous | 0.38 | Likely Benign | 1.06 | Destabilizing | 0.261 | Likely Benign | -2.78 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.05 | Affected | 3.37 | 32 | 0.0607 | 0.1959 | 1 | 2 | -2.6 | 18.03 | ||||||||||||||||||||||||
| c.144C>A | F48L 2D AIThe SynGAP1 missense variant F48L 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, and FATHMM. Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions lean toward a benign impact, but the high‑accuracy tools provide conflicting evidence and no Foldetta data is available. Thus, the variant is most likely benign based on the consensus of available predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.298791 | Structured | 0.440452 | Uncertain | 0.558 | 0.707 | 0.125 | -4.955 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.052 | Likely Benign | -1.56 | Neutral | 0.022 | Benign | 0.016 | Benign | 4.16 | Benign | 0.00 | Affected | 0.2641 | 0.3082 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.144C>G | F48L 2D AIThe SynGAP1 missense variant F48L 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, and FATHMM. Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions lean toward a benign impact, but the high‑accuracy tools provide conflicting evidence and no Foldetta data is available. Thus, the variant is most likely benign based on the consensus of available predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.298791 | Structured | 0.440452 | Uncertain | 0.558 | 0.707 | 0.125 | -4.955 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.053 | Likely Benign | -1.56 | Neutral | 0.022 | Benign | 0.016 | Benign | 4.16 | Benign | 0.00 | Affected | 0.2641 | 0.3082 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.1450T>A | F484I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are inconclusive or missing. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -16.197 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.62 | Destabilizing | 0.2 | 5.62 | Destabilizing | 5.62 | Destabilizing | 1.33 | Destabilizing | 0.399 | Likely Benign | -5.70 | Deleterious | 0.894 | Possibly Damaging | 0.332 | Benign | 2.74 | Benign | 0.00 | Affected | 0.1516 | 0.1885 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1450T>C | F484L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic vs. 1 benign) and therefore also indicates pathogenicity. AlphaMissense‑Optimized independently predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, seven tools predict pathogenicity versus four predicting benign, and the high‑accuracy consensus supports a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -11.052 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.52 | Ambiguous | 0.0 | 1.32 | Ambiguous | 1.42 | Ambiguous | 1.20 | Destabilizing | 0.275 | Likely Benign | -5.64 | Deleterious | 0.054 | Benign | 0.022 | Benign | 3.20 | Benign | 0.04 | Affected | 0.1737 | 0.2956 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1450T>G | F484V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta, which integrates 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 any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -15.492 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 6.08 | Destabilizing | 0.1 | 6.07 | Destabilizing | 6.08 | Destabilizing | 1.28 | Destabilizing | 0.455 | Likely Benign | -6.70 | Deleterious | 0.859 | Possibly Damaging | 0.526 | Possibly Damaging | 2.75 | Benign | 0.00 | Affected | 0.1696 | 0.1902 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1451T>A | F484Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FATHMM, and polyPhen‑2 HumVar, whereas the majority of other in silico predictors (SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic effect. Stability‑based methods FoldX and Rosetta are inconclusive, and Foldetta likewise reports no definitive change. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence supports a pathogenic classification for F484Y, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -14.223 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 1.70 | Ambiguous | 0.1 | 0.92 | Ambiguous | 1.31 | Ambiguous | 1.26 | Destabilizing | 0.356 | Likely Benign | -2.92 | Deleterious | 0.733 | Possibly Damaging | 0.344 | Benign | 2.66 | Benign | 0.02 | Affected | 0.1056 | 0.1595 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1451T>C | F484S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -15.666 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.68 | Destabilizing | 0.1 | 4.42 | Destabilizing | 4.55 | Destabilizing | 2.26 | Destabilizing | 0.705 | Likely Pathogenic | -7.76 | Deleterious | 1.000 | Probably Damaging | 0.986 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 0.3993 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1451T>G | F484C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; 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, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -14.988 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.01 | Destabilizing | 0.0 | 3.54 | Destabilizing | 3.78 | Destabilizing | 2.07 | Destabilizing | 0.675 | Likely Pathogenic | -7.73 | Deleterious | 1.000 | Probably Damaging | 0.969 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 0.2449 | 0.0902 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1452C>A | F484L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic vs. 1 benign) and therefore also indicates pathogenicity. AlphaMissense‑Optimized independently predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, seven tools predict pathogenicity versus four predicting benign, and the high‑accuracy consensus supports a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -11.052 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.52 | Ambiguous | 0.0 | 1.32 | Ambiguous | 1.42 | Ambiguous | 1.20 | Destabilizing | 0.214 | Likely Benign | -5.64 | Deleterious | 0.054 | Benign | 0.022 | Benign | 3.20 | Benign | 0.04 | Affected | 0.1737 | 0.2956 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1452C>G | F484L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. Overall, seven tools predict pathogenicity versus four predicting benign, and the high‑accuracy methods reinforce the pathogenic signal. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -11.052 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.52 | Ambiguous | 0.0 | 1.32 | Ambiguous | 1.42 | Ambiguous | 1.20 | Destabilizing | 0.214 | Likely Benign | -5.64 | Deleterious | 0.054 | Benign | 0.022 | Benign | 3.20 | Benign | 0.04 | Affected | 0.1737 | 0.2956 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1453C>A | R485S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FoldX, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that return uncertain results are Rosetta, Foldetta, and premPS. 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 R485S, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | Uncertain | 1 | -15.603 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 1.07 | Ambiguous | 0.74 | Ambiguous | 0.82 | Ambiguous | 0.609 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0.2968 | 0.3266 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||
| c.1453C>G | R485G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485G is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33438485‑C‑G). Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tools predict a benign outcome. Uncertain or inconclusive predictions come from FoldX, Rosetta, Foldetta, 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 as Uncertain. Overall, the evidence strongly favors a pathogenic classification, 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 | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | 6-33438485-C-G | 1 | 6.20e-7 | -15.777 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.84 | Ambiguous | 0.1 | 1.60 | Ambiguous | 1.22 | Ambiguous | 0.98 | Ambiguous | 0.631 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.92 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.3140 | 0.2678 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||
| c.1453C>T | R485C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485C (gnomAD ID 6‑33438485‑C‑T) is listed in ClinVar with an uncertain significance. Functional prediction tools largely disagree: benign calls come from Rosetta 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 (which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus is labeled likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. With the majority of evidence pointing to pathogenicity and no contradictory data from ClinVar, the variant is most likely pathogenic, although ClinVar has not yet reached a definitive classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | Uncertain | 2 | 6-33438485-C-T | 9 | 5.58e-6 | -14.294 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 0.26 | Likely Benign | 0.63 | Ambiguous | 0.44 | Likely Benign | 0.597 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.90 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.3350 | 0.2762 | -4 | -3 | 7.0 | -53.05 | 225.5 | 99.6 | -0.1 | 0.0 | -0.3 | 0.2 | X | Uncertain | The guanidinium group of Arg485 is located in a short helical structure (res. Glu480-Leu482) within an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. The side chain of Arg485 acts as the “arginine finger” of SynGAP, playing a crucial role in Ras-GTPase activation. Consequently, the residue swap inhibits the conversion of GTP to GDP at the enzyme’s active site. Although no negative effects on the protein structure are observed during the simulations, no definite conclusions can be drawn due to the critical role of Arg485 in GTPase activation. | |||||||||||||
| c.1454G>A | R485H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 R485H missense variant is listed in ClinVar as Benign (ClinVar ID 3707943.0) and is present in the gnomAD database (gnomAD ID 6‑33438486‑G‑A). Functional prediction tools that agree on a benign effect are Rosetta and Foldetta, while the majority of tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the preponderance of evidence points to a pathogenic effect, which contradicts the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | Likely Benign | 1 | 6-33438486-G-A | 13 | 8.05e-6 | -13.628 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.77 | Ambiguous | 0.1 | 0.12 | Likely Benign | 0.45 | Likely Benign | 1.13 | Destabilizing | 0.618 | Likely Pathogenic | -4.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.2990 | 0.1602 | 0 | 2 | 1.3 | -19.05 | ||||||||||||||||||||||
| c.1454G>C | R485P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485P is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic or likely pathogenic scores. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. 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 currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | -16.356 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.26 | Destabilizing | 0.3 | 6.86 | Destabilizing | 6.06 | Destabilizing | 0.56 | Ambiguous | 0.692 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.94 | Pathogenic | 0.00 | Affected | 0.2059 | 0.3941 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1454G>T | R485L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485L is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which is currently unreported. 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 | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | -15.807 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.23 | Likely Benign | 0.2 | 0.14 | Likely Benign | 0.19 | Likely Benign | 0.39 | Likely Benign | 0.631 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.92 | Pathogenic | 0.00 | Affected | 0.1715 | 0.3784 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1456G>A | E486K 2D 3DClick to see structure in 3D Viewer AISynGAP1 E486K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a benign effect. Because the predictions are split evenly and the high‑accuracy tools are contradictory, the variant’s impact remains uncertain; thus, the variant is most likely pathogenic based on the high‑accuracy predictions, a conclusion that contradicts its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | Uncertain | 2 | -14.545 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.06 | Likely Benign | 0.1 | 0.37 | Likely Benign | 0.22 | Likely Benign | 0.41 | Likely Benign | 0.435 | Likely Benign | -3.58 | Deleterious | 1.000 | Probably Damaging | 0.988 | Probably Damaging | 3.40 | Benign | 0.12 | Tolerated | 3.37 | 35 | 0.1940 | 0.6392 | 0 | 1 | -0.4 | -0.94 | 206.8 | 52.1 | -0.3 | 0.1 | 0.2 | 0.0 | X | X | Uncertain | Glu486 is located in an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. It is adjacent to the arginine finger (Arg485) and is expected to closely interact with Ras. The residue swap could affect complex formation with the GTPase and its activation. In the WT simulations, the carboxylate group of Glu486 forms salt bridges with Arg485 and Arg475 on the preceding α-helix (res. Ala461-Phe476). In the variant simulations, Lys486 does not form any specific interactions. Although the amino group of the Lys486 side chain cannot form these salt bridges, no negative effects on the protein structure are observed. Nevertheless, the potential role of Glu486 in SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations, and no definite conclusions can be drawn. | |||||||||||||||
| c.1456G>C | E486Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E486Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) as benign, and AlphaMissense‑Optimized as uncertain. No prediction or stability result is missing or inconclusive beyond the stated uncertainty. Overall, the evidence is balanced, with an equal number of benign and pathogenic calls, and the high‑accuracy tools provide opposing conclusions. Thus, the variant is most likely benign based on the preponderance of benign predictions, 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 | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -10.549 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 0.12 | Likely Benign | 0.1 | 0.00 | Likely Benign | 0.06 | Likely Benign | 0.24 | Likely Benign | 0.334 | Likely Benign | -2.68 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.38 | Benign | 0.09 | Tolerated | 0.0888 | 0.5880 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1457A>C | E486A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E486A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, premPS, SIFT, and FATHMM, whereas pathogenic predictions are made by SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore unavailable. Overall, the majority of evidence supports a pathogenic effect. The prediction aligns 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 Pathogenic | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -11.902 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.63 | Ambiguous | 0.0 | 0.32 | Likely Benign | 0.48 | Likely Benign | -0.03 | Likely Benign | 0.398 | Likely Benign | -5.17 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.44 | Benign | 0.39 | Tolerated | 0.3561 | 0.5859 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1457A>G | E486G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E486G missense change is not listed in ClinVar and has no gnomAD entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, SIFT, and FATHMM. Those that predict a damaging outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. 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 uncertain. Overall, the majority of evidence points toward a pathogenic effect. This conclusion is consistent with the absence of a ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -12.488 | Likely Pathogenic | 0.924 | Likely Pathogenic | Ambiguous | 1.09 | Ambiguous | 0.1 | 1.59 | Ambiguous | 1.34 | Ambiguous | -0.14 | Likely Benign | 0.328 | Likely Benign | -5.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.80 | Benign | 0.40 | Tolerated | 0.2918 | 0.5385 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1457A>T | E486V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E486V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, SIFT, FATHMM, and Foldetta. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Uncertain results from FoldX and Rosetta are treated as unavailable. Overall, the majority of predictions support a pathogenic classification, and 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 | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -15.115 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.54 | Ambiguous | 0.1 | -0.65 | Ambiguous | -0.06 | Likely Benign | 0.31 | Likely Benign | 0.490 | Likely Benign | -6.36 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 3.37 | Benign | 0.06 | Tolerated | 0.0493 | 0.6445 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1458G>C | E486D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E486D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign calls (REVEL, FoldX, Rosetta, SIFT, FATHMM) and pathogenic calls (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). Two tools are uncertain (premPS, AlphaMissense‑Optimized). High‑accuracy assessments give mixed results: AlphaMissense‑Optimized is inconclusive; the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Because the majority of standard predictors lean toward pathogenic and the SGM‑Consensus also indicates pathogenic, the variant is most likely pathogenic, although the Foldetta benign prediction and the presence of uncertain calls leave room for ambiguity. This assessment 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 | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -10.363 | Likely Pathogenic | 0.914 | Likely Pathogenic | Ambiguous | 0.19 | Likely Benign | 0.0 | 0.38 | Likely Benign | 0.29 | Likely Benign | 0.54 | Ambiguous | 0.166 | Likely Benign | -2.58 | Deleterious | 0.994 | Probably Damaging | 0.979 | Probably Damaging | 3.43 | Benign | 0.16 | Tolerated | 0.1453 | 0.4115 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1458G>T | E486D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E486D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign calls (REVEL, FoldX, Rosetta, SIFT, FATHMM) and pathogenic calls (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). Two tools are uncertain (premPS, AlphaMissense‑Optimized). High‑accuracy assessments give mixed results: AlphaMissense‑Optimized is inconclusive; the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Because the majority of standard predictors lean toward pathogenic and the SGM‑Consensus also indicates pathogenic, the variant is most likely pathogenic, although the Foldetta benign prediction and the presence of uncertain calls leave room for ambiguity. This assessment 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 | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -10.363 | Likely Pathogenic | 0.914 | Likely Pathogenic | Ambiguous | 0.19 | Likely Benign | 0.0 | 0.38 | Likely Benign | 0.29 | Likely Benign | 0.54 | Ambiguous | 0.166 | Likely Benign | -2.58 | Deleterious | 0.994 | Probably Damaging | 0.979 | Probably Damaging | 3.43 | Benign | 0.16 | Tolerated | 0.1453 | 0.4115 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1459A>C | N487H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N487H has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus) predict a pathogenic or likely pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from these tools contradicts the lack of ClinVar annotation. Overall, the preponderance of pathogenic predictions indicates that the variant is most likely pathogenic, consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -11.403 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 1.15 | Ambiguous | 0.1 | 0.84 | Ambiguous | 1.00 | Ambiguous | 0.72 | Ambiguous | 0.548 | Likely Pathogenic | -4.97 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.68 | Benign | 0.00 | Affected | 0.1123 | 0.3411 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.1459A>G | N487D 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N487D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, Foldetta, and FATHMM, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX and premPS are inconclusive. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, while Foldetta indicates a benign folding stability change. Overall, the preponderance of evidence points to 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 | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -13.330 | Likely Pathogenic | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.2 | -0.21 | Likely Benign | 0.30 | Likely Benign | 0.84 | Ambiguous | 0.513 | Likely Pathogenic | -4.97 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.81 | Benign | 0.01 | Affected | 0.1728 | 0.1815 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1459A>T | N487Y 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N487Y has no ClinVar entry and is absent from gnomAD. Prediction tools that classify it as benign include Rosetta, premPS, and FATHMM, whereas the majority of algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—label it pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports it as likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for N487Y, 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 | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -14.921 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 1.15 | Ambiguous | 0.0 | -0.05 | Likely Benign | 0.55 | Ambiguous | 0.33 | Likely Benign | 0.652 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.69 | Benign | 0.00 | Affected | 0.0587 | 0.2946 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.145T>A | C49S 2D  AIThe SynGAP1 missense variant C49S is 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. Those 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 (2 benign vs. 2 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of standard predictors lean toward pathogenicity, but the high‑accuracy tools do not provide definitive support. Thus, the variant is most likely pathogenic based on the 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. | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -6.575 | Likely Benign | 0.704 | Likely Pathogenic | Likely Benign | 0.260 | Likely Benign | -3.07 | Deleterious | 0.462 | Possibly Damaging | 0.478 | Possibly Damaging | 3.91 | Benign | 0.00 | Affected | 0.3855 | 0.1686 | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.145T>C | C49R 2D  AIThe SynGAP1 missense variant C49R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain and no Foldetta (FoldX‑MD/Rosetta) result is available. Taken together, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -10.000 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.320 | Likely Benign | -3.53 | Deleterious | 0.676 | Possibly Damaging | 0.761 | Possibly Damaging | 3.95 | Benign | 0.00 | Affected | 0.1605 | 0.2120 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||||||||||||
| c.145T>G | C49G 2D  AIThe SynGAP1 missense variant C49G is 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, 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‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic versus four benign) lean toward a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -6.464 | Likely Benign | 0.674 | Likely Pathogenic | Likely Benign | 0.351 | Likely Benign | -3.64 | Deleterious | 0.462 | Possibly Damaging | 0.599 | Possibly Damaging | 3.87 | Benign | 0.00 | Affected | 0.2419 | 0.2528 | -3 | -3 | -2.9 | -46.09 | ||||||||||||||||||||||||||||||||||||||||
| c.1460A>C | N487T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N487T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: 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 classified as “Likely Pathogenic.” High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No evidence from FoldX, Rosetta, or premPS is available to alter this assessment. Overall, the preponderance of computational evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -12.618 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 1.92 | Ambiguous | 0.1 | 1.94 | Ambiguous | 1.93 | Ambiguous | 0.68 | Ambiguous | 0.481 | Likely Benign | -5.97 | Deleterious | 0.987 | Probably Damaging | 0.980 | Probably Damaging | 2.78 | Benign | 0.05 | Affected | 0.1200 | 0.3441 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.1460A>G | N487S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N487S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is inconclusive, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as Likely Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is also inconclusive. Overall, the preponderance of evidence from multiple in silico predictors and the SGM Consensus indicates that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -10.297 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 1.42 | Ambiguous | 0.0 | 1.49 | Ambiguous | 1.46 | Ambiguous | 0.65 | Ambiguous | 0.459 | Likely Benign | -4.97 | Deleterious | 0.999 | Probably Damaging | 0.979 | Probably Damaging | 2.74 | Benign | 0.01 | Affected | 0.3065 | 0.3656 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.1460A>T | N487I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N487I has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely disagree, but the majority indicate a deleterious effect. Benign predictions come from Rosetta, 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. Uncertain results are provided by FoldX and Foldetta. 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 predicts pathogenic; Foldetta remains inconclusive. Overall, the preponderance of evidence supports a pathogenic classification for N487I, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -16.592 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.71 | Ambiguous | 0.1 | 0.13 | Likely Benign | 0.92 | Ambiguous | 0.33 | Likely Benign | 0.591 | Likely Pathogenic | -8.95 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.67 | Benign | 0.00 | Affected | 0.0633 | 0.3531 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.1461C>A | N487K 2D AIThe SynGAP1 missense variant N487K lies in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. The remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other stability predictions are available. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -13.520 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.10 | Ambiguous | 0.9 | 1.28 | Ambiguous | 1.19 | Ambiguous | 0.80 | Ambiguous | 0.489 | Likely Benign | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 0.1953 | 0.2721 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1461C>G | N487K 2D AIThe SynGAP1 missense variant N487K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely disagree: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑related methods (FoldX, Rosetta, premPS, Foldetta) yield uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar annotation (none is available). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -13.520 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.10 | Ambiguous | 0.9 | 1.28 | Ambiguous | 1.19 | Ambiguous | 0.80 | Ambiguous | 0.488 | Likely Benign | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 0.1953 | 0.2721 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1462A>C | T488P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T488P is not reported in ClinVar (ClinVar status: not listed) 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, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity; premPS is uncertain and therefore not counted. 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. Based on the overwhelming consensus of 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 | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -13.432 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 4.40 | Destabilizing | 0.7 | 5.68 | Destabilizing | 5.04 | Destabilizing | 0.68 | Ambiguous | 0.505 | Likely Pathogenic | -5.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0.1518 | 0.3557 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1462A>G | T488A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T488A is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while the majority of tools (FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) predict pathogenicity; Rosetta and premPS are uncertain. 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, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the preponderance of evidence indicates that T488A is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -11.341 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 2.12 | Destabilizing | 0.2 | 1.99 | Ambiguous | 2.06 | Destabilizing | 0.57 | Ambiguous | 0.497 | Likely Benign | -4.64 | Deleterious | 0.996 | Probably Damaging | 0.989 | Probably Damaging | 3.24 | Benign | 0.01 | Affected | 0.2871 | 0.2872 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1462A>T | T488S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T488S 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, and Rosetta) 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 standard tools lean toward a benign interpretation, but the high‑accuracy consensus is split, leaving the variant’s impact ambiguous. No ClinVar annotation contradicts these predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -7.662 | In-Between | 0.745 | Likely Pathogenic | Likely Benign | 0.35 | Likely Benign | 0.1 | 0.90 | Ambiguous | 0.63 | Ambiguous | 0.77 | Ambiguous | 0.257 | Likely Benign | -3.51 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.73 | Benign | 0.31 | Tolerated | 0.2256 | 0.2813 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||
| c.1463C>A | T488K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T488K 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 eleven tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all classify the variant as pathogenic. The high‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta outputs)—all predict 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 assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -14.391 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.09 | Destabilizing | 0.2 | 2.33 | Destabilizing | 2.21 | Destabilizing | 0.90 | Ambiguous | 0.692 | Likely Pathogenic | -5.64 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0.0871 | 0.2104 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||
| c.1463C>G | T488R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T488R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate 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) all predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -14.353 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 1.29 | Ambiguous | 0.3 | 1.55 | Ambiguous | 1.42 | Ambiguous | 0.85 | Ambiguous | 0.726 | Likely Pathogenic | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.22 | Benign | 0.00 | Affected | 0.0711 | 0.2048 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||
| c.1463C>T | T488M 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant T488M is listed in ClinVar with an uncertain significance (ClinVar ID 2824521.0) and is present in gnomAD (ID 6‑33438495‑C‑T). Prediction tools that indicate a benign effect include premPS and FATHMM, whereas the majority of algorithms predict a pathogenic outcome: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as inconclusive. No other tools provide definitive evidence. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | Uncertain | 1 | 6-33438495-C-T | 2 | 1.24e-6 | -12.459 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.66 | Ambiguous | 0.3 | 1.62 | Ambiguous | 1.14 | Ambiguous | 0.46 | Likely Benign | 0.746 | Likely Pathogenic | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 3.37 | 35 | 0.1027 | 0.4857 | -1 | -1 | 2.6 | 30.09 | ||||||||||||||||||||||
| c.1465C>A | L489I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into three groups: benign predictions come from REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; the remaining methods (FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default) yield uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is indeterminate due to a tie between pathogenic and benign signals, and Foldetta reports an uncertain stability change. Overall, the preponderance 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. | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | -7.333 | In-Between | 0.342 | Ambiguous | Likely Benign | 1.01 | Ambiguous | 0.0 | 0.52 | Ambiguous | 0.77 | Ambiguous | 0.90 | Ambiguous | 0.490 | Likely Benign | -1.55 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.42 | Pathogenic | 0.21 | Tolerated | 0.1069 | 0.4080 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1465C>G | L489V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM, while only AlphaMissense‑Optimized predicts a benign outcome. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, 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 for L489V. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database record. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | -9.345 | Likely Pathogenic | 0.467 | Ambiguous | Likely Benign | 2.09 | Destabilizing | 0.0 | 1.70 | Ambiguous | 1.90 | Ambiguous | 1.25 | Destabilizing | 0.586 | Likely Pathogenic | -2.55 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.34 | Pathogenic | 0.01 | Affected | 0.1665 | 0.4108 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1465C>T | L489F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489F is listed in ClinVar with an uncertain significance (ClinVar ID 522018.0) and is present in the gnomAD database (gnomAD ID 6‑33438497‑C‑T). In silico 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 report a pathogenic outcome, while no tool predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No prediction or folding‑stability result is missing or ambiguous. **Thus, the variant is most likely pathogenic based on the collective predictions, and this does not contradict the ClinVar uncertain status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | Uncertain | 2 | 6-33438497-C-T | 1 | 6.20e-7 | -12.066 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 1.72 | Ambiguous | 0.5 | 1.14 | Ambiguous | 1.43 | Ambiguous | 0.56 | Ambiguous | 0.724 | Likely Pathogenic | -3.76 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.51 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.0791 | 0.3729 | 2 | 0 | -1.0 | 34.02 | 246.4 | -17.8 | 0.0 | 0.0 | 0.6 | 0.1 | X | Potentially Benign | The iso-butyl side chain of Leu489, located in the α-helix (res. Leu489-Glu519) within an inter-helix space of four helices (res. Ala461-Phe476, res. Val441-Ser457, and res. Met414-Glu436), packs with hydrophobic residues (e.g., Cys432, Ala448, Lys444, Ala493, Val447, Met468) in the inter-helix space. In the variant simulations, the phenyl ring of the Phe489 side chain can also pack favorably in the hydrophobic region. However, due to the size difference, the aromatic side chain of Phe489 tends to reposition to escape the tight region to accommodate the larger side chain, stacking with Lys444. Although no apparent negative changes are observed during the variant simulation, the size difference between the swapped residues could affect the protein folding process. | |||||||||||||
| c.1466T>A | L489H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489H is not reported in ClinVar (ClinVar status: 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. Therefore, 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. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | -15.946 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.12 | Destabilizing | 0.2 | 2.13 | Destabilizing | 2.63 | Destabilizing | 1.99 | Destabilizing | 0.919 | Likely Pathogenic | -6.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.60 | Pathogenic | 0.00 | Affected | 0.1132 | 0.0871 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.1466T>C | L489P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All evaluated 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 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 outputs, also predicts pathogenic. Overall, the variant is most likely pathogenic based on the consensus of predictive tools, 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 | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | Conflicting | 2 | -13.520 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.50 | Destabilizing | 0.1 | 4.69 | Destabilizing | 3.60 | Destabilizing | 1.73 | Destabilizing | 0.939 | Likely Pathogenic | -6.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.56 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.3673 | 0.1474 | -3 | -3 | -5.4 | -16.04 | 209.9 | 61.9 | 0.1 | 0.0 | 0.6 | 0.1 | X | Potentially Pathogenic | The iso-butyl side chain of Leu489, located in the α-helix (res. Leu489-Glu519) within an inter-helix space of four helices (res. Ala461-Phe476, res. Val441-Ser457, and res. Met414-Glu436), packs with hydrophobic residues (e.g., Cys432, Ala448, Lys444, Ala493, Val447, Met468). In the variant simulations, Pro489 is located near the beginning of the α-helix, so the residue swap with Leu489 does not affect the continuity of the secondary structure element. However, the side chain of proline is not as optimal as that of leucine for maintaining hydrophobic packing with nearby residues (e.g., Ala448, Lys444). Additionally, the consistently maintained hydrogen bond interaction between the backbone amide group of Leu489 and the carbonyl of Glu436 is lost due to the residue swap, potentially affecting the tertiary structure integrity. | ||||||||||||||||
| c.1466T>G | L489R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign effect. High‑accuracy methods 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 destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, 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 | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | -15.365 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.32 | Destabilizing | 0.3 | 4.90 | Destabilizing | 4.61 | Destabilizing | 1.74 | Destabilizing | 0.949 | Likely Pathogenic | -5.86 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.61 | Pathogenic | 0.00 | Affected | 0.1306 | 0.1145 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1468G>A | A490T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A490T is listed in gnomAD (variant ID 6‑33438500‑G‑A) but has no ClinVar entry. Prediction tools that agree on a pathogenic effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Tools that are inconclusive or uncertain are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. No tool predicts a benign outcome. High‑accuracy assessments show that the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while AlphaMissense‑Optimized remains uncertain and Foldetta is also uncertain. Based on the preponderance of pathogenic predictions and the lack of any benign calls, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.120615 | Structured | 0.322979 | Uncertain | 0.938 | 0.210 | 0.125 | 6-33438500-G-A | 1 | 6.20e-7 | -10.266 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.80 | Ambiguous | 0.2 | 1.70 | Ambiguous | 1.25 | Ambiguous | 1.00 | Destabilizing | 0.821 | Likely Pathogenic | -3.87 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.34 | Pathogenic | 0.03 | Affected | 3.37 | 35 | 0.1065 | 0.4495 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||
| c.1468G>C | A490P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A490P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Among the available in‑silico predictors, 10 tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) uniformly predict a pathogenic effect, whereas only Foldetta predicts a benign outcome; FoldX, Rosetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) is benign. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.120615 | Structured | 0.322979 | Uncertain | 0.938 | 0.210 | 0.125 | Uncertain | 1 | -12.905 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | -1.27 | Ambiguous | 0.1 | 1.31 | Ambiguous | 0.02 | Likely Benign | 1.07 | Destabilizing | 0.878 | Likely Pathogenic | -4.81 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.42 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.1755 | 0.3071 | -1 | 1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1468G>T | A490S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A490S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Optimized, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM) indicate a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts it to be likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an inconclusive result. No other tools provide definitive evidence. Overall, the preponderance of pathogenic predictions suggests that A490S is most likely pathogenic, and this assessment does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.120615 | Structured | 0.322979 | Uncertain | 0.938 | 0.210 | 0.125 | -8.307 | Likely Pathogenic | 0.426 | Ambiguous | Likely Benign | 0.76 | Ambiguous | 0.1 | 1.55 | Ambiguous | 1.16 | Ambiguous | 0.89 | Ambiguous | 0.766 | Likely Pathogenic | -2.82 | Deleterious | 0.983 | Probably Damaging | 0.993 | Probably Damaging | -1.41 | Pathogenic | 0.02 | Affected | 0.2338 | 0.3116 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1469C>A | A490D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A490D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that assess pathogenicity are unanimous: AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, SIFT, polyPhen‑2 (HumDiv and HumVar), REVEL, premPS, FoldX, Rosetta, and Foldetta all classify the variant as pathogenic. No tool predicts a benign effect, so the benign group is empty. 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 reports pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this assessment is consistent with the absence of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.120615 | Structured | 0.322979 | Uncertain | 0.938 | 0.210 | 0.125 | -16.643 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.33 | Destabilizing | 0.1 | 4.23 | Destabilizing | 3.78 | Destabilizing | 1.33 | Destabilizing | 0.946 | Likely Pathogenic | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.48 | Pathogenic | 0.00 | Affected | 0.1532 | 0.1741 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1469C>G | A490G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A490G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Pathogenic). Predictions that are uncertain or inconclusive are FoldX, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for A490G. 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 | GAP | 0.120615 | Structured | 0.322979 | Uncertain | 0.938 | 0.210 | 0.125 | -9.767 | Likely Pathogenic | 0.384 | Ambiguous | Likely Benign | 1.24 | Ambiguous | 0.0 | 2.00 | Destabilizing | 1.62 | Ambiguous | 1.13 | Destabilizing | 0.744 | Likely Pathogenic | -3.44 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.46 | Pathogenic | 0.01 | Affected | 0.2051 | 0.2228 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1469C>T | A490V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A490V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly favor a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate pathogenicity. No tool predicts a benign outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus remains likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the consensus of the majority of algorithms points to a pathogenic effect, and this conclusion does not conflict with the absence of ClinVar annotation. Thus, the variant is most likely pathogenic, with no contradiction from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.120615 | Structured | 0.322979 | Uncertain | 0.938 | 0.210 | 0.125 | -10.348 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.73 | Ambiguous | 0.3 | 0.62 | Ambiguous | 0.68 | Ambiguous | 0.69 | Ambiguous | 0.817 | Likely Pathogenic | -3.93 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | -1.26 | Pathogenic | 0.04 | Affected | 0.0983 | 0.4213 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.146G>A | C49Y 2D  AIThe SynGAP1 missense variant C49Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is classified as Likely Pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for C49Y. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -11.097 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 0.312 | Likely Benign | -3.38 | Deleterious | 0.676 | Possibly Damaging | 0.761 | Possibly Damaging | 3.85 | Benign | 0.00 | Affected | 0.1016 | 0.3172 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||||||||||||
| c.146G>C | C49S 2D AIThe SynGAP1 missense variant C49S is 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. Those 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 (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the majority of conventional tools (five pathogenic vs four benign) lean toward a pathogenic interpretation, but the single high‑accuracy benign prediction and the inconclusive SGM Consensus leave the assessment uncertain. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this 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. | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -6.575 | Likely Benign | 0.704 | Likely Pathogenic | Likely Benign | 0.224 | Likely Benign | -3.07 | Deleterious | 0.462 | Possibly Damaging | 0.478 | Possibly Damaging | 3.91 | Benign | 0.00 | Affected | 0.3855 | 0.1686 | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.146G>T | C49F 2D  AIThe SynGAP1 missense variant C49F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect are REVEL and FATHMM, while a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default) predict a pathogenic impact. The remaining tools, ESM1b and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—classifies the variant as pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -7.194 | In-Between | 0.893 | Likely Pathogenic | Ambiguous | 0.301 | Likely Benign | -3.21 | Deleterious | 0.676 | Possibly Damaging | 0.695 | Possibly Damaging | 3.86 | Benign | 0.00 | Affected | 0.1199 | 0.3690 | -4 | -2 | 0.3 | 44.04 | ||||||||||||||||||||||||||||||||||||||||
| c.1471A>C | T491P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T491P 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, and PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | -13.603 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 3.19 | Destabilizing | 0.6 | 4.32 | Destabilizing | 3.76 | Destabilizing | 0.96 | Ambiguous | 0.882 | Likely Pathogenic | -5.89 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.49 | Pathogenic | 0.00 | Affected | 0.2024 | 0.3759 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1471A>G | T491A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T491A is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (gnomAD ID: 6‑33438503‑A‑G). Prediction tools that agree on a benign effect include FoldX, Rosetta, and Foldetta. Tools that predict a pathogenic effect include SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions (10 pathogenic vs. 3 benign) indicate a likely 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 | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | 6-33438503-A-G | 1 | 6.20e-7 | -11.033 | Likely Pathogenic | 0.934 | Likely Pathogenic | Ambiguous | 0.10 | Likely Benign | 0.3 | -0.27 | Likely Benign | -0.09 | Likely Benign | 1.06 | Destabilizing | 0.851 | Likely Pathogenic | -4.82 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | -1.47 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.3903 | 0.2874 | 0 | 1 | 2.5 | -30.03 | ||||||||||||||||||||||||
| c.1471A>T | T491S 2D AIThe SynGAP1 missense variant T491S 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 SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. No evidence from FoldX or Rosetta is available to support a stability change. Overall, the preponderance of evidence points to a pathogenic effect for T491S, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | -7.273 | In-Between | 0.924 | Likely Pathogenic | Ambiguous | 0.93 | Ambiguous | 0.7 | 1.27 | Ambiguous | 1.10 | Ambiguous | 1.00 | Destabilizing | 0.704 | Likely Pathogenic | -3.90 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.25 | Pathogenic | 0.19 | Tolerated | 0.3119 | 0.2815 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1472C>A | T491N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T491N is not reported in ClinVar and is absent from gnomAD. Prediction tools that reach consensus on pathogenicity include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, all of which classify the substitution as pathogenic. No tool predicts a benign effect. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. The remaining tools, Rosetta and Foldetta, provide inconclusive evidence. Overall, the collective evidence indicates that T491N is most likely pathogenic, 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 | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | -11.952 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 2.39 | Destabilizing | 0.4 | 1.44 | Ambiguous | 1.92 | Ambiguous | 1.43 | Destabilizing | 0.842 | Likely Pathogenic | -4.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.50 | Pathogenic | 0.02 | Affected | 0.0959 | 0.2902 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.1472C>G | T491S 2D AIThe SynGAP1 missense variant T491S 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 SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. No evidence from FoldX or Rosetta is available to support a stability change. Overall, the preponderance of evidence points to a pathogenic effect for T491S, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | -7.273 | In-Between | 0.924 | Likely Pathogenic | Ambiguous | 0.93 | Ambiguous | 0.7 | 1.27 | Ambiguous | 1.10 | Ambiguous | 1.00 | Destabilizing | 0.666 | Likely Pathogenic | -3.90 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.25 | Pathogenic | 0.19 | Tolerated | 0.3119 | 0.2815 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1472C>T | T491I 2D AIThe SynGAP1 missense variant T491I is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS; all other evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact, while FoldX is uncertain and therefore not counted in either group. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized reports a pathogenic change, 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 conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | -12.525 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.48 | Ambiguous | 1.8 | 3.73 | Destabilizing | 2.61 | Destabilizing | 0.49 | Likely Benign | 0.915 | Likely Pathogenic | -5.89 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.42 | Pathogenic | 0.00 | Affected | 0.0898 | 0.4942 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1474A>C | K492Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K492Q 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, whereas pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 outputs, yields an uncertain result. No evidence from ClinVar contradicts these findings. Therefore, the variant is most likely pathogenic based on the collective predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.685 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.34 | Likely Benign | 0.0 | 0.93 | Ambiguous | 0.64 | Ambiguous | 1.13 | Destabilizing | 0.463 | Likely Benign | -3.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.02 | Affected | 0.3534 | 0.0830 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1474A>G | K492E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K492E 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. The remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, which contradicts its current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | Conflicting | 2 | -16.175 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.53 | Ambiguous | 0.1 | 1.90 | Ambiguous | 1.72 | Ambiguous | 1.42 | Destabilizing | 0.510 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.99 | Benign | 0.01 | Affected | 3.37 | 35 | 0.2968 | 0.0650 | 1 | 0 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.1475A>C | K492T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K492T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the majority—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized—predict a pathogenic impact. Four methods (FoldX, Rosetta, Foldetta, premPS) return uncertain results. High‑accuracy predictors give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta remains uncertain. Overall, the evidence strongly favors a pathogenic classification, 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 | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -16.126 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.09 | Ambiguous | 0.1 | 0.88 | Ambiguous | 0.99 | Ambiguous | 0.98 | Ambiguous | 0.595 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.96 | Benign | 0.04 | Affected | 0.1691 | 0.2825 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1475A>G | K492R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K492R is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of tools (seven pathogenic vs. six benign) lean toward a pathogenic interpretation, and this does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -11.290 | Likely Pathogenic | 0.599 | Likely Pathogenic | Likely Benign | -0.20 | Likely Benign | 0.1 | 0.45 | Likely Benign | 0.13 | Likely Benign | 0.84 | Ambiguous | 0.487 | Likely Benign | -2.98 | Deleterious | 0.997 | Probably Damaging | 0.990 | Probably Damaging | 3.25 | Benign | 0.05 | Affected | 0.3911 | 0.0835 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.1475A>T | K492I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K492I is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions from premPS and FATHMM; pathogenic predictions from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results come from FoldX, Rosetta, and Foldetta. High‑accuracy methods give a pathogenic verdict: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenic (3/4 votes). Foldetta remains inconclusive. Overall, the majority of evidence points to 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 | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -18.661 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.54 | Ambiguous | 0.1 | -0.59 | Ambiguous | -0.57 | Ambiguous | 0.49 | Likely Benign | 0.645 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.94 | Benign | 0.00 | Affected | 0.0875 | 0.2810 | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||
| c.1476A>C | K492N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K492N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. 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 pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No folding‑stability predictions are definitive. Based on the preponderance of pathogenic predictions and the lack of benign 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 | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.048 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 1.09 | Ambiguous | 1.01 | Ambiguous | 1.25 | Destabilizing | 0.512 | Likely Pathogenic | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.92 | Benign | 0.00 | Affected | 0.2814 | 0.0926 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1476A>T | K492N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K492N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. 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 pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No folding‑stability predictions are definitive. Based on the preponderance of pathogenic predictions and the lack of benign 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 | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.048 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 1.09 | Ambiguous | 1.01 | Ambiguous | 1.25 | Destabilizing | 0.512 | Likely Pathogenic | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.92 | Benign | 0.00 | Affected | 0.2814 | 0.0926 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1477G>A | A493T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A493T missense variant is not reported in ClinVar and is absent from gnomAD. Consensus among most in silico predictors indicates a deleterious effect: REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, premPS, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as pathogenic or likely pathogenic. Only Rosetta predicts a benign outcome; FoldX, Foldetta, and AlphaMissense‑Optimized are uncertain or unavailable. High‑accuracy tools give the following: AlphaMissense‑Optimized – uncertain; SGM Consensus – likely pathogenic; Foldetta – uncertain. Taken together, the preponderance of evidence supports a pathogenic effect for A493T. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -10.366 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.82 | Ambiguous | 0.0 | 0.39 | Likely Benign | 0.61 | Ambiguous | 1.10 | Destabilizing | 0.727 | Likely Pathogenic | -3.41 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.36 | Pathogenic | 0.04 | Affected | 0.0964 | 0.3972 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1477G>C | A493P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A493P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact all converge on a pathogenic interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict deleterious effects. No tool in the dataset indicates a benign outcome. 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 (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 | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -15.797 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.96 | Destabilizing | 0.1 | 10.79 | Destabilizing | 7.88 | Destabilizing | 1.32 | Destabilizing | 0.883 | Likely Pathogenic | -4.54 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.41 | Pathogenic | 0.02 | Affected | 0.1490 | 0.2907 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1477G>T | A493S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A493S is 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, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are uncertain or inconclusive (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as unavailable. Based on the consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -6.271 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.66 | Ambiguous | 0.1 | 1.10 | Ambiguous | 0.88 | Ambiguous | 0.53 | Ambiguous | 0.507 | Likely Pathogenic | -2.12 | Neutral | 0.983 | Probably Damaging | 0.993 | Probably Damaging | -1.27 | Pathogenic | 0.44 | Tolerated | 0.1821 | 0.2763 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1478C>A | A493D 2D AISynGAP1 missense variant A493D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Consequently, the variant is most likely pathogenic, and this assessment is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -16.834 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.45 | Destabilizing | 1.5 | 3.59 | Destabilizing | 4.02 | Destabilizing | 1.60 | Destabilizing | 0.925 | Likely Pathogenic | -5.25 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.41 | Pathogenic | 0.01 | Affected | 0.1437 | 0.1541 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1478C>G | A493G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A493G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus all predict pathogenicity, while only AlphaMissense‑Optimized predicts a benign outcome. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) remains pathogenic; Foldetta likewise yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect for A493G, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -11.379 | Likely Pathogenic | 0.571 | Likely Pathogenic | Likely Benign | 1.85 | Ambiguous | 0.0 | 1.63 | Ambiguous | 1.74 | Ambiguous | 1.40 | Destabilizing | 0.764 | Likely Pathogenic | -3.54 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.40 | Pathogenic | 0.02 | Affected | 0.1673 | 0.2228 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1478C>T | A493V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A493V missense variant has no ClinVar entry and is reported in gnomAD (6‑33438510‑C‑T). Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Benign predictions are limited to SIFT and Foldetta. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus indicates likely pathogenic, and Foldetta predicts benign stability. No other tools provide conclusive evidence. Overall, the preponderance of pathogenic predictions, including the consensus and multiple independent algorithms, suggests the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | 6-33438510-C-T | 3 | 1.86e-6 | -12.511 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.56 | Ambiguous | 0.1 | -0.67 | Ambiguous | -0.06 | Likely Benign | 0.91 | Ambiguous | 0.735 | Likely Pathogenic | -3.84 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | -1.31 | Pathogenic | 0.10 | Tolerated | 3.37 | 35 | 0.0877 | 0.3860 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||
| c.147C>G | C49W 2D  AIThe SynGAP1 missense variant C49W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic and the SGM‑Consensus is “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that C49W 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 | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -12.247 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.291 | Likely Benign | -3.56 | Deleterious | 0.880 | Possibly Damaging | 0.914 | Probably Damaging | 3.83 | Benign | 0.00 | Affected | 0.1380 | 0.3172 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||||||||||||
| c.1480A>C | I494L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I494L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the balance of evidence (five pathogenic versus four benign predictions, with several uncertain calls) leans toward a pathogenic interpretation. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -10.175 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.28 | Likely Benign | 0.1 | 1.11 | Ambiguous | 0.70 | Ambiguous | 0.91 | Ambiguous | 0.513 | Likely Pathogenic | -1.69 | Neutral | 0.645 | Possibly Damaging | 0.718 | Possibly Damaging | -0.88 | Pathogenic | 0.11 | Tolerated | 0.0816 | 0.2851 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1480A>G | I494V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant I494V is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438512‑A‑G). Functional prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Pathogenic predictions come from premPS and FATHMM. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign; Foldetta remains uncertain. Overall, the majority of evidence supports a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | Conflicting | 2 | 6-33438512-A-G | 36 | 2.23e-5 | -7.102 | In-Between | 0.112 | Likely Benign | Likely Benign | 1.16 | Ambiguous | 0.0 | 0.71 | Ambiguous | 0.94 | Ambiguous | 1.02 | Destabilizing | 0.439 | Likely Benign | -0.83 | Neutral | 0.278 | Benign | 0.179 | Benign | -1.30 | Pathogenic | 0.07 | Tolerated | 3.37 | 35 | 0.0965 | 0.2491 | 4 | 3 | -0.3 | -14.03 | 248.6 | 29.3 | 0.0 | 0.0 | -1.1 | 0.5 | X | Potentially Benign | The sec-butyl side chain of Ile494, located in an α-helix (res. Leu489-Glu519), packs against hydrophobic residues (e.g., Phe484, Leu465, Trp572, Ala493, Met468) in an inter-helix space (res. Leu489-Glu519 and res. Ala461-Phe476). In the variant simulations, the hydrophobic iso-propyl side chain of Val494, which is of a similar size and has similar physicochemical properties to Ile494 in the WT, resides similarly in the inter-helix hydrophobic space. Thus, no negative effects on the protein structure are observed. | ||||||||||||||
| c.1480A>T | I494L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I494L variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta indicating uncertain stability change. Overall, the balance of evidence leans toward pathogenicity, with a majority of tools and the SGM Consensus supporting a deleterious effect. This conclusion does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -10.175 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.28 | Likely Benign | 0.1 | 1.11 | Ambiguous | 0.70 | Ambiguous | 0.91 | Ambiguous | 0.513 | Likely Pathogenic | -1.69 | Neutral | 0.645 | Possibly Damaging | 0.718 | Possibly Damaging | -0.88 | Pathogenic | 0.11 | Tolerated | 0.0816 | 0.2851 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1481T>A | I494K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I494K is not reported in ClinVar (ClinVar ID None) 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 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 (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -15.950 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 4.23 | Destabilizing | 0.2 | 5.33 | Destabilizing | 4.78 | Destabilizing | 1.89 | Destabilizing | 0.925 | Likely Pathogenic | -6.40 | Deleterious | 0.987 | Probably Damaging | 0.937 | Probably Damaging | -1.41 | Pathogenic | 0.00 | Affected | 0.1015 | 0.0870 | -2 | -3 | -8.4 | 15.01 | |||||||||||||||||||||||||||||
| c.1481T>C | I494T 2D AIThe SynGAP1 missense variant I494T 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. All other evaluated tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -10.033 | Likely Pathogenic | 0.754 | Likely Pathogenic | Likely Benign | 2.45 | Destabilizing | 0.7 | 2.12 | Destabilizing | 2.29 | Destabilizing | 1.73 | Destabilizing | 0.907 | Likely Pathogenic | -4.61 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.38 | Pathogenic | 0.01 | Affected | 0.1003 | 0.0640 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.1481T>G | I494R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I494R is listed in ClinVar as Pathogenic (ClinVar ID 1685460.0) and is not reported in gnomAD. Prediction tools that assess functional impact all converge on a pathogenic outcome: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity. 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. 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 | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | Likely Pathogenic | 1 | -15.758 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 6.71 | Destabilizing | 0.3 | 3.40 | Destabilizing | 5.06 | Destabilizing | 2.19 | Destabilizing | 0.911 | Likely Pathogenic | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.957 | Probably Damaging | -1.41 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.1180 | 0.0870 | -2 | -3 | -9.0 | 43.03 | 273.9 | -59.8 | 0.0 | 0.0 | 0.0 | 0.1 | X | X | X | X | Potentially Pathogenic | The sec-butyl side chain of Ile494, located in an α-helix (res. Leu489-Glu519), packs against hydrophobic residues (e.g., Phe484, Leu465, Trp572, Ala493, Met468) in an inter-helix space (res. Leu489-Glu519 and res. Ala461-Phe476). In the variant simulations, the bulkier and positively charged residue, Arg494, weakens the integrity of the opposing helix. Additionally, the bulkier Arg494 stacks with Phe484, causing the α-helices to move farther apart to accommodate it. This mutation could have substantial negative effects due to the fundamental role of hydrophobic packing, which is disrupted by Arg494 during protein folding. | |||||||||||||
| c.1482A>G | I494M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I494M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the balance of evidence leans toward pathogenicity, with a majority of tools predicting a deleterious effect. 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. | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -8.223 | Likely Pathogenic | 0.356 | Ambiguous | Likely Benign | 0.35 | Likely Benign | 0.2 | 1.98 | Ambiguous | 1.17 | Ambiguous | 0.98 | Ambiguous | 0.542 | Likely Pathogenic | -2.25 | Neutral | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.15 | Pathogenic | 0.23 | Tolerated | 0.0676 | 0.1789 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||
| c.1483G>A | E495K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495K is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include FoldX and Foldetta, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools with inconclusive results (Rosetta and premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also as pathogenic, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) indicates a benign effect. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect for E495K, which is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | Uncertain | 1 | -11.478 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.15 | Likely Benign | 0.2 | 0.66 | Ambiguous | 0.41 | Likely Benign | 0.70 | Ambiguous | 0.869 | Likely Pathogenic | -3.91 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.1974 | 0.5039 | 1 | 0 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.1483G>C | E495Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E495Q missense variant is not listed in ClinVar and has no reported allele in gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, and Foldetta, all of which score the substitution as benign. Tools that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and 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 pathogenicity, AlphaMissense‑Optimized is uncertain, and Foldetta predicts benign stability. Overall, the majority of evidence points to a pathogenic impact. 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 | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -11.050 | Likely Pathogenic | 0.899 | Likely Pathogenic | Ambiguous | -0.27 | Likely Benign | 0.1 | 0.11 | Likely Benign | -0.08 | Likely Benign | 0.89 | Ambiguous | 0.748 | Likely Pathogenic | -2.92 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.42 | Pathogenic | 0.01 | Affected | 0.1093 | 0.4973 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1484A>C | E495A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E495A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include FoldX, while the remaining evaluated algorithms (REVEL, SIFT, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and the SGM‑Consensus) all predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. No contradictory evidence is present from ClinVar or population databases. Overall, the preponderance of predictions supports a pathogenic classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -9.229 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.42 | Likely Benign | 0.1 | 0.85 | Ambiguous | 0.64 | Ambiguous | 0.69 | Ambiguous | 0.834 | Likely Pathogenic | -5.84 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.38 | Pathogenic | 0.01 | Affected | 0.2711 | 0.4259 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1484A>G | E495G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E495G missense variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438516‑A‑G). Among the available in‑silico predictors, the following tools uniformly indicate a pathogenic effect: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which itself is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool in the dataset predicts a benign outcome; predictions that are uncertain (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Pathogenic,” and Foldetta as “Uncertain.” Overall, the preponderance of pathogenic predictions strongly suggests that 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 | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | Uncertain | 1 | 6-33438516-A-G | 1 | 6.20e-7 | -9.400 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | 1.21 | Ambiguous | 0.0 | 2.06 | Destabilizing | 1.64 | Ambiguous | 0.78 | Ambiguous | 0.867 | Likely Pathogenic | -6.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.46 | Pathogenic | 0.02 | Affected | 3.37 | 35 | 0.2177 | 0.4784 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||||||
| c.1484A>T | E495V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495V is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as benign. Taken together, the preponderance of evidence (10 pathogenic‑predicted tools versus 4 benign) indicates that E495V is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -12.031 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.43 | Likely Benign | 0.2 | -0.32 | Likely Benign | 0.06 | Likely Benign | 0.47 | Likely Benign | 0.887 | Likely Pathogenic | -6.83 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.44 | Pathogenic | 0.00 | Affected | 0.0646 | 0.5457 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1485A>C | E495D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E495D is listed in ClinVar with an uncertain significance (ClinVar ID 2000233.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions from SIFT and ESM1b, and pathogenic predictions from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN classifies the variant as likely pathogenic. AlphaMissense‑Optimized also predicts pathogenicity, whereas Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of deleterious impact. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | Conflicting | 2 | -3.574 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 1.39 | Ambiguous | 0.1 | 1.03 | Ambiguous | 1.21 | Ambiguous | 0.98 | Ambiguous | 0.566 | Likely Pathogenic | -2.52 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | -1.41 | Pathogenic | 0.17 | Tolerated | 3.37 | 35 | 0.1778 | 0.3064 | 3 | 2 | 0.0 | -14.03 | 220.6 | 38.8 | 0.0 | 0.0 | 0.1 | 0.1 | X | X | Uncertain | Glu495 is located in the α-helix (res. Leu489-Glu519), and its carboxylate group forms salt bridges with the neighboring Lys492 and with Arg596 on an opposing α-helix (res. Glu582-Met603) in the WT simulations. In the variant simulations, the acidic carboxylate side chain of Asp495 can also form salt bridges with both Lys492 and Arg596. However, the shorter side chain of aspartate tends to favor forming a salt bridge with the nearby Arg499 on the same α-helix instead. Asp495 might not maintain the salt bridge with Arg596 on the opposing α-helix as efficiently as Glu495 in the WT, potentially weakening the tertiary structure. Regardless, the potential negative effect is likely to be minor, with no deleterious effects observed on the protein structure during the simulations. However, due to its location at the GAP-Ras interface, the effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||||||
| c.1485A>T | E495D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495D is not reported in ClinVar (status: None) and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from SIFT and ESM1b, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta provides no definitive stability change. Overall, the variant is most likely pathogenic based on the consensus of predictive algorithms, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -3.574 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 1.39 | Ambiguous | 0.1 | 1.03 | Ambiguous | 1.21 | Ambiguous | 0.98 | Ambiguous | 0.566 | Likely Pathogenic | -2.52 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | -1.41 | Pathogenic | 0.17 | Tolerated | 3.37 | 35 | 0.1778 | 0.3064 | 3 | 2 | 0.0 | -14.03 | 220.6 | 38.8 | 0.0 | 0.0 | 0.1 | 0.1 | X | X | Uncertain | Glu495 is located in the α-helix (res. Leu489-Glu519), and its carboxylate group forms salt bridges with the neighboring Lys492 and with Arg596 on an opposing α-helix (res. Glu582-Met603) in the WT simulations. In the variant simulations, the acidic carboxylate side chain of Asp495 can also form salt bridges with both Lys492 and Arg596. However, the shorter side chain of aspartate tends to favor forming a salt bridge with the nearby Arg499 on the same α-helix instead. Asp495 might not maintain the salt bridge with Arg596 on the opposing α-helix as efficiently as Glu495 in the WT, potentially weakening the tertiary structure. Regardless, the potential negative effect is likely to be minor, with no deleterious effects observed on the protein structure during the simulations. However, due to its location at the GAP-Ras interface, the effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||||||||
| c.1486G>A | E496K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E496K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FoldX, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. Uncertain predictions come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Overall, the evidence strongly favors a pathogenic classification for E496K, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | -15.795 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.38 | Likely Benign | 0.1 | 1.77 | Ambiguous | 1.08 | Ambiguous | 0.76 | Ambiguous | 0.743 | Likely Pathogenic | -3.58 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.40 | Pathogenic | 0.04 | Affected | 0.1810 | 0.3528 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1486G>C | E496Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E496Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). In silico predictors that classify the variant as benign include FoldX, Foldetta, premPS, SIFT, and AlphaMissense‑Optimized, whereas those that predict pathogenicity are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; Rosetta is inconclusive. High‑accuracy tools give a mixed picture: AlphaMissense‑Optimized indicates a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign impact. Overall, the majority of predictions (8 pathogenic vs. 5 benign) and the consensus of high‑accuracy methods lean toward a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment is not contradicted by the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | -11.868 | Likely Pathogenic | 0.651 | Likely Pathogenic | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.61 | Ambiguous | 0.37 | Likely Benign | 0.50 | Likely Benign | 0.586 | Likely Pathogenic | -2.68 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.36 | Pathogenic | 0.15 | Tolerated | 0.0884 | 0.3262 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1487A>C | E496A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E496A missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include Rosetta, Foldetta, premPS, SIFT, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. FoldX is uncertain and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. Overall, the majority of predictions (8 pathogenic vs. 5 benign) indicate a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | -11.159 | Likely Pathogenic | 0.598 | Likely Pathogenic | Likely Benign | 0.68 | Ambiguous | 0.0 | 0.23 | Likely Benign | 0.46 | Likely Benign | 0.47 | Likely Benign | 0.681 | Likely Pathogenic | -4.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.41 | Pathogenic | 0.09 | Tolerated | 0.2806 | 0.3548 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1487A>G | E496G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E496G missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: no tool predicts a benign outcome, while eight tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus remains likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the preponderance of evidence points to a pathogenic effect, contradicting the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | Uncertain | 1 | -13.529 | Likely Pathogenic | 0.850 | Likely Pathogenic | Ambiguous | 1.83 | Ambiguous | 0.1 | 1.76 | Ambiguous | 1.80 | Ambiguous | 0.92 | Ambiguous | 0.825 | Likely Pathogenic | -6.16 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.45 | Pathogenic | 0.02 | Affected | 3.37 | 35 | 0.2435 | 0.3473 | 0 | -2 | 3.1 | -72.06 | 173.9 | 103.1 | 0.0 | 0.0 | -0.7 | 0.0 | X | X | Potentially Pathogenic | Glu496 is located in the α-helix (res. Leu489-Glu519), and its carboxylate group forms salt bridges with the neighbouring residues Lys492 and Arg499 in the WT simulations. Glu496 also forms a hydrogen bond with Ser449 on an opposing helix (res. Val441-Ser457). In the variant simulations, Gly496 cannot form these salt bridges, which could weaken the secondary structure. Additionally, the loss of the hydrogen bond with Ser449 on the opposite helix can weaken the tertiary structure assembly. Moreover, glycine is an α-helix breaker, and it is seen to weaken the integrity of the helix as the hydrogen bonding between the backbone atoms of Gly496 and Ala493 breaks down. Also, due to its location at the GAP-Ras interface, the interaction of Glu496 with Arg499 and Lys492 might play a role in complex association and stability, which cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||||||
| c.1487A>T | E496V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E496V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Foldetta, and premPS, while pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments give mixed results: AlphaMissense‑Optimized is Uncertain; SGM‑Consensus remains Likely Pathogenic; Foldetta, a folding‑stability predictor that integrates FoldX‑MD and Rosetta outputs, classifies the variant as Benign. Because the variant is not present in ClinVar, there is no clinical annotation to contradict the computational evidence. Overall, the preponderance of pathogenic predictions, including the consensus score, suggests that E496V is most likely pathogenic, though the conflicting high‑accuracy folding stability result indicates uncertainty that warrants further functional validation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | -14.290 | Likely Pathogenic | 0.873 | Likely Pathogenic | Ambiguous | 0.17 | Likely Benign | 0.1 | -0.67 | Ambiguous | -0.25 | Likely Benign | 0.26 | Likely Benign | 0.823 | Likely Pathogenic | -6.16 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.43 | Pathogenic | 0.02 | Affected | 0.0556 | 0.3746 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1488G>C | E496D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E496D 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 FoldX, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain predictions come from Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a unanimous majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect. 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 | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | -10.552 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.43 | Likely Benign | 0.2 | 1.78 | Ambiguous | 1.11 | Ambiguous | 1.18 | Destabilizing | 0.583 | Likely Pathogenic | -2.78 | Deleterious | 0.996 | Probably Damaging | 0.989 | Probably Damaging | -1.45 | Pathogenic | 0.04 | Affected | 3.37 | 35 | 0.1576 | 0.1912 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||
| c.1488G>T | E496D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E496D is reported in gnomAD (ID 6‑33438520‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions are provided only by FoldX, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—classify the change as pathogenic. Uncertain results come from Rosetta, Foldetta, and AlphaMissense‑Optimized and are treated as unavailable. 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 preponderance of evidence points to a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | 6-33438520-G-T | 2 | 1.24e-6 | -10.552 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.43 | Likely Benign | 0.2 | 1.78 | Ambiguous | 1.11 | Ambiguous | 1.18 | Destabilizing | 0.583 | Likely Pathogenic | -2.78 | Deleterious | 0.996 | Probably Damaging | 0.989 | Probably Damaging | -1.45 | Pathogenic | 0.04 | Affected | 3.37 | 35 | 0.1576 | 0.1912 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||
| c.1489T>A | Y497N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497N 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, predicts pathogenic. Based on these concordant predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -11.884 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 3.64 | Destabilizing | 0.1 | 3.97 | Destabilizing | 3.81 | Destabilizing | 2.49 | Destabilizing | 0.870 | Likely Pathogenic | -8.85 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.66 | Pathogenic | 0.01 | Affected | 0.2114 | 0.0612 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1489T>C | Y497H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497H is not reported in ClinVar (ClinVar status: 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 | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -10.970 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 2.46 | Destabilizing | 0.1 | 2.40 | Destabilizing | 2.43 | Destabilizing | 1.29 | Destabilizing | 0.819 | Likely Pathogenic | -4.94 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.65 | Pathogenic | 0.02 | Affected | 0.1983 | 0.0612 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.1489T>G | Y497D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497D 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 collective computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -12.128 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 4.70 | Destabilizing | 0.2 | 4.29 | Destabilizing | 4.50 | Destabilizing | 2.36 | Destabilizing | 0.918 | Likely Pathogenic | -9.81 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.67 | Pathogenic | 0.01 | Affected | 0.3621 | 0.0612 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.148A>C | I50L 2D AIThe SynGAP1 missense variant I50L 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, also reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is benign; Foldetta results are not available. Overall, the consensus of the available predictions 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 | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -3.509 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.73 | Neutral | 0.010 | Benign | 0.004 | Benign | 3.91 | Benign | 0.00 | Affected | 0.0749 | 0.3247 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.148A>G | I50V 2D AIThe SynGAP1 missense variant I50V 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 methods also support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that I50V 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 | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -1.051 | Likely Benign | 0.141 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.24 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.18 | Benign | 0.00 | Affected | 0.1091 | 0.3159 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.148A>T | I50F 2D AIThe SynGAP1 missense variant I50F 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are 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 for I50F, 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 | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -5.631 | Likely Benign | 0.681 | Likely Pathogenic | Likely Benign | 0.100 | Likely Benign | -1.27 | Neutral | 0.334 | Benign | 0.074 | Benign | 3.75 | Benign | 0.00 | Affected | 0.0483 | 0.2560 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.1490A>C | Y497S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497S 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, and AlphaMissense‑Optimized) classifies the change as pathogenic, leaving no benign predictions. High‑accuracy methods reinforce this assessment: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, indicates a destabilizing, pathogenic effect. No prediction or stability result is missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar annotation, the variant is most likely pathogenic, with no contradictory ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -13.171 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 3.65 | Destabilizing | 0.1 | 4.68 | Destabilizing | 4.17 | Destabilizing | 2.22 | Destabilizing | 0.814 | Likely Pathogenic | -8.82 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.64 | Pathogenic | 0.03 | Affected | 0.3770 | 0.1419 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.1490A>G | Y497C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497C is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all return a deleterious signal: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenic. No tool reports a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM Consensus as “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) as “Pathogenic.” Overall, the variant is most likely pathogenic based on the consensus of predictive algorithms, which contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | Uncertain | 1 | -11.872 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 3.88 | Destabilizing | 0.1 | 4.76 | Destabilizing | 4.32 | Destabilizing | 1.40 | Destabilizing | 0.806 | Likely Pathogenic | -8.82 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.65 | Pathogenic | 0.03 | Affected | 3.37 | 35 | 0.2905 | 0.1488 | 0 | -2 | 3.8 | -60.04 | 209.9 | 59.1 | -0.1 | 0.0 | -0.3 | 0.1 | X | X | Potentially Pathogenic | Tyr497 is located in the α-helix (res. Leu489-Glu519) within the inter-helix space of four α-helices (res. Leu489-Ile501, res. Val441-Ser457, res. Arg563-Glu578, res. Ala461-Val473). In the WT simulations, the phenol ring of Tyr497 hydrophobically packs with other residues in the inter-helix space (e.g., Leu465, Leu565, Val568). The hydroxyl group of Tyr497 also alternately forms hydrogen bonds with the carboxylate side chain of Gln456 and the backbone carbonyl of Glu564. Thus, Tyr497 plays a role in the folding and maintenance of the tertiary structure assembly between these four helices.In the variant simulations, the comparatively smaller residue, Cys497, cannot maintain any of the interactions seen with Tyr497 in the WT. Although no severe deleterious consequences are observed in the simulations, the structural effects could be more pronounced during actual protein folding. Indeed, the tertiary structure is seen to slightly break apart in the variant simulations. | |||||||||||||||
| c.1490A>T | Y497F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497F 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 FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, ESM1b, and FATHMM; premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions lean toward a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. Thus, the variant is most likely benign based on the current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -8.566 | Likely Pathogenic | 0.199 | Likely Benign | Likely Benign | -0.27 | Likely Benign | 0.1 | 0.47 | Likely Benign | 0.10 | Likely Benign | 0.61 | Ambiguous | 0.578 | Likely Pathogenic | -3.75 | Deleterious | 0.367 | Benign | 0.131 | Benign | -1.15 | Pathogenic | 0.19 | Tolerated | 0.2074 | 0.2242 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||
| c.1492A>C | M498L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, 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, Foldetta, and premPS are inconclusive. 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. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | 2.556 | Likely Benign | 0.072 | Likely Benign | Likely Benign | -0.23 | Likely Benign | 0.1 | -0.89 | Ambiguous | -0.56 | Ambiguous | -0.53 | Ambiguous | 0.271 | Likely Benign | 0.62 | Neutral | 0.000 | Benign | 0.000 | Benign | -1.24 | Pathogenic | 0.92 | Tolerated | 0.1319 | 0.3551 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1492A>G | M498V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M498V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign (REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (FoldX, Foldetta, premPS, polyPhen‑2 HumDiv, SIFT, FATHMM). Rosetta is uncertain. 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, while Foldetta predicts a pathogenic effect on protein stability. Overall, the majority of predictions lean toward a benign impact, 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 | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -3.229 | Likely Benign | 0.317 | Likely Benign | Likely Benign | 2.74 | Destabilizing | 0.1 | 1.26 | Ambiguous | 2.00 | Destabilizing | 1.17 | Destabilizing | 0.483 | Likely Benign | -1.82 | Neutral | 0.752 | Possibly Damaging | 0.279 | Benign | -1.28 | Pathogenic | 0.04 | Affected | 0.2737 | 0.2737 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||
| c.1492A>T | M498L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, 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 Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. 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 | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | 2.556 | Likely Benign | 0.072 | Likely Benign | Likely Benign | -0.23 | Likely Benign | 0.1 | -0.89 | Ambiguous | -0.56 | Ambiguous | -0.53 | Ambiguous | 0.271 | Likely Benign | 0.62 | Neutral | 0.000 | Benign | 0.000 | Benign | -1.24 | Pathogenic | 0.92 | Tolerated | 0.1319 | 0.3551 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1493T>A | M498K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498K is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign calls come only from polyPhen‑2 HumDiv and HumVar, whereas the remaining 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict pathogenicity. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a destabilizing, pathogenic effect. Taken together, the overwhelming majority of evidence indicates that M498K 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 | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -11.622 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 2.82 | Destabilizing | 0.1 | 2.86 | Destabilizing | 2.84 | Destabilizing | 1.79 | Destabilizing | 0.867 | Likely Pathogenic | -4.53 | Deleterious | 0.287 | Benign | 0.120 | Benign | -1.37 | Pathogenic | 0.00 | Affected | 0.1281 | 0.0656 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.1493T>C | M498T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: all but one (polyPhen‑2 HumVar) predict pathogenicity, while polyPhen‑2 HumVar alone predicts benign. Uncertain predictions (ESM1b and AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy methods reinforce the pathogenic view: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. AlphaMissense‑Optimized remains inconclusive. Overall, the preponderance of evidence indicates that M498T is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -7.477 | In-Between | 0.869 | Likely Pathogenic | Ambiguous | 2.46 | Destabilizing | 0.1 | 2.62 | Destabilizing | 2.54 | Destabilizing | 1.41 | Destabilizing | 0.672 | Likely Pathogenic | -3.80 | Deleterious | 0.803 | Possibly Damaging | 0.343 | Benign | -1.19 | Pathogenic | 0.02 | Affected | 0.1925 | 0.1630 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||
| c.1493T>G | M498R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498R is listed in ClinVar as Pathogenic (ClinVar ID 3907767.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only polyPhen‑2 HumVar; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, 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, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions or stability results are missing or inconclusive. Based on the overwhelming consensus of pathogenic 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 | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | Likely Pathogenic | 1 | -8.812 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 3.85 | Destabilizing | 0.2 | 2.35 | Destabilizing | 3.10 | Destabilizing | 1.76 | Destabilizing | 0.869 | Likely Pathogenic | -4.53 | Deleterious | 0.464 | Possibly Damaging | 0.120 | Benign | -1.36 | Pathogenic | 0.00 | Affected | 0.1482 | 0.0757 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||
| c.1494G>A | M498I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498I has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, SIFT, FATHMM, and AlphaMissense‑Default. Two tools, Rosetta and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by ClinVar status, which lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -4.796 | Likely Benign | 0.760 | Likely Pathogenic | Likely Benign | 2.56 | Destabilizing | 0.3 | 1.65 | Ambiguous | 2.11 | Destabilizing | 0.88 | Ambiguous | 0.418 | Likely Benign | -1.09 | Neutral | 0.018 | Benign | 0.012 | Benign | -1.28 | Pathogenic | 0.04 | Affected | 0.1184 | 0.2537 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1494G>C | M498I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498I has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, SIFT, FATHMM, and AlphaMissense‑Default. Two tools, Rosetta and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by ClinVar status, which lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -4.796 | Likely Benign | 0.760 | Likely Pathogenic | Likely Benign | 2.56 | Destabilizing | 0.3 | 1.65 | Ambiguous | 2.11 | Destabilizing | 0.88 | Ambiguous | 0.418 | Likely Benign | -1.09 | Neutral | 0.018 | Benign | 0.012 | Benign | -1.28 | Pathogenic | 0.04 | Affected | 0.1184 | 0.2537 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1494G>T | M498I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498I has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, SIFT, FATHMM, and AlphaMissense‑Default. Two tools, Rosetta and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by ClinVar status, which lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -4.796 | Likely Benign | 0.760 | Likely Pathogenic | Likely Benign | 2.56 | Destabilizing | 0.3 | 1.65 | Ambiguous | 2.11 | Destabilizing | 0.88 | Ambiguous | 0.414 | Likely Benign | -1.09 | Neutral | 0.018 | Benign | 0.012 | Benign | -1.28 | Pathogenic | 0.04 | Affected | 0.1184 | 0.2537 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1495A>G | R499G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499G is listed in gnomAD (variant ID 6‑33438527‑A‑G) but has no ClinVar entry. Prediction tools that assess the variant’s effect on protein function overwhelmingly indicate a deleterious outcome: REVEL, FoldX‑MD (Rosetta component), Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify it as pathogenic. Only FoldX (overall) and AlphaMissense‑Optimized report uncertain results, which are treated as unavailable evidence. No tool predicts a benign effect. High‑accuracy assessments specifically show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as pathogenic. Taken together, the preponderance of evidence supports a pathogenic classification for R499G, and this conclusion is not contradicted by any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | 6-33438527-A-G | 3 | 1.86e-6 | -9.960 | Likely Pathogenic | 0.789 | Likely Pathogenic | Ambiguous | 1.55 | Ambiguous | 0.1 | 2.75 | Destabilizing | 2.15 | Destabilizing | 1.41 | Destabilizing | 0.681 | Likely Pathogenic | -4.50 | Deleterious | 0.958 | Probably Damaging | 0.769 | Possibly Damaging | -1.47 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2888 | 0.1798 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||
| c.1496G>A | R499K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499K 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 and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive, providing no evidence for either direction. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign prediction; Foldetta remains uncertain. Overall, the preponderance of evidence points to a benign effect for R499K, and this conclusion is consistent with the absence of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | 4.366 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 1.37 | Ambiguous | 0.1 | 0.53 | Ambiguous | 0.95 | Ambiguous | -0.77 | Ambiguous | 0.248 | Likely Benign | 1.94 | Neutral | 0.001 | Benign | 0.008 | Benign | -1.03 | Pathogenic | 1.00 | Tolerated | 0.3531 | 0.1881 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||||
| c.1496G>C | R499T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and ESM1b, whereas a majority of tools (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic, AlphaMissense‑Optimized is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No evidence from ClinVar contradicts these predictions. Overall, the preponderance of computational evidence points to a pathogenic effect for R499T. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | -6.797 | Likely Benign | 0.855 | Likely Pathogenic | Ambiguous | 2.47 | Destabilizing | 0.1 | 1.43 | Ambiguous | 1.95 | Ambiguous | 0.73 | Ambiguous | 0.664 | Likely Pathogenic | -3.51 | Deleterious | 0.843 | Possibly Damaging | 0.403 | Benign | -1.44 | Pathogenic | 0.02 | Affected | 0.1732 | 0.2074 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||
| c.1496G>T | R499I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the change as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely pathogenic. No tool predicts a benign outcome; the remaining predictions (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are uncertain or inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the overwhelming majority of evidence supports a pathogenic effect, and this is consistent with the absence of a ClinVar entry; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | -9.069 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 1.53 | Ambiguous | 0.1 | 0.61 | Ambiguous | 1.07 | Ambiguous | 0.57 | Ambiguous | 0.713 | Likely Pathogenic | -5.50 | Deleterious | 0.998 | Probably Damaging | 0.922 | Probably Damaging | -1.47 | Pathogenic | 0.00 | Affected | 0.1401 | 0.2146 | -2 | -3 | 9.0 | -43.03 | |||||||||||||||||||||||||||||
| c.1497A>C | R499S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499S is catalogued in gnomAD (ID 6‑33438529‑A‑C) but has no ClinVar entry. Functional prediction tools largely converge on a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate pathogenicity. No tool reports a benign outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized and Foldetta are uncertain, whereas the SGM‑Consensus remains likely pathogenic. Protein‑stability predictions are inconclusive (FoldX uncertain, Rosetta pathogenic, Foldetta uncertain). Taken together, the overwhelming majority of evidence supports a pathogenic classification for R499S. This conclusion is consistent with the absence of a ClinVar status, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | 6-33438529-A-C | 1 | 6.20e-7 | -9.559 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.03 | Ambiguous | 0.0 | 2.19 | Destabilizing | 1.61 | Ambiguous | 1.40 | Destabilizing | 0.632 | Likely Pathogenic | -2.69 | Deleterious | 0.958 | Probably Damaging | 0.702 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2443 | 0.1649 | -1 | 0 | 3.7 | -69.11 | ||||||||||||||||||||||||
| c.1497A>T | R499S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499S is not reported in ClinVar and has no entry in gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Rosetta all predict pathogenicity, while FoldX, AlphaMissense‑Optimized, and Foldetta are uncertain. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic, and Foldetta likewise yields an uncertain result. Taken together, the overwhelming majority of reliable tools predict a pathogenic effect, and there is no ClinVar annotation to contradict this assessment. Therefore, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | -9.559 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.03 | Ambiguous | 0.0 | 2.19 | Destabilizing | 1.61 | Ambiguous | 1.40 | Destabilizing | 0.632 | Likely Pathogenic | -2.69 | Deleterious | 0.958 | Probably Damaging | 0.702 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2443 | 0.1649 | -1 | 0 | 3.7 | -69.11 | |||||||||||||||||||||||||||
| c.1498C>A | L500M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500M is 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The premPS score is uncertain. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; Foldetta predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it yields a 2‑to‑2 split. No other high‑accuracy predictions are available. Overall, the majority of high‑accuracy tools lean toward a benign interpretation, and this assessment does not contradict the lack of ClinVar reporting. 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. | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | -9.945 | Likely Pathogenic | 0.301 | Likely Benign | Likely Benign | 0.15 | Likely Benign | 0.0 | -0.09 | Likely Benign | 0.03 | Likely Benign | 0.92 | Ambiguous | 0.590 | Likely Pathogenic | -1.99 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 0.0710 | 0.2202 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1498C>G | L500V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L500V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on benign effect include SIFT and AlphaMissense‑Optimized, whereas a majority of tools predict pathogenicity: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, 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, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | -12.963 | Likely Pathogenic | 0.379 | Ambiguous | Likely Benign | 1.92 | Ambiguous | 0.0 | 0.81 | Ambiguous | 1.37 | Ambiguous | 1.11 | Destabilizing | 0.565 | Likely Pathogenic | -2.98 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.24 | Pathogenic | 0.11 | Tolerated | 0.1205 | 0.1860 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1499T>A | L500Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500Q has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated predictors—SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently classify the variant as pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are treated as unavailable. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized (benign) stands alone, whereas the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic. Foldetta remains uncertain. Overall, the preponderance of evidence from multiple independent pathogenic predictors indicates that the variant is most likely pathogenic, and 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 | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | -13.431 | Likely Pathogenic | 0.649 | Likely Pathogenic | Likely Benign | 1.92 | Ambiguous | 0.1 | 1.78 | Ambiguous | 1.85 | Ambiguous | 1.49 | Destabilizing | 0.878 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.35 | Pathogenic | 0.00 | Affected | 0.0950 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1499T>C | L500P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500P is listed in ClinVar (ID 2708686.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors 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 confirm 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) 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 | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | Pathogenic | 1 | -15.898 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 5.91 | Destabilizing | 0.3 | 8.90 | Destabilizing | 7.41 | Destabilizing | 1.92 | Destabilizing | 0.894 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.37 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.3103 | 0.0625 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1499T>G | L500R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as pathogenic include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a benign effect; the benign group is empty. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overwhelming agreement among pathogenic predictors and the lack of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | -15.576 | Likely Pathogenic | 0.789 | Likely Pathogenic | Ambiguous | 2.23 | Destabilizing | 0.1 | 1.04 | Ambiguous | 1.64 | Ambiguous | 1.11 | Destabilizing | 0.794 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.02 | Pathogenic | 0.03 | Affected | 0.1204 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.149T>A | I50N 2D AIThe SynGAP1 missense variant I50N is 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 HumVar, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as benign. Foldetta results are unavailable. Overall, the predictions are mixed, with an equal split between benign and pathogenic calls, but the most reliable single‑tool prediction (AlphaMissense‑Optimized) and the majority of individual tools lean toward pathogenicity. Thus, the variant is most likely pathogenic based on current computational evidence, 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. | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -7.091 | In-Between | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.135 | Likely Benign | -2.37 | Neutral | 0.842 | Possibly Damaging | 0.272 | Benign | 3.73 | Benign | 0.00 | Affected | 0.0824 | 0.0412 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.149T>C | I50T 2D AIThe SynGAP1 missense variant I50T is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools largely agree that the change is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM all classify it as benign. In contrast, SIFT and AlphaMissense‑Default predict a pathogenic effect. AlphaMissense‑Optimized returns an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments therefore point to a benign outcome: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus is benign, and Foldetta data are missing. Based on the collective evidence, 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 | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -5.121 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.128 | Likely Benign | -1.61 | Neutral | 0.092 | Benign | 0.037 | Benign | 3.76 | Benign | 0.00 | Affected | 0.0950 | 0.0708 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||||||
| c.149T>G | I50S 2D AIThe SynGAP1 I50S missense variant 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, and FATHMM all classify it as benign. In contrast, SIFT and AlphaMissense‑Default predict a pathogenic impact. AlphaMissense‑Optimized yields an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this residue. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments therefore point to a benign outcome: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus is likely benign, and Foldetta data are missing. 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 | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -4.257 | Likely Benign | 0.946 | Likely Pathogenic | Ambiguous | 0.209 | Likely Benign | -2.03 | Neutral | 0.334 | Benign | 0.099 | Benign | 3.74 | Benign | 0.00 | Affected | 0.2626 | 0.0800 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.14G>A | R5Q 2D AIThe SynGAP1 missense variant R5Q is reported in gnomAD (variant ID 6‑33420278‑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 a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign impact. This prediction 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 | 0.595080 | Disordered | 0.547847 | Binding | 0.363 | 0.920 | 0.750 | 6-33420278-G-A | 2 | 1.30e-6 | -4.261 | Likely Benign | 0.223 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.06 | Neutral | 0.403 | Benign | 0.007 | Benign | 4.15 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3740 | 0.3122 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||||
| c.14G>C | R5P 2D AIThe SynGAP1 missense variant R5P 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 (majority vote) is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that R5P 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 | 0.595080 | Disordered | 0.547847 | Binding | 0.363 | 0.920 | 0.750 | -3.438 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.286 | Likely Benign | -0.35 | Neutral | 0.233 | Benign | 0.013 | Benign | 4.10 | Benign | 0.00 | Affected | 0.2294 | 0.5530 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.14G>T | R5L 2D AIThe SynGAP1 missense variant R5L 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 further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Based on the preponderance of evidence, 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 | 0.595080 | Disordered | 0.547847 | Binding | 0.363 | 0.920 | 0.750 | -3.297 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.158 | Likely Benign | -0.06 | Neutral | 0.030 | Benign | 0.003 | Benign | 4.14 | Benign | 0.00 | Affected | 0.2256 | 0.5914 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.1501A>C | I501L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, Rosetta, Foldetta, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. Uncertain or inconclusive results are reported for FoldX, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign, all supporting a non‑deleterious effect. Based on the preponderance of benign predictions and the concordant high‑accuracy tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -7.348 | In-Between | 0.282 | Likely Benign | Likely Benign | 0.78 | Ambiguous | 0.2 | -0.34 | Likely Benign | 0.22 | Likely Benign | 0.86 | Ambiguous | 0.219 | Likely Benign | -1.92 | Neutral | 0.930 | Possibly Damaging | 0.985 | Probably Damaging | 3.51 | Benign | 0.05 | Affected | 0.0817 | 0.2261 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.1501A>G | I501V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions from FoldX, Rosetta, and Foldetta are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for I501V, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -2.326 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.94 | Ambiguous | 0.0 | 0.56 | Ambiguous | 0.75 | Ambiguous | 0.06 | Likely Benign | 0.200 | Likely Benign | 0.20 | Neutral | 0.951 | Possibly Damaging | 0.960 | Probably Damaging | 3.52 | Benign | 1.00 | Tolerated | 0.0985 | 0.2491 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.1501A>T | I501F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I501F missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain (a stability method that integrates FoldX‑MD and Rosetta outputs). No predictions are missing or inconclusive. Overall, the majority of evidence points 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. | Likely Pathogenic | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -12.113 | Likely Pathogenic | 0.664 | Likely Pathogenic | Likely Benign | 3.06 | Destabilizing | 0.1 | 0.26 | Likely Benign | 1.66 | Ambiguous | 0.71 | Ambiguous | 0.385 | Likely Benign | -3.88 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 3.40 | Benign | 0.03 | Affected | 0.0574 | 0.1594 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1502T>A | I501N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, while a majority of tools (SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Uncertain results come from AlphaMissense‑Optimized, Foldetta, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, whereas the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta likewise remains inconclusive. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -11.105 | Likely Pathogenic | 0.854 | Likely Pathogenic | Ambiguous | 2.22 | Destabilizing | 0.0 | 1.70 | Ambiguous | 1.96 | Ambiguous | 1.90 | Destabilizing | 0.445 | Likely Benign | -6.13 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.37 | Benign | 0.01 | Affected | 0.0825 | 0.0270 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1502T>C | I501T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501T 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and premPS, while Rosetta remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | Uncertain | 1 | -5.996 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 2.40 | Destabilizing | 0.1 | 1.81 | Ambiguous | 2.11 | Destabilizing | 1.57 | Destabilizing | 0.362 | Likely Benign | -3.48 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.44 | Benign | 0.16 | Tolerated | 3.37 | 35 | 0.0972 | 0.0640 | 0 | -1 | -5.2 | -12.05 | 214.5 | 26.9 | 0.0 | 0.0 | 0.5 | 0.0 | X | Potentially Pathogenic | Ile501 is located near a hinge in the middle of an α-helix (res. Leu489-Glu519). The sec-butyl side chain of Ile501 is hydrophobically packed with other residues in the inter-helix space (e.g., Leu500, Tyr497, Phe679) in the WT simulations. In the variant simulations, the hydroxyl group of Thr501 forms a hydrogen bond with the backbone atoms of Tyr497 on the same α-helix, which may weaken the α-helix integrity. Additionally, the polar hydroxyl group of Thr501 is not suitable for the hydrophobic inter-helix space, and thus, the residue swap could affect protein folding. However, Ile501 is followed by Gly502, which facilitates a hinge in the middle of the α-helix, making further weakening caused by Thr501 unlikely to be harmful to the α-helix integrity. | ||||||||||||||||
| c.1502T>G | I501S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized; all other evaluated algorithms (SGM‑Consensus, 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 this: AlphaMissense‑Optimized indicates a benign change, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. Overall, the preponderance of evidence points to a pathogenic effect for I501S. 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 | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -9.914 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 3.23 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.82 | Destabilizing | 1.79 | Destabilizing | 0.511 | Likely Pathogenic | -5.14 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.04 | Affected | 0.2370 | 0.0858 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1503T>G | I501M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Predictions that are inconclusive or unavailable are FoldX, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Taken together, the majority of evidence points to a benign impact for I501M. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -7.452 | In-Between | 0.259 | Likely Benign | Likely Benign | 1.32 | Ambiguous | 0.2 | -0.19 | Likely Benign | 0.57 | Ambiguous | 0.95 | Ambiguous | 0.294 | Likely Benign | -2.32 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.36 | Benign | 0.01 | Affected | 0.0680 | 0.1589 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.1504G>A | G502S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502S is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated predictors—SGM Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently classify the variant as pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts a benign outcome, whereas the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of evidence points to a pathogenic 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 Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -11.357 | Likely Pathogenic | 0.616 | Likely Pathogenic | Likely Benign | 2.09 | Destabilizing | 0.6 | 0.71 | Ambiguous | 1.40 | Ambiguous | 0.96 | Ambiguous | 0.839 | Likely Pathogenic | -5.74 | Deleterious | 0.975 | Probably Damaging | 0.862 | Possibly Damaging | -1.64 | Pathogenic | 0.01 | Affected | 0.2429 | 0.3217 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.1504G>C | G502R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502R 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the only inconclusive result is from premPS, which is listed as uncertain. High‑accuracy methods reinforce this view: 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, predicts a destabilizing, pathogenic effect. Based on the collective evidence, 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 | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -15.571 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 8.80 | Destabilizing | 0.3 | 10.07 | Destabilizing | 9.44 | Destabilizing | 0.88 | Ambiguous | 0.917 | Likely Pathogenic | -7.73 | Deleterious | 1.000 | Probably Damaging | 0.985 | Probably Damaging | -1.65 | Pathogenic | 0.00 | Affected | 0.1014 | 0.3317 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1504G>T | G502C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502C lies in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include only premPS. The majority of tools predict a pathogenic effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. Tools with uncertain or inconclusive outputs are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a unanimous majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. Overall, the preponderance of evidence points to a pathogenic impact for G502C, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -12.086 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 1.02 | Ambiguous | 0.5 | 1.55 | Ambiguous | 1.29 | Ambiguous | 0.30 | Likely Benign | 0.845 | Likely Pathogenic | -8.65 | Deleterious | 1.000 | Probably Damaging | 0.988 | Probably Damaging | -1.67 | Pathogenic | 0.00 | Affected | 0.1279 | 0.2691 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.1505G>A | G502D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502D 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 report a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments 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. Based on the uniform predictions, 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 | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | Uncertain | 1 | -14.796 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.79 | Destabilizing | 0.9 | 5.69 | Destabilizing | 4.74 | Destabilizing | 1.38 | Destabilizing | 0.915 | Likely Pathogenic | -6.80 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | -1.66 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.1715 | 0.1172 | 1 | -1 | -3.1 | 58.04 | 224.2 | -80.0 | -0.8 | 0.7 | 0.6 | 0.3 | X | X | X | Potentially Pathogenic | Gly502 is located in a hinge in the middle of an α-helix (res. Leu489-Glu519). In the WT, Gly502 acts as an α-helix breaker due to its lack of a side chain, facilitating a bend in the middle of the α-helix. In the variant simulations, the carboxylate group of Asp502 forms hydrogen bonds with neighboring residues (e.g., Ser677, Lys504), disrupting the hinge. Additionally, Asp502 struggles to fit into the α-helix hinge and cannot generate a similar bend as Gly502, which would drastically affect the secondary structure during folding. Thus, the deleterious effect seen in the simulations is likely an underestimate of the impact of the residue swap on the protein structure during protein folding. | ||||||||||||||
| c.1505G>C | G502A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G502A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Foldetta, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and premPS. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized indicates a benign effect, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—concludes pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign outcome. Overall, the majority of evidence points to a pathogenic impact for G502A, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -10.191 | Likely Pathogenic | 0.607 | Likely Pathogenic | Likely Benign | 0.82 | Ambiguous | 0.4 | -0.53 | Ambiguous | 0.15 | Likely Benign | 0.54 | Ambiguous | 0.725 | Likely Pathogenic | -5.64 | Deleterious | 0.512 | Possibly Damaging | 0.157 | Benign | -1.59 | Pathogenic | 0.17 | Tolerated | 0.3548 | 0.3393 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1505G>T | G502V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: all evaluated algorithms except premPS (which predicts benign) classify the substitution as pathogenic or likely pathogenic. The consensus of high‑accuracy predictors is consistent: 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; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a destabilizing, pathogenic outcome. In contrast, premPS is the sole tool suggesting a benign impact. Overall, the overwhelming majority of evidence points to a pathogenic effect for G502V, and this conclusion does not conflict with the absence of a ClinVar classification. Thus, the variant is most likely pathogenic, and this assessment is not contradicted by ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -15.278 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 3.56 | Destabilizing | 1.0 | 5.50 | Destabilizing | 4.53 | Destabilizing | 0.43 | Likely Benign | 0.917 | Likely Pathogenic | -8.65 | Deleterious | 0.999 | Probably Damaging | 0.944 | Probably Damaging | -1.67 | Pathogenic | 0.00 | Affected | 0.1406 | 0.3387 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1507C>A | Q503K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503K is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM, while premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools lean toward a benign effect, and this conclusion is not contradicted by ClinVar data, which contains no entry for this variant. Thus, the variant is most likely benign, with no ClinVar evidence contradicting this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -12.276 | Likely Pathogenic | 0.217 | Likely Benign | Likely Benign | -0.01 | Likely Benign | 0.1 | -0.26 | Likely Benign | -0.14 | Likely Benign | 0.70 | Ambiguous | 0.603 | Likely Pathogenic | -3.37 | Deleterious | 0.676 | Possibly Damaging | 0.297 | Benign | -1.42 | Pathogenic | 0.12 | Tolerated | 0.1601 | 0.2419 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.1507C>G | Q503E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and Rosetta. Uncertain or inconclusive results come from FoldX, Foldetta, premPS, 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. Overall, the majority of available predictions favor a benign impact, 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. | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -7.909 | In-Between | 0.146 | Likely Benign | Likely Benign | 0.51 | Ambiguous | 0.1 | 2.11 | Destabilizing | 1.31 | Ambiguous | 0.85 | Ambiguous | 0.410 | Likely Benign | -2.21 | Neutral | 0.931 | Possibly Damaging | 0.500 | Possibly Damaging | -1.43 | Pathogenic | 0.17 | Tolerated | 0.1168 | 0.1508 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.1508A>C | Q503P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; the remaining tools (FoldX, premPS, AlphaMissense‑Default) are inconclusive. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta both predict pathogenic. Because the majority of evidence points to a deleterious effect, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -10.915 | Likely Pathogenic | 0.414 | Ambiguous | Likely Benign | 1.06 | Ambiguous | 0.7 | 5.94 | Destabilizing | 3.50 | Destabilizing | 0.75 | Ambiguous | 0.860 | Likely Pathogenic | -5.20 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | -1.53 | Pathogenic | 0.03 | Affected | 0.2076 | 0.3610 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.1508A>G | Q503R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. The high‑accuracy methods give a benign result for AlphaMissense‑Optimized, a pathogenic result for the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and a benign result for Foldetta (combining FoldX‑MD and Rosetta). Overall, the majority of tools and the high‑accuracy methods lean toward a benign effect. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -11.396 | Likely Pathogenic | 0.232 | Likely Benign | Likely Benign | -0.40 | Likely Benign | 0.3 | 0.60 | Ambiguous | 0.10 | Likely Benign | 0.50 | Likely Benign | 0.640 | Likely Pathogenic | -3.34 | Deleterious | 0.577 | Possibly Damaging | 0.395 | Benign | -1.42 | Pathogenic | 0.06 | Tolerated | 0.1426 | 0.0963 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1508A>T | Q503L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503L is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, premPS, Rosetta, and polyPhen‑2 (HumVar). Those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv), SIFT, ESM1b, and FATHMM; FoldX is uncertain and therefore not counted. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of tools (seven versus six) predict pathogenicity, and the high‑accuracy trio is split but leans toward pathogenic. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -8.203 | Likely Pathogenic | 0.261 | Likely Benign | Likely Benign | -0.56 | Ambiguous | 0.2 | -0.07 | Likely Benign | -0.32 | Likely Benign | 0.24 | Likely Benign | 0.711 | Likely Pathogenic | -6.29 | Deleterious | 0.911 | Possibly Damaging | 0.369 | Benign | -1.52 | Pathogenic | 0.05 | Affected | 0.0715 | 0.3578 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||
| c.1509G>C | Q503H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503H 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, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, SIFT, and FATHMM. FoldX, Rosetta, and Foldetta report uncertain or inconclusive stability changes and are therefore considered unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus inconclusive, and Foldetta remains uncertain. Overall, the majority of evaluated predictors (7 benign vs. 3 pathogenic) lean toward 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. | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -5.335 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.94 | Ambiguous | 0.2 | 0.88 | Ambiguous | 0.91 | Ambiguous | 0.48 | Likely Benign | 0.331 | Likely Benign | -3.40 | Deleterious | 0.002 | Benign | 0.004 | Benign | -1.52 | Pathogenic | 0.01 | Affected | 0.1091 | 0.2125 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1509G>T | Q503H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503H 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, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, SIFT, and FATHMM. FoldX, Rosetta, and Foldetta report uncertain or inconclusive stability changes and are therefore considered unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus inconclusive, and Foldetta remains uncertain. Overall, the majority of evaluated predictors (7 benign vs. 3 pathogenic) lean toward 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. | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -5.335 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.94 | Ambiguous | 0.2 | 0.88 | Ambiguous | 0.91 | Ambiguous | 0.48 | Likely Benign | 0.331 | Likely Benign | -3.40 | Deleterious | 0.002 | Benign | 0.004 | Benign | -1.52 | Pathogenic | 0.01 | Affected | 0.1091 | 0.2125 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.150C>G | I50M 2D AIThe SynGAP1 missense variant I50M is not reported in ClinVar and is absent from gnomAD. 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 and SIFT, 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 outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools indicates that the I50M variant is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -5.707 | Likely Benign | 0.383 | Ambiguous | Likely Benign | 0.030 | Likely Benign | -0.95 | Neutral | 0.637 | Possibly Damaging | 0.202 | Benign | 3.76 | Benign | 0.00 | Affected | 0.0603 | 0.2524 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.1510A>C | K504Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K504Q 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, 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, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta predicts a benign stability change. Overall, seven tools support a benign outcome while four support pathogenicity, with no ClinVar evidence 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. | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -6.685 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.2 | -0.01 | Likely Benign | 0.06 | Likely Benign | 0.91 | Ambiguous | 0.269 | Likely Benign | -3.07 | Deleterious | 0.945 | Possibly Damaging | 0.918 | Probably Damaging | -1.37 | Pathogenic | 0.46 | Tolerated | 0.3104 | 0.0780 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||
| c.1510A>G | K504E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K504E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -9.890 | Likely Pathogenic | 0.587 | Likely Pathogenic | Likely Benign | 0.63 | Ambiguous | 0.4 | 0.78 | Ambiguous | 0.71 | Ambiguous | 1.06 | Destabilizing | 0.386 | Likely Benign | -3.40 | Deleterious | 0.924 | Possibly Damaging | 0.674 | Possibly Damaging | -1.25 | Pathogenic | 0.21 | Tolerated | 0.2583 | 0.0650 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1511A>C | K504T 2D 3DClick to see structure in 3D Viewer AISynGAP1 K504T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Other tools (AlphaMissense‑Default, Foldetta, premPS, Rosetta) were inconclusive and are not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of predictions support a pathogenic classification, and this is not contradicted by the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -9.572 | Likely Pathogenic | 0.494 | Ambiguous | Likely Benign | 0.12 | Likely Benign | 0.3 | -0.85 | Ambiguous | -0.37 | Likely Benign | 0.84 | Ambiguous | 0.498 | Likely Benign | -5.36 | Deleterious | 0.961 | Probably Damaging | 0.990 | Probably Damaging | -1.44 | Pathogenic | 0.10 | Tolerated | 0.1482 | 0.2619 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1511A>G | K504R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K504R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438543‑A‑G). Consensus from most in‑silico predictors is benign: REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a benign effect, while only FATHMM predicts pathogenicity. Uncertain calls come from Rosetta and premPS. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the preponderance of evidence indicates the variant is most likely benign, 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 | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | Uncertain | 1 | 6-33438543-A-G | 2 | 1.24e-6 | -4.365 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.32 | Likely Benign | 0.94 | Ambiguous | 0.238 | Likely Benign | -2.16 | Neutral | 0.002 | Benign | 0.015 | Benign | -1.41 | Pathogenic | 0.11 | Tolerated | 3.37 | 35 | 0.3363 | 0.0647 | 2 | 3 | -0.6 | 28.01 | ||||||||||||||||||||||
| c.1511A>T | K504I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K504I is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess the variant’s effect fall into two groups: benign predictions include REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized; pathogenic predictions include 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, labels the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus as pathogenic. Because the majority of tools (seven) predict pathogenicity while three high‑accuracy methods provide conflicting evidence, the overall prediction leans toward pathogenic. This assessment 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 | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -12.597 | Likely Pathogenic | 0.727 | Likely Pathogenic | Likely Benign | -0.04 | Likely Benign | 0.3 | -0.36 | Likely Benign | -0.20 | Likely Benign | 0.40 | Likely Benign | 0.491 | Likely Benign | -7.35 | Deleterious | 0.996 | Probably Damaging | 0.993 | Probably Damaging | -1.49 | Pathogenic | 0.02 | Affected | 0.0769 | 0.2713 | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||
| c.1512A>C | K504N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K504N is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools (8/13) predict pathogenicity, while 4 predict benign and one is uncertain. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -8.908 | Likely Pathogenic | 0.720 | Likely Pathogenic | Likely Benign | 0.26 | Likely Benign | 0.2 | 0.57 | Ambiguous | 0.42 | Likely Benign | 1.00 | Destabilizing | 0.430 | Likely Benign | -4.37 | Deleterious | 0.993 | Probably Damaging | 0.922 | Probably Damaging | -1.44 | Pathogenic | 0.07 | Tolerated | 0.2470 | 0.0926 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1512A>T | K504N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K504N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, AlphaMissense‑Optimized, and the folding‑stability method Foldetta. Tools that predict a pathogenic effect comprise SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling it likely pathogenic, and Foldetta indicating a benign folding‑stability outcome. Overall, the majority of predictions (8 out of 13) support a pathogenic interpretation. 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 | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -8.908 | Likely Pathogenic | 0.720 | Likely Pathogenic | Likely Benign | 0.26 | Likely Benign | 0.2 | 0.57 | Ambiguous | 0.42 | Likely Benign | 1.00 | Destabilizing | 0.430 | Likely Benign | -4.37 | Deleterious | 0.993 | Probably Damaging | 0.922 | Probably Damaging | -1.44 | Pathogenic | 0.07 | Tolerated | 0.2470 | 0.0926 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1513T>A | Y505N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505N is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools largely agree on a deleterious effect: all available predictors except FATHMM classify the variant as pathogenic or likely pathogenic. The benign group contains only FATHMM, whereas the pathogenic group includes SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a damaging outcome: 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 based on the collective predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -14.139 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 3.38 | Destabilizing | 0.0 | 4.33 | Destabilizing | 3.86 | Destabilizing | 2.47 | Destabilizing | 0.695 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 0.2124 | 0.0612 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1513T>C | Y505H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505H is listed in ClinVar as Pathogenic (ClinVar ID 3064218.0) 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, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. High‑accuracy consensus methods reinforce this view: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also Pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among predictive tools, the variant is most likely pathogenic, consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | Likely Pathogenic | 1 | -11.383 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 2.91 | Destabilizing | 0.1 | 2.88 | Destabilizing | 2.90 | Destabilizing | 1.60 | Destabilizing | 0.646 | Likely Pathogenic | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.64 | Benign | 0.00 | Affected | 3.37 | 35 | 0.2148 | 0.0612 | 2 | 0 | -1.9 | -26.03 | |||||||||||||||||||||||||
| c.1513T>G | Y505D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505D is listed in ClinVar as Pathogenic (ClinVar ID 3172759.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect are limited to FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized scores the variant as Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as Pathogenic. Based on the overwhelming agreement among these 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 | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | Likely Pathogenic | 1 | -14.078 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 4.98 | Destabilizing | 0.1 | 4.72 | Destabilizing | 4.85 | Destabilizing | 2.49 | Destabilizing | 0.718 | Likely Pathogenic | -9.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 3.37 | 35 | 0.3940 | 0.0612 | -3 | -4 | -2.2 | -48.09 | |||||||||||||||||||||||||
| c.1514A>C | Y505S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only FATHMM, whereas all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores 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 outputs, also predicts pathogenicity. No predictions are missing or inconclusive. Overall, the consensus of the available computational evidence indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently contains no entry for Y505S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -14.053 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 3.49 | Destabilizing | 0.1 | 4.86 | Destabilizing | 4.18 | Destabilizing | 2.33 | Destabilizing | 0.559 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.61 | Benign | 0.00 | Affected | 0.4056 | 0.1945 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.1514A>G | Y505C 2D AIThe SynGAP1 missense variant Y505C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -11.784 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 3.41 | Destabilizing | 0.5 | 4.37 | Destabilizing | 3.89 | Destabilizing | 2.32 | Destabilizing | 0.578 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 0.3203 | 0.1814 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.1514A>T | Y505F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505F is 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (five benign versus four pathogenic) lean toward a benign interpretation, and this is consistent with the lack of ClinVar evidence; 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. | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -8.855 | Likely Pathogenic | 0.437 | Ambiguous | Likely Benign | 0.40 | Likely Benign | 0.0 | 0.76 | Ambiguous | 0.58 | Ambiguous | 0.69 | Ambiguous | 0.434 | Likely Benign | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.93 | Benign | 0.07 | Tolerated | 0.2409 | 0.2598 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||
| c.1516C>A | L506I 2D AIThe SynGAP1 missense variant L506I is not reported in ClinVar and is absent from gnomAD. Consensus from standard in‑silico predictors shows a split: benign calls come from REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Uncertain results are reported by FoldX, premPS, and AlphaMissense‑Default. High‑accuracy assessments give a pathogenic verdict from Foldetta (a combined FoldX‑MD/Rosetta stability analysis) and from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). AlphaMissense‑Optimized, however, predicts benign. Overall, the majority of reliable tools and the high‑accuracy methods favor a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | -10.386 | Likely Pathogenic | 0.501 | Ambiguous | Likely Benign | 1.73 | Ambiguous | 1.0 | 2.85 | Destabilizing | 2.29 | Destabilizing | 0.98 | Ambiguous | 0.365 | Likely Benign | -1.99 | Neutral | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 1.65 | Pathogenic | 0.01 | Affected | 0.0745 | 0.2033 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1516C>G | L506V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM Consensus) all indicate a pathogenic impact. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy tools’ results, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | -10.220 | Likely Pathogenic | 0.512 | Ambiguous | Likely Benign | 2.61 | Destabilizing | 0.2 | 3.27 | Destabilizing | 2.94 | Destabilizing | 1.36 | Destabilizing | 0.420 | Likely Benign | -2.98 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 1.62 | Pathogenic | 0.04 | Affected | 0.1126 | 0.1660 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1516C>T | L506F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506F is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact; premPS and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, which is consistent with its ClinVar “Uncertain” classification and does not contradict the available data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | Uncertain | 1 | -11.262 | Likely Pathogenic | 0.883 | Likely Pathogenic | Ambiguous | 4.92 | Destabilizing | 0.8 | 5.76 | Destabilizing | 5.34 | Destabilizing | 0.91 | Ambiguous | 0.464 | Likely Benign | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.62 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.0566 | 0.1471 | 0 | 2 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.1517T>A | L506H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506H 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 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 (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | -12.999 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 4.45 | Destabilizing | 0.3 | 3.47 | Destabilizing | 3.96 | Destabilizing | 2.18 | Destabilizing | 0.758 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.54 | Pathogenic | 0.00 | Affected | 0.0919 | 0.0488 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.1517T>C | L506P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506P is listed in ClinVar (ID 975474.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors 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 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) is Pathogenic. Based on the unanimous computational evidence, 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 | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | Likely Pathogenic | 1 | -12.088 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.48 | Destabilizing | 0.7 | 10.19 | Destabilizing | 7.84 | Destabilizing | 2.50 | Destabilizing | 0.737 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.55 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.3047 | 0.0625 | -3 | -3 | -5.4 | -16.04 | 182.6 | 64.9 | 0.1 | 0.0 | 0.2 | 0.1 | X | Potentially Pathogenic | Leu506 is located in the middle of an α-helix (res. Gly502-Tyr518) within the inter-helix space of two helices (res. Gly502-Tyr518 and res. Glu582-Met603). In the WT simulations, the iso-butyl side chain of Leu506 hydrophobically packs with residues in the inter-helix space (e.g., Ile510, Phe597, Leu598, Ala601). In the variant simulations, the cyclic five-membered pyrrolidine ring of Pro506 is not as optimal as Leu506 for hydrophobic packing with nearby residues. Additionally, Pro506 cannot maintain the hydrogen bond with the backbone oxygen of Gly502 as Leu506 does in the WT, which disrupts the secondary structure element. | ||||||||||||||||
| c.1517T>G | L506R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506R 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) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Thus, all available evidence indicates that the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | -14.119 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 4.92 | Destabilizing | 0.6 | 5.85 | Destabilizing | 5.39 | Destabilizing | 1.77 | Destabilizing | 0.738 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.54 | Pathogenic | 0.00 | Affected | 0.1207 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1519A>C | K507Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K507Q is 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain results come from Rosetta, premPS, and ESM1b. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. Taken together, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -7.698 | In-Between | 0.180 | Likely Benign | Likely Benign | 0.28 | Likely Benign | 0.0 | -0.70 | Ambiguous | -0.21 | Likely Benign | -0.52 | Ambiguous | 0.443 | Likely Benign | 0.22 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | -1.52 | Pathogenic | 0.86 | Tolerated | 0.2952 | 0.0713 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||
| c.1519A>G | K507E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K507E missense change is not listed in ClinVar and has no gnomAD allele, indicating it is not a common polymorphism. Functional prediction tools cluster into two groups: benign predictions come from Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, while pathogenic predictions arise from REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Four tools give uncertain results: FoldX, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments provide a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic, and Foldetta remains uncertain. Overall, the majority of standard predictors favor a pathogenic effect, and the high‑accuracy consensus also tilts toward pathogenicity, though not decisively. Therefore, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status because the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -11.507 | Likely Pathogenic | 0.448 | Ambiguous | Likely Benign | 0.70 | Ambiguous | 0.0 | 0.31 | Likely Benign | 0.51 | Ambiguous | 0.67 | Ambiguous | 0.536 | Likely Pathogenic | -0.84 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.45 | Pathogenic | 0.21 | Tolerated | 0.2537 | 0.0488 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||
| c.151A>C | I51L 2D AIThe SynGAP1 missense variant I51L 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 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 | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | 0.408 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.080 | Likely Benign | 0.14 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.35 | Benign | 0.00 | Affected | 0.0924 | 0.3993 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.151A>G | I51V 2D AIThe SynGAP1 missense variant I51V 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. 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 | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | -3.397 | Likely Benign | 0.195 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -0.24 | Neutral | 0.004 | Benign | 0.007 | Benign | 4.26 | Benign | 0.00 | Affected | 0.1330 | 0.3602 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.151A>T | I51F 2D AIThe SynGAP1 missense variant I51F 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, SGM‑Consensus indicates Likely Benign, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for I51F, 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 Benign | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | -5.687 | Likely Benign | 0.526 | Ambiguous | Likely Benign | 0.114 | Likely Benign | -0.87 | Neutral | 0.099 | Benign | 0.039 | Benign | 4.13 | Benign | 0.00 | Affected | 0.0565 | 0.3070 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.1520A>C | K507T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K507T missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT, Rosetta, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifying it as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain result. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the absence of a ClinVar classification. **The variant is most likely pathogenic based on the current predictive evidence.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -10.244 | Likely Pathogenic | 0.468 | Ambiguous | Likely Benign | 0.82 | Ambiguous | 0.1 | 0.31 | Likely Benign | 0.57 | Ambiguous | 0.78 | Ambiguous | 0.724 | Likely Pathogenic | -2.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.55 | Pathogenic | 0.12 | Tolerated | 0.1501 | 0.2451 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1520A>G | K507R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K507R is not listed in ClinVar (ClinVar status: not reported) but is present in gnomAD (gnomAD ID 6-33438552-A-G). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. 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 ClinVar status, which has no pathogenic annotation for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | 6-33438552-A-G | 1 | 6.20e-7 | -7.363 | In-Between | 0.085 | Likely Benign | Likely Benign | -0.08 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.15 | Likely Benign | 0.36 | Likely Benign | 0.503 | Likely Pathogenic | -0.68 | Neutral | 0.992 | Probably Damaging | 0.980 | Probably Damaging | -1.48 | Pathogenic | 0.27 | Tolerated | 3.37 | 35 | 0.3155 | 0.0579 | 2 | 3 | -0.6 | 28.01 | |||||||||||||||||||||||||
| c.1520A>T | K507M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K507M missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, more tools (8) predict pathogenicity than benign (5), and the high‑accuracy consensus leans toward pathogenicity. Therefore, 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 | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -9.548 | Likely Pathogenic | 0.576 | Likely Pathogenic | Likely Benign | 0.12 | Likely Benign | 0.1 | -0.74 | Ambiguous | -0.31 | Likely Benign | -0.22 | Likely Benign | 0.850 | Likely Pathogenic | -2.39 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.63 | Pathogenic | 0.03 | Affected | 0.0783 | 0.2251 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1521G>C | K507N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K507N is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, whereas a pathogenic signal is reported by REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and Foldetta give 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) predicts pathogenic. Foldetta’s stability prediction is unavailable. Overall, the majority of tools (10 out of 14 with definitive calls) predict a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists. 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 | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -10.682 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | 0.81 | Ambiguous | 0.1 | 0.18 | Likely Benign | 0.50 | Ambiguous | 1.06 | Destabilizing | 0.579 | Likely Pathogenic | -1.63 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.57 | Pathogenic | 0.11 | Tolerated | 0.2417 | 0.0764 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1521G>T | K507N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K507N is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, while those that predict a pathogenic effect comprise REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (10 pathogenic vs. 4 benign) predict a deleterious impact. Thus, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -10.682 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | 0.81 | Ambiguous | 0.1 | 0.18 | Likely Benign | 0.50 | Ambiguous | 1.06 | Destabilizing | 0.579 | Likely Pathogenic | -1.63 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.57 | Pathogenic | 0.11 | Tolerated | 0.2417 | 0.0764 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1522G>A | D508N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508N missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, premPS, FATHMM, AlphaMissense‑Optimized) and pathogenic predictions (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b). Three tools remain uncertain (Rosetta, Foldetta, AlphaMissense‑Default). High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized classifies the change as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—returns a pathogenic verdict; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an inconclusive result. Because the consensus of the high‑accuracy methods is split, the overall prediction is ambiguous, but the balance of evidence leans toward pathogenicity. This assessment does not contradict ClinVar, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -9.909 | Likely Pathogenic | 0.411 | Ambiguous | Likely Benign | 0.11 | Likely Benign | 0.1 | 1.24 | Ambiguous | 0.68 | Ambiguous | -0.12 | Likely Benign | 0.265 | Likely Benign | -4.62 | Deleterious | 0.870 | Possibly Damaging | 0.615 | Possibly Damaging | 3.32 | Benign | 0.04 | Affected | 0.1577 | 0.4599 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.1522G>C | D508H 2D AISynGAP1 D508H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show an even split: benign calls come from REVEL, FoldX, premPS, SIFT, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments give a pathogenic consensus from the SGM method (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), an uncertain outcome from AlphaMissense‑Optimized, and an uncertain outcome from Foldetta (combining FoldX‑MD and Rosetta). Overall, the balance of evidence leans toward pathogenicity, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -12.074 | Likely Pathogenic | 0.849 | Likely Pathogenic | Ambiguous | 0.15 | Likely Benign | 0.4 | 0.97 | Ambiguous | 0.56 | Ambiguous | -0.14 | Likely Benign | 0.336 | Likely Benign | -6.38 | Deleterious | 0.998 | Probably Damaging | 0.919 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 0.1804 | 0.5096 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1522G>T | D508Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508Y missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling it likely pathogenic, and Foldetta predicting a benign outcome. Overall, the majority of evidence (seven pathogenic vs. five benign) points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -12.917 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | -0.53 | Ambiguous | 0.2 | 0.72 | Ambiguous | 0.10 | Likely Benign | 0.06 | Likely Benign | 0.363 | Likely Benign | -8.37 | Deleterious | 1.000 | Probably Damaging | 0.965 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.0908 | 0.4736 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1523A>C | D508A 2D 3DClick to see structure in 3D Viewer AISynGAP1 D508A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy methods give a split result: AlphaMissense‑Optimized predicts benign, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is uncertain. No prediction or stability result is missing; all available outputs are considered. Overall, the predictions are evenly divided between benign and pathogenic, with no clear consensus. Therefore, the variant is inconclusive; it is not contradictory to the ClinVar status, which has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -11.434 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | -0.18 | Likely Benign | 0.2 | 1.84 | Ambiguous | 0.83 | Ambiguous | 0.09 | Likely Benign | 0.339 | Likely Benign | -7.37 | Deleterious | 0.988 | Probably Damaging | 0.762 | Possibly Damaging | 3.37 | Benign | 0.06 | Tolerated | 0.3758 | 0.4241 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1523A>G | D508G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508G missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. FoldX‑MD is inconclusive and is treated as unavailable. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM Consensus, and a pathogenic prediction from Foldetta. Overall, the majority of evidence, including the high‑accuracy tools, supports a pathogenic effect. This conclusion does not contradict ClinVar, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -8.478 | Likely Pathogenic | 0.622 | Likely Pathogenic | Likely Benign | 0.87 | Ambiguous | 0.2 | 3.20 | Destabilizing | 2.04 | Destabilizing | 0.13 | Likely Benign | 0.368 | Likely Benign | -6.61 | Deleterious | 0.997 | Probably Damaging | 0.933 | Probably Damaging | 3.30 | Benign | 0.07 | Tolerated | 0.3821 | 0.4528 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1523A>T | D508V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508V missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (a folding‑stability method combining FoldX‑MD and Rosetta outputs) as benign. With seven benign versus six pathogenic calls and two of the three high‑accuracy tools supporting benign, the variant is most likely benign. 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 | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -13.529 | Likely Pathogenic | 0.691 | Likely Pathogenic | Likely Benign | 0.07 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.37 | Likely Benign | 0.07 | Likely Benign | 0.381 | Likely Benign | -8.37 | Deleterious | 0.985 | Probably Damaging | 0.895 | Possibly Damaging | 3.27 | Benign | 0.08 | Tolerated | 0.1050 | 0.4604 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1524T>A | D508E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D508E is reported in gnomAD (ID 6‑33438556‑T‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the protein‑stability method Foldetta. Only PROVEAN predicts a pathogenic outcome, while Rosetta and premPS are inconclusive. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign. Overall, the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | 6-33438556-T-A | 1 | 6.20e-7 | -5.959 | Likely Benign | 0.242 | Likely Benign | Likely Benign | -0.39 | Likely Benign | 0.1 | 0.99 | Ambiguous | 0.30 | Likely Benign | 0.59 | Ambiguous | 0.118 | Likely Benign | -3.16 | Deleterious | 0.005 | Benign | 0.006 | Benign | 3.43 | Benign | 0.20 | Tolerated | 3.37 | 35 | 0.1766 | 0.4304 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||
| c.1524T>G | D508E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all classify the change as benign. Only PROVEAN predicts a pathogenic outcome, while Rosetta and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign stability. 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 | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -5.959 | Likely Benign | 0.242 | Likely Benign | Likely Benign | -0.39 | Likely Benign | 0.1 | 0.99 | Ambiguous | 0.30 | Likely Benign | 0.59 | Ambiguous | 0.118 | Likely Benign | -3.16 | Deleterious | 0.005 | Benign | 0.006 | Benign | 3.43 | Benign | 0.20 | Tolerated | 3.37 | 35 | 0.1766 | 0.4304 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||
| c.1525G>A | A509T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509T is 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain and therefore unavailable for interpretation. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -8.961 | Likely Pathogenic | 0.171 | Likely Benign | Likely Benign | 0.95 | Ambiguous | 0.4 | 0.61 | Ambiguous | 0.78 | Ambiguous | 0.04 | Likely Benign | 0.360 | Likely Benign | -2.15 | Neutral | 0.031 | Benign | 0.058 | Benign | -1.25 | Pathogenic | 0.32 | Tolerated | 0.1344 | 0.5593 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.1525G>C | A509P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign effect, so the benign‑prediction group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports a pathogenic effect; 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 a pathogenic impact. Based on the collective evidence, 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 | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -13.234 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 5.82 | Destabilizing | 0.6 | 7.70 | Destabilizing | 6.76 | Destabilizing | 1.13 | Destabilizing | 0.884 | Likely Pathogenic | -4.15 | Deleterious | 0.987 | Probably Damaging | 0.844 | Possibly Damaging | -1.39 | Pathogenic | 0.01 | Affected | 0.1940 | 0.4570 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1525G>T | A509S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509S is 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Four tools give uncertain or inconclusive results (FoldX, Rosetta, Foldetta, premPS). High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus inconclusive, and Foldetta is also inconclusive. Overall, the majority of standard predictors lean toward pathogenicity, while the most reliable single‑tool prediction (AlphaMissense‑Optimized) suggests benign. Given the balance of 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. | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -9.997 | Likely Pathogenic | 0.171 | Likely Benign | Likely Benign | 0.83 | Ambiguous | 0.1 | 1.63 | Ambiguous | 1.23 | Ambiguous | 0.59 | Ambiguous | 0.621 | Likely Pathogenic | -2.18 | Neutral | 0.119 | Benign | 0.468 | Possibly Damaging | -1.35 | Pathogenic | 0.01 | Affected | 0.2410 | 0.4384 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1526C>A | A509D 2D AIThe SynGAP1 missense variant A509D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Pathogenic” verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a pathogenic effect. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -17.026 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 4.02 | Destabilizing | 1.6 | 3.09 | Destabilizing | 3.56 | Destabilizing | 1.36 | Destabilizing | 0.915 | Likely Pathogenic | -4.94 | Deleterious | 0.963 | Probably Damaging | 0.844 | Possibly Damaging | -1.40 | Pathogenic | 0.00 | Affected | 0.1610 | 0.1360 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1526C>G | A509G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that clearly indicate benign effect include only AlphaMissense‑Optimized. All other evaluated tools that provide a definitive call predict pathogenicity: SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Tools with inconclusive results (AlphaMissense‑Default, FoldX, and Foldetta) are treated as unavailable and do not influence the overall assessment. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta, combining FoldX‑MD (uncertain) and Rosetta (pathogenic), is uncertain. Overall, the majority of definitive predictions support 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 | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -11.873 | Likely Pathogenic | 0.541 | Ambiguous | Likely Benign | 1.36 | Ambiguous | 0.2 | 2.33 | Destabilizing | 1.85 | Ambiguous | 1.14 | Destabilizing | 0.804 | Likely Pathogenic | -3.57 | Deleterious | 0.911 | Possibly Damaging | 0.706 | Possibly Damaging | -1.39 | Pathogenic | 0.00 | Affected | 0.2193 | 0.4213 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1526C>T | A509V 2D 3DClick to see structure in 3D Viewer AISynGAP1 A509V is not reported in ClinVar and is absent from gnomAD. High‑accuracy predictors give mixed results: AlphaMissense‑Optimized classifies the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive because FoldX is uncertain and Rosetta is benign. Among the remaining tools, benign predictions come from REVEL, Rosetta, premPS, polyPhen2_HumDiv, polyPhen2_HumVar, and SIFT, whereas pathogenic predictions come from SGM‑Consensus, PROVEAN, ESM1b, and FATHMM. AlphaMissense‑Default and FoldX remain uncertain. Overall, the majority of evidence points toward a benign effect, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -11.987 | Likely Pathogenic | 0.382 | Ambiguous | Likely Benign | 0.52 | Ambiguous | 0.5 | 0.35 | Likely Benign | 0.44 | Likely Benign | -0.25 | Likely Benign | 0.474 | Likely Benign | -3.11 | Deleterious | 0.064 | Benign | 0.048 | Benign | -1.15 | Pathogenic | 0.18 | Tolerated | 0.1333 | 0.5706 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.1528A>C | I510L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all indicate a benign effect. No prediction or folding‑stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -2.362 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.2 | -0.05 | Likely Benign | 0.13 | Likely Benign | -1.01 | Stabilizing | 0.338 | Likely Benign | 0.69 | Neutral | 0.016 | Benign | 0.130 | Benign | -0.74 | Pathogenic | 1.00 | Tolerated | 0.0819 | 0.2461 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.1528A>G | I510V 2D 3DClick to see structure in 3D Viewer AISynGAP1 I510V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Pathogenic predictions arise from polyPhen‑2 HumDiv, SIFT, FATHMM, and premPS. FoldX and Rosetta analyses are inconclusive, and Foldetta stability assessment is unavailable. High‑accuracy methods reinforce the benign trend: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta provides no definitive result. Overall, the majority of evidence points to a benign effect for I510V, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -6.072 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 1.45 | Ambiguous | 0.2 | 0.50 | Ambiguous | 0.98 | Ambiguous | 1.13 | Destabilizing | 0.461 | Likely Benign | -1.00 | Neutral | 0.792 | Possibly Damaging | 0.332 | Benign | -1.36 | Pathogenic | 0.02 | Affected | 0.0999 | 0.2291 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.1528A>T | I510F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510F is 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 AlphaMissense‑Optimized, whereas the majority of tools (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Foldetta) predict a pathogenic impact; Rosetta remains uncertain. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Overall, the preponderance of evidence indicates that the variant 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 | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -8.185 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 4.66 | Destabilizing | 0.7 | 1.38 | Ambiguous | 3.02 | Destabilizing | 0.50 | Likely Benign | 0.692 | Likely Pathogenic | -2.64 | Deleterious | 0.991 | Probably Damaging | 0.854 | Possibly Damaging | -1.14 | Pathogenic | 0.01 | Affected | 0.0552 | 0.1794 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1529T>A | I510N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510N is not reported in ClinVar and is absent from 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 indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic impact. Based on the uniform predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -12.784 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 3.09 | Destabilizing | 0.1 | 3.00 | Destabilizing | 3.05 | Destabilizing | 2.08 | Destabilizing | 0.925 | Likely Pathogenic | -5.62 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.45 | Pathogenic | 0.00 | Affected | 0.0761 | 0.0270 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1529T>C | I510T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Foldetta—classify the variant as pathogenic, while Rosetta remains uncertain. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -9.993 | Likely Pathogenic | 0.701 | Likely Pathogenic | Likely Benign | 3.08 | Destabilizing | 0.2 | 1.99 | Ambiguous | 2.54 | Destabilizing | 1.95 | Destabilizing | 0.914 | Likely Pathogenic | -3.63 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.43 | Pathogenic | 0.00 | Affected | 0.0960 | 0.0440 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.1529T>G | I510S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510S is listed in ClinVar as Pathogenic (ClinVar ID 449946.0) and is not reported in gnomAD. Prediction tools that assess the variant’s effect all converge on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate pathogenicity. No tool predicts a benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized is uncertain, SGM‑Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, 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 | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | Likely Pathogenic | 1 | -11.661 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 4.00 | Destabilizing | 0.1 | 3.78 | Destabilizing | 3.89 | Destabilizing | 2.34 | Destabilizing | 0.926 | Likely Pathogenic | -4.63 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.44 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.2395 | 0.0858 | -1 | -2 | -5.3 | -26.08 | 201.4 | 45.9 | -0.4 | 0.2 | 0.0 | 0.3 | X | Potentially Pathogenic | Ile510 is located in the middle of an α-helix (res. Gly502-Tyr518) within the inter-helix space of three helices (res. Gly502-Tyr518, Ala533-Val560, and res. Glu582-Met603). In the WT simulations, the sec-butyl side chain of Ile510 hydrophobically packs with other residues in the inter-helix space (e.g., Leu506, Leu610, Ile514, Ile602, Leu598). In the variant simulations, the hydroxyl group of Ser510 forms a hydrogen bond with the backbone atoms of Leu506 and Gly511 in the same α-helix, which could further weaken the α-helix integrity. This α-helix already shows weakness in the WT simulations due to Gly511. Although the simulations do not show large-scale effects, the residue swap could have a substantial impact due to the fundamental role of hydrophobic packing during protein folding. | ||||||||||||||||
| c.152T>A | I51N 2D AIThe SynGAP1 missense variant I51N is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD: not present). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method, has no available output for this variant. Consequently, the evidence is split evenly between benign and pathogenic predictions, with no decisive support from the most accurate methods. The variant is therefore inconclusive; it is not contradicted by any ClinVar record. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | -9.287 | Likely Pathogenic | 0.909 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.77 | Neutral | 0.704 | Possibly Damaging | 0.272 | Benign | 4.13 | Benign | 0.00 | Affected | 0.1005 | 0.0769 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.152T>C | I51T 2D AIThe SynGAP1 missense variant I51T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default, while AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show that the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign, AlphaMissense‑Optimized remains Uncertain, and no Foldetta stability result is available. 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. | Likely Benign | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | -5.861 | Likely Benign | 0.881 | Likely Pathogenic | Ambiguous | 0.135 | Likely Benign | -1.07 | Neutral | 0.084 | Benign | 0.050 | Benign | 4.16 | Benign | 0.00 | Affected | 0.1180 | 0.1265 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||||||
| c.152T>G | I51S 2D AIThe SynGAP1 missense variant I51S is 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, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The remaining tools, ESM1b and AlphaMissense‑Optimized, are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign (2 benign vs. 1 pathogenic vote). Foldetta, a protein‑folding stability method, 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. | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | -7.603 | In-Between | 0.879 | Likely Pathogenic | Ambiguous | 0.220 | Likely Benign | -1.39 | Neutral | 0.182 | Benign | 0.099 | Benign | 4.15 | Benign | 0.00 | Affected | 0.3142 | 0.0957 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.1530T>G | I510M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I510M 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 impact include PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (benign), ESM1b (uncertain), FATHMM (pathogenic), and PROVEAN (benign)—also favors benign. Foldetta, a protein‑folding stability method, yielded an uncertain outcome. Taken together, the consensus of the most reliable predictors indicates a benign effect. This conclusion does not contradict the ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -7.988 | In-Between | 0.235 | Likely Benign | Likely Benign | 0.56 | Ambiguous | 0.3 | 1.61 | Ambiguous | 1.09 | Ambiguous | 0.55 | Ambiguous | 0.532 | Likely Pathogenic | -0.97 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.42 | Pathogenic | 0.02 | Affected | 0.0674 | 0.1789 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||
| c.1531G>A | G511R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G511R is listed in ClinVar as Pathogenic (ClinVar ID 1774641.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: 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 outputs, is inconclusive. Stability calculations from FoldX and Rosetta are uncertain, and premPS is unavailable. Overall, the majority of evidence points to a pathogenic impact, aligning with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | Likely Pathogenic | 1 | -11.327 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.94 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.63 | Ambiguous | 0.94 | Ambiguous | 0.416 | Likely Benign | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 3.37 | 35 | 0.1307 | 0.4104 | -3 | -2 | -4.1 | 99.14 | 279.4 | -159.9 | 0.0 | 0.0 | 0.7 | 0.1 | X | X | Potentially Pathogenic | Gly511 is located in an α-helix (res. Gly502-Tyr518), facing hydrophobic residues in an inter-helix space (e.g., Leu610, Ile514) in the WT simulations. In contrast, in the variant simulations, the bulkier and positively charged guanidinium side chain of Arg511 forms a salt bridge with the carboxylate group of Glu217 or hydrogen bonds with the backbone carbonyl group of Leu610. Although the residue swap introduces a third positively charged residue in close vicinity (Arg511, Lys507, Arg515), the protein structure seems to remain stable in the variant simulations. Importantly, according to ClinVar, the residue swap alters the last nucleotide of an exon and is predicted to destroy the splice donor site, resulting in aberrant splicing and pathogenic status. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||
| c.1531G>C | G511R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511R is listed in ClinVar (ID 452818.0) as Pathogenic and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain, which is treated as unavailable evidence. Overall, the majority of available predictions support a pathogenic impact, aligning with the ClinVar classification. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | Pathogenic | 1 | -11.327 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.94 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.63 | Ambiguous | 0.94 | Ambiguous | 0.415 | Likely Benign | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 3.37 | 35 | 0.1307 | 0.4104 | -3 | -2 | -4.1 | 99.14 | 279.4 | -159.9 | 0.0 | 0.0 | 0.7 | 0.1 | X | X | Potentially Pathogenic | Gly511 is located in an α-helix (res. Gly502-Tyr518), facing hydrophobic residues in an inter-helix space (e.g., Leu610, Ile514) in the WT simulations. In contrast, in the variant simulations, the bulkier and positively charged guanidinium side chain of Arg511 forms a salt bridge with the carboxylate group of Glu217 or hydrogen bonds with the backbone carbonyl group of Leu610. Although the residue swap introduces a third positively charged residue in close vicinity (Arg511, Lys507, Arg515), the protein structure seems to remain stable in the variant simulations. Importantly, according to ClinVar, the residue swap alters the last nucleotide of an exon and is predicted to destroy the splice donor site, resulting in aberrant splicing and pathogenic status. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||
| c.1532G>A | G511E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Based on the preponderance 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 | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -12.263 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.17 | Destabilizing | 0.2 | 2.62 | Destabilizing | 2.40 | Destabilizing | 1.15 | Destabilizing | 0.479 | Likely Benign | -7.69 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.24 | Benign | 0.02 | Affected | 0.1882 | 0.4240 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||
| c.1532G>C | G511A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta remains uncertain. 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 any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -9.621 | Likely Pathogenic | 0.844 | Likely Pathogenic | Ambiguous | 0.80 | Ambiguous | 0.2 | 0.25 | Likely Benign | 0.53 | Ambiguous | 0.55 | Ambiguous | 0.275 | Likely Benign | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.23 | Benign | 0.02 | Affected | 0.3793 | 0.2778 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1532G>T | G511V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511V 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 FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy methods further support pathogenicity: 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. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no classification for G511V. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -11.738 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 3.47 | Destabilizing | 0.2 | 0.79 | Ambiguous | 2.13 | Destabilizing | 0.65 | Ambiguous | 0.540 | Likely Pathogenic | -8.71 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.16 | Benign | 0.01 | Affected | 0.1557 | 0.3019 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1534G>A | E512K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E512K missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, FATHMM, premPS, and Foldetta, while those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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, seven tools predict pathogenicity versus six predicting benignity, with one uncertain result. Thus, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -13.927 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.17 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.40 | Likely Benign | -0.03 | Likely Benign | 0.344 | Likely Benign | -3.85 | Deleterious | 0.962 | Probably Damaging | 0.658 | Possibly Damaging | 3.32 | Benign | 0.06 | Tolerated | 0.2844 | 0.4776 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1534G>C | E512Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E512Q missense change is not reported in ClinVar and has no gnomAD entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Because the variant is absent from ClinVar and gnomAD, there is no external evidence to contradict the computational predictions. Overall, the balance of high‑confidence tools leans toward a pathogenic interpretation, though the presence of an equal number of benign predictions indicates that the evidence remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -9.964 | Likely Pathogenic | 0.847 | Likely Pathogenic | Ambiguous | 0.09 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.26 | Likely Benign | 0.00 | Likely Benign | 0.283 | Likely Benign | -2.86 | Deleterious | 0.947 | Possibly Damaging | 0.706 | Possibly Damaging | 3.32 | Benign | 0.14 | Tolerated | 0.1523 | 0.4815 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1535A>C | E512A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E512A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results come from Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments show SGM‑Consensus as likely pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -10.979 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 0.45 | Likely Benign | 0.1 | 0.97 | Ambiguous | 0.71 | Ambiguous | 0.04 | Likely Benign | 0.309 | Likely Benign | -5.71 | Deleterious | 0.987 | Probably Damaging | 0.937 | Probably Damaging | 3.31 | Benign | 0.12 | Tolerated | 0.4293 | 0.5162 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1535A>G | E512G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E512G 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, premPS, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. The remaining tools—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—return uncertain or inconclusive 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, and PROVEAN), and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E512G, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -11.996 | Likely Pathogenic | 0.817 | Likely Pathogenic | Ambiguous | 0.86 | Ambiguous | 0.1 | 1.84 | Ambiguous | 1.35 | Ambiguous | 0.17 | Likely Benign | 0.381 | Likely Benign | -6.46 | Deleterious | 0.997 | Probably Damaging | 0.915 | Probably Damaging | 3.30 | Benign | 0.02 | Affected | 0.3262 | 0.4185 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1535A>T | E512V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E512V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; 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 | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -14.011 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 0.72 | Ambiguous | 0.1 | 1.00 | Ambiguous | 0.86 | Ambiguous | 0.14 | Likely Benign | 0.439 | Likely Benign | -6.71 | Deleterious | 0.989 | Probably Damaging | 0.854 | Possibly Damaging | 3.23 | Benign | 0.01 | Affected | 0.0994 | 0.4884 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1536A>C | E512D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E512D is not reported in ClinVar or gnomAD. Across a broad panel of in silico predictors, the majority indicate a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only the ESM1b model assigns a pathogenic label, while Rosetta and Foldetta provide uncertain results. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta remains inconclusive. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -8.354 | Likely Pathogenic | 0.198 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.3 | 1.05 | Ambiguous | 0.59 | Ambiguous | 0.00 | Likely Benign | 0.259 | Likely Benign | -2.10 | Neutral | 0.016 | Benign | 0.012 | Benign | 3.34 | Benign | 0.23 | Tolerated | 0.2055 | 0.3089 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1536A>T | E512D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change E512D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Across the broad panel of in‑silico predictors, the majority (REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all classify the variant as benign, whereas only ESM1b predicts it as pathogenic. The high‑accuracy tools give a consistent benign signal: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Overall, the evidence strongly supports a benign effect; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -8.354 | Likely Pathogenic | 0.198 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.3 | 1.05 | Ambiguous | 0.59 | Ambiguous | 0.00 | Likely Benign | 0.259 | Likely Benign | -2.10 | Neutral | 0.016 | Benign | 0.012 | Benign | 3.34 | Benign | 0.23 | Tolerated | 0.2055 | 0.3089 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1537T>A | F513I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513I is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools largely converge on a deleterious effect: SIFT is the sole benign caller, whereas REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. Grouping by consensus, the single benign prediction (SIFT) is outweighed by the 13 pathogenic calls. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a pathogenic effect; 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 a pathogenic outcome. 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 | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -12.003 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.42 | Destabilizing | 0.4 | 2.18 | Destabilizing | 2.80 | Destabilizing | 1.12 | Destabilizing | 0.766 | Likely Pathogenic | -5.70 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.24 | Pathogenic | 0.22 | Tolerated | 0.1473 | 0.1766 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1537T>C | F513L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513L is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions are provided only by SIFT, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic)—all predict a deleterious effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. No evidence from FoldX or Rosetta is considered decisive. Overall, the preponderance of predictions indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -10.370 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 1.36 | Ambiguous | 0.2 | 1.63 | Ambiguous | 1.50 | Ambiguous | 1.14 | Destabilizing | 0.674 | Likely Pathogenic | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.07 | Pathogenic | 0.19 | Tolerated | 0.1645 | 0.2447 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1537T>G | F513V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513V is 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 SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (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 the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -10.675 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 3.54 | Destabilizing | 0.4 | 2.68 | Destabilizing | 3.11 | Destabilizing | 1.13 | Destabilizing | 0.799 | Likely Pathogenic | -6.70 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.21 | Pathogenic | 0.44 | Tolerated | 0.1656 | 0.1583 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1538T>A | F513Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SIFT classifies it as benign, whereas REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenicity. Stability‑based methods (FoldX, Rosetta, Foldetta) and AlphaMissense‑Optimized return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as uncertain. With 10 of 12 evaluated tools indicating pathogenicity and no conflicting ClinVar annotation, 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 | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -10.022 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 1.09 | Ambiguous | 0.2 | 1.03 | Ambiguous | 1.06 | Ambiguous | 1.09 | Destabilizing | 0.791 | Likely Pathogenic | -2.92 | Deleterious | 0.988 | Probably Damaging | 0.976 | Probably Damaging | -1.39 | Pathogenic | 0.07 | Tolerated | 0.1046 | 0.1087 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1538T>C | F513S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513S is 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 SIFT, whereas all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta (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 assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -12.172 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.21 | Destabilizing | 0.4 | 4.43 | Destabilizing | 4.32 | Destabilizing | 2.25 | Destabilizing | 0.917 | Likely Pathogenic | -7.75 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.27 | Pathogenic | 0.10 | Tolerated | 0.3864 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1538T>G | F513C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513C is not reported in ClinVar and is absent from 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 indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also labels it pathogenic. Based on the uniform 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 | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -11.389 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.92 | Destabilizing | 0.3 | 4.20 | Destabilizing | 4.06 | Destabilizing | 1.64 | Destabilizing | 0.919 | Likely Pathogenic | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.40 | Pathogenic | 0.03 | Affected | 0.2384 | 0.0783 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1539C>A | F513L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513L is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions are provided only by SIFT, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic)—all predict a deleterious effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. No evidence from FoldX or Rosetta is considered decisive. Overall, the preponderance of predictions indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -10.370 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 1.36 | Ambiguous | 0.2 | 1.63 | Ambiguous | 1.50 | Ambiguous | 1.14 | Destabilizing | 0.537 | Likely Pathogenic | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.07 | Pathogenic | 0.19 | Tolerated | 0.1645 | 0.2447 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1539C>G | F513L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F513L missense variant has no ClinVar entry and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions are provided only by SIFT, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it likely pathogenic, and the Foldetta stability analysis is inconclusive and therefore not considered evidence. FoldX and Rosetta predictions are uncertain and treated as unavailable. Overall, the preponderance of evidence indicates that F513L 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 | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -10.370 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 1.36 | Ambiguous | 0.2 | 1.63 | Ambiguous | 1.50 | Ambiguous | 1.14 | Destabilizing | 0.537 | Likely Pathogenic | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.07 | Pathogenic | 0.19 | Tolerated | 0.1645 | 0.2447 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.153C>G | I51M 2D AIThe SynGAP1 missense variant I51M 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, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic call comes from SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as likely benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, the I51M substitution 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 | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | -4.732 | Likely Benign | 0.381 | Ambiguous | Likely Benign | 0.093 | Likely Benign | -0.27 | Neutral | 0.099 | Benign | 0.075 | Benign | 4.13 | Benign | 0.00 | Affected | 0.0764 | 0.3281 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.1540A>C | I514L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools (premPS and AlphaMissense‑Default) give uncertain results. 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 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. | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -10.239 | Likely Pathogenic | 0.490 | Ambiguous | Likely Benign | -0.05 | Likely Benign | 0.2 | 0.34 | Likely Benign | 0.15 | Likely Benign | 0.81 | Ambiguous | 0.310 | Likely Benign | -1.99 | Neutral | 0.879 | Possibly Damaging | 0.985 | Probably Damaging | 3.31 | Benign | 0.12 | Tolerated | 0.0767 | 0.2678 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1540A>G | I514V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514V is catalogued in gnomAD (variant ID 6‑33438783‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are limited to polyPhen‑2 HumDiv and HumVar. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence indicates that I514V is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | 6-33438783-A-G | 7 | 4.34e-6 | -5.187 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 1.39 | Ambiguous | 0.0 | 0.44 | Likely Benign | 0.92 | Ambiguous | 0.89 | Ambiguous | 0.173 | Likely Benign | -0.79 | Neutral | 0.914 | Possibly Damaging | 0.960 | Probably Damaging | 3.15 | Benign | 0.13 | Tolerated | 3.37 | 35 | 0.0939 | 0.2130 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||
| c.1540A>T | I514F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514F 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, premPS (uncertain), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—report it as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity; 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 stability calculations, classifies the variant as pathogenic. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | Uncertain | 1 | -13.383 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 2.35 | Destabilizing | 0.3 | 3.74 | Destabilizing | 3.05 | Destabilizing | 0.93 | Ambiguous | 0.601 | Likely Pathogenic | -3.98 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.89 | Benign | 0.00 | Affected | 3.37 | 35 | 0.0574 | 0.1629 | 0 | 1 | -1.7 | 34.02 | |||||||||||||||||||||||||
| c.1541T>A | I514N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the overwhelming consensus of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic. This assessment 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 | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -13.869 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.41 | Destabilizing | 0.3 | 2.41 | Destabilizing | 2.91 | Destabilizing | 2.61 | Destabilizing | 0.582 | Likely Pathogenic | -6.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.82 | Benign | 0.00 | Affected | 0.0770 | 0.0142 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1541T>C | I514T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514T has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. Rosetta reports an uncertain outcome and is not included in the consensus groups. 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, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Taken together, the evidence overwhelmingly points to a pathogenic effect, and this conclusion is not contradicted by the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -8.820 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 2.92 | Destabilizing | 0.1 | 1.88 | Ambiguous | 2.40 | Destabilizing | 1.94 | Destabilizing | 0.617 | Likely Pathogenic | -4.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.82 | Benign | 0.00 | Affected | 0.0962 | 0.0480 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.1541T>G | I514S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -12.512 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 4.03 | Destabilizing | 0.2 | 3.70 | Destabilizing | 3.87 | Destabilizing | 2.11 | Destabilizing | 0.625 | Likely Pathogenic | -5.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.82 | Benign | 0.00 | Affected | 0.2296 | 0.0530 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1542C>G | I514M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514M is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise 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, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, while the SGM‑Consensus (majority of the four high‑accuracy inputs) remains Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is Uncertain. Overall, seven of the twelve evaluated tools predict pathogenicity versus four predicting benign, with no evidence from ClinVar 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. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -9.753 | Likely Pathogenic | 0.727 | Likely Pathogenic | Likely Benign | 0.48 | Likely Benign | 0.2 | 0.78 | Ambiguous | 0.63 | Ambiguous | 1.13 | Destabilizing | 0.335 | Likely Benign | -2.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.88 | Benign | 0.00 | Affected | 0.0647 | 0.1816 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.1543C>A | R515S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R515S missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on benign impact include only SIFT, while the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the four pathogenic‑predicted tools) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Other stability‑based predictions (FoldX, Rosetta, premPS) are also uncertain. Overall, the majority of evidence points to a pathogenic effect. 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 | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | -10.615 | Likely Pathogenic | 0.928 | Likely Pathogenic | Ambiguous | 1.54 | Ambiguous | 0.3 | 1.11 | Ambiguous | 1.33 | Ambiguous | 0.92 | Ambiguous | 0.586 | Likely Pathogenic | -3.03 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.28 | Pathogenic | 0.17 | Tolerated | 0.2707 | 0.1849 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||
| c.1543C>G | R515G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R515G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus classify the change as pathogenic: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a deleterious effect. Tools with inconclusive results—Rosetta, Foldetta, and AlphaMissense‑Optimized—do not provide evidence for benignity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the overwhelming majority of predictions support a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | -11.562 | Likely Pathogenic | 0.807 | Likely Pathogenic | Ambiguous | 2.07 | Destabilizing | 0.3 | 1.87 | Ambiguous | 1.97 | Ambiguous | 1.29 | Destabilizing | 0.674 | Likely Pathogenic | -4.66 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.34 | Pathogenic | 0.04 | Affected | 0.2920 | 0.1998 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1543C>T | R515C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R515C is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (6‑33438786‑C‑T). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—SGM Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—predict a pathogenic impact. The remaining tools (FoldX, Rosetta, Foldetta, premPS) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion 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 | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | 6-33438786-C-T | 1 | 6.20e-7 | -10.973 | Likely Pathogenic | 0.628 | Likely Pathogenic | Likely Benign | 1.00 | Ambiguous | 0.0 | 1.13 | Ambiguous | 1.07 | Ambiguous | 0.72 | Ambiguous | 0.691 | Likely Pathogenic | -5.49 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.3055 | 0.1546 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||||
| c.1544G>A | R515H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R515H is listed in ClinVar with an uncertain significance (ClinVar ID 638438.0) and is present in gnomAD (variant ID 6‑33438787‑G‑A). Prediction tools that agree on a benign effect include AlphaMissense‑Default and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Overall, the balance of evidence favors 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 | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | Uncertain | 1 | 6-33438787-G-A | 3 | 1.86e-6 | -10.774 | Likely Pathogenic | 0.337 | Likely Benign | Likely Benign | 1.07 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.91 | Ambiguous | 1.09 | Destabilizing | 0.730 | Likely Pathogenic | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2343 | 0.0746 | 2 | 0 | 1.3 | -19.05 | 239.2 | 77.8 | 0.0 | 0.0 | 0.4 | 0.2 | X | Potentially Benign | The guanidinium group of Arg515, located in the middle of an α-helix at the GAP domain (res. Gly502-Tyr518), forms salt bridges with the carboxylate groups of Glu512 on the same helix and Glu217 on a loop in the PH domain. Additionally, the positively charged Arg515 side chain forms hydrogen bonds with Leu610 and Gln612 in an opposing loop (res. Gly609-Asp616). In contrast, in the variant simulations, the imidazole ring of His515 cannot form salt bridges with either of the acidic residues, and its side chain is too short to form hydrogen bonds with the loop residues. Accordingly, the residue swap could weaken the tertiary structure assembly of the protein. Due to the missing N-terminal part of the SynGAP model, the effect could be largely underestimated or missing. Notably, the doubly protonated and positively charged form of histidine was not simulated here. | |||||||||||||
| c.1544G>C | R515P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R515P has no ClinVar entry and is absent from gnomAD. In silico prediction tools uniformly indicate a deleterious effect: benign‑predicting algorithms are not reported, while pathogenic‑predicting tools—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—all classify the substitution as pathogenic. 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, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. Consequently, the variant is most likely pathogenic based on the collective computational evidence, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | -14.291 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.69 | Destabilizing | 0.1 | 8.87 | Destabilizing | 6.28 | Destabilizing | 1.02 | Destabilizing | 0.823 | Likely Pathogenic | -4.24 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.36 | Pathogenic | 0.03 | Affected | 0.2223 | 0.2725 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1544G>T | R515L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R515L is 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, Foldetta, SIFT, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome; FoldX and premPS are uncertain. 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, the balance of evidence favors a pathogenic interpretation, 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 | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | -10.738 | Likely Pathogenic | 0.744 | Likely Pathogenic | Likely Benign | 0.71 | Ambiguous | 0.2 | -0.33 | Likely Benign | 0.19 | Likely Benign | 0.52 | Ambiguous | 0.686 | Likely Pathogenic | -4.53 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.26 | Pathogenic | 0.11 | Tolerated | 0.1666 | 0.2857 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1546G>A | A516T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A516T is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include SIFT, Rosetta, and Foldetta, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. 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 stability outputs) as benign. With the pathogenic predictions outweighing the benign ones, the variant is most likely pathogenic. 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 | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -9.716 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.57 | Ambiguous | 0.2 | -0.14 | Likely Benign | 0.22 | Likely Benign | 0.63 | Ambiguous | 0.520 | Likely Pathogenic | -3.21 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | -1.29 | Pathogenic | 0.17 | Tolerated | 0.1586 | 0.5739 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1546G>C | A516P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A516P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; premPS is inconclusive. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized scores it as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies it as pathogenic. Based on the consensus of 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 | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -15.348 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.67 | Destabilizing | 0.3 | 10.96 | Destabilizing | 6.82 | Destabilizing | 0.83 | Ambiguous | 0.750 | Likely Pathogenic | -4.41 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.29 | Pathogenic | 0.06 | Tolerated | 0.2214 | 0.4328 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1546G>T | A516S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A516S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools remain uncertain: premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points to a benign effect, 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. | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -9.639 | Likely Pathogenic | 0.562 | Ambiguous | Likely Benign | 0.22 | Likely Benign | 0.2 | 0.24 | Likely Benign | 0.23 | Likely Benign | 0.52 | Ambiguous | 0.448 | Likely Benign | -2.45 | Neutral | 0.973 | Probably Damaging | 0.993 | Probably Damaging | -1.24 | Pathogenic | 0.17 | Tolerated | 0.2730 | 0.4730 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1547C>A | A516D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A516D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, which scores the substitution as tolerated. In contrast, the majority of algorithms predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, while Foldetta remains uncertain. Overall, the preponderance of evidence indicates that A516D is most likely pathogenic, 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 | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -14.621 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.65 | Ambiguous | 0.2 | 1.04 | Ambiguous | 0.85 | Ambiguous | 0.62 | Ambiguous | 0.725 | Likely Pathogenic | -5.17 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.23 | Pathogenic | 0.15 | Tolerated | 0.1890 | 0.1679 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1547C>G | A516G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A516G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are limited to SIFT, whereas the remaining seven tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) all predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. No stability‑change predictions are definitive. Overall, the majority of evidence points to a pathogenic impact for A516G. 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 | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -10.673 | Likely Pathogenic | 0.864 | Likely Pathogenic | Ambiguous | 0.86 | Ambiguous | 0.2 | 1.12 | Ambiguous | 0.99 | Ambiguous | 0.88 | Ambiguous | 0.557 | Likely Pathogenic | -3.52 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.31 | Pathogenic | 0.10 | Tolerated | 0.2379 | 0.4370 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1547C>T | A516V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A516V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess the variant’s effect fall into two groups: benign predictions come from FoldX, Rosetta, and SIFT, while pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. 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 tools, including the high‑accuracy predictors, lean toward a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -11.545 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.42 | Likely Benign | 0.1 | 0.16 | Likely Benign | 0.29 | Likely Benign | 0.62 | Ambiguous | 0.639 | Likely Pathogenic | -3.61 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | -1.32 | Pathogenic | 0.09 | Tolerated | 0.1336 | 0.5263 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.1549C>A | L517M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. Benign predictions are provided by FoldX and PROVEAN. High‑accuracy assessments are mixed: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenic, whereas AlphaMissense‑Optimized and Foldetta yield uncertain results and are treated as unavailable. No evidence from ClinVar contradicts these findings. Overall, the preponderance of evidence supports a pathogenic classification for L517M, with no conflict from existing database annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -11.613 | Likely Pathogenic | 0.799 | Likely Pathogenic | Ambiguous | 0.38 | Likely Benign | 0.2 | 1.22 | Ambiguous | 0.80 | Ambiguous | 0.93 | Ambiguous | 0.665 | Likely Pathogenic | -1.74 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.47 | Pathogenic | 0.01 | Affected | 0.0775 | 0.2558 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1549C>G | L517V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the change is deleterious: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM, while benign predictions are made by SIFT and AlphaMissense‑Optimized; the remaining tools (Rosetta, Foldetta, AlphaMissense‑Default) are uncertain. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the preponderance of evidence points to a likely pathogenic effect of the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -10.691 | Likely Pathogenic | 0.498 | Ambiguous | Likely Benign | 2.04 | Destabilizing | 0.3 | 1.37 | Ambiguous | 1.71 | Ambiguous | 1.14 | Destabilizing | 0.577 | Likely Pathogenic | -2.68 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.26 | Pathogenic | 0.17 | Tolerated | 0.1405 | 0.2398 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.154T>A | S52T 2D AIThe SynGAP1 missense variant S52T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar and SIFT. The high‑accuracy consensus (SGM‑Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -5.731 | Likely Benign | 0.224 | Likely Benign | Likely Benign | 0.070 | Likely Benign | 0.06 | Neutral | 0.140 | Benign | 0.481 | Possibly Damaging | 4.33 | Benign | 0.00 | Affected | 0.1505 | 0.6751 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.154T>C | S52P 2D AIThe SynGAP1 missense variant S52P 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, and FATHMM, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict a pathogenic outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic versus two benign votes); and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for S52P. This conclusion does not contradict ClinVar, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -10.007 | Likely Pathogenic | 0.797 | Likely Pathogenic | Ambiguous | 0.144 | Likely Benign | -1.28 | Neutral | 0.676 | Possibly Damaging | 0.693 | Possibly Damaging | 4.07 | Benign | 0.00 | Affected | 0.2276 | 0.5909 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||||||
| c.154T>G | S52A 2D AIThe SynGAP1 missense variant S52A 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, AlphaMissense‑Default, and AlphaMissense‑Optimized; the only tool predicting a pathogenic outcome is SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions strongly supports 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 | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -5.326 | Likely Benign | 0.196 | Likely Benign | Likely Benign | 0.040 | Likely Benign | -0.69 | Neutral | 0.140 | Benign | 0.355 | Benign | 4.17 | Benign | 0.00 | Affected | 0.5389 | 0.5073 | Strenghten | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.1550T>A | L517Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517Q is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. 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, so the benign group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a pathogenic impact. Thus, 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 | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -11.660 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.17 | Destabilizing | 0.1 | 2.07 | Destabilizing | 2.12 | Destabilizing | 1.87 | Destabilizing | 0.946 | Likely Pathogenic | -5.71 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | 0.1031 | 0.0888 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1550T>C | L517P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517P is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: pathogenic predictions are returned by REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change 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 reports a 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 | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -15.546 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.88 | Destabilizing | 0.8 | 7.96 | Destabilizing | 6.92 | Destabilizing | 1.92 | Destabilizing | 0.937 | Likely Pathogenic | -6.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | 0.3570 | 0.1963 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1550T>G | L517R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517R 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 outcome 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 | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -14.761 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.75 | Ambiguous | 0.2 | 4.33 | Destabilizing | 3.04 | Destabilizing | 1.83 | Destabilizing | 0.936 | Likely Pathogenic | -5.79 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | 0.1202 | 0.0688 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1552T>A | Y518N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 Y518N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and Foldetta) uniformly predict a pathogenic impact. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta also predicts pathogenicity. Taken together, the overwhelming majority of evidence indicates a pathogenic effect. 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 | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | -12.036 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 2.99 | Destabilizing | 0.8 | 1.50 | Ambiguous | 2.25 | Destabilizing | 1.29 | Destabilizing | 0.506 | Likely Pathogenic | -8.45 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.48 | Benign | 0.04 | Affected | 0.1791 | 0.0212 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1552T>C | Y518H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y518H 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, and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive are Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the 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 points to a pathogenic effect for Y518H, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | Uncertain | 1 | -9.797 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 2.39 | Destabilizing | 0.4 | 0.82 | Ambiguous | 1.61 | Ambiguous | 1.31 | Destabilizing | 0.496 | Likely Benign | -4.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.08 | Tolerated | 0.1927 | 0.0212 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||
| c.1552T>G | Y518D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y518D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (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. 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 | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | -12.247 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 3.92 | Destabilizing | 0.9 | 2.68 | Destabilizing | 3.30 | Destabilizing | 1.36 | Destabilizing | 0.619 | Likely Pathogenic | -9.41 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.03 | Affected | 0.3682 | 0.0212 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1553A>C | Y518S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y518S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SIFT and FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic”; AlphaMissense‑Optimized is uncertain; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic effect. Taken together, the preponderance of evidence points to a pathogenic effect for Y518S, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | -12.453 | Likely Pathogenic | 0.912 | Likely Pathogenic | Ambiguous | 2.76 | Destabilizing | 0.8 | 2.45 | Destabilizing | 2.61 | Destabilizing | 1.61 | Destabilizing | 0.551 | Likely Pathogenic | -8.38 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.06 | Tolerated | 0.3948 | 0.1059 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.1553A>G | Y518C 2D AIThe SynGAP1 missense variant Y518C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; and uncertain results from Rosetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus indicates likely pathogenic, and Foldetta predicts pathogenic folding instability. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | -9.813 | Likely Pathogenic | 0.794 | Likely Pathogenic | Ambiguous | 2.99 | Destabilizing | 0.9 | 1.70 | Ambiguous | 2.35 | Destabilizing | 0.69 | Ambiguous | 0.415 | Likely Benign | -8.35 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.45 | Benign | 0.16 | Tolerated | 0.2905 | 0.1128 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.1553A>T | Y518F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 Y518F missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools are uncertain: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of individual predictors (seven benign vs. four pathogenic) support a benign classification, and this does not contradict the ClinVar status, which has no entry for this variant. Thus, based on the available predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | -10.617 | Likely Pathogenic | 0.466 | Ambiguous | Likely Benign | 0.34 | Likely Benign | 0.1 | -0.61 | Ambiguous | -0.14 | Likely Benign | 0.41 | Likely Benign | 0.318 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.50 | Benign | 0.22 | Tolerated | 0.2107 | 0.2230 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||
| c.1555G>A | E519K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519K missense variant is listed in gnomAD (ID 6‑33438798‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by FoldX, 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 E519K, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | 6-33438798-G-A | 1 | 6.20e-7 | -13.532 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | -0.55 | Ambiguous | 0.0 | -0.60 | Ambiguous | -0.58 | Ambiguous | 0.06 | Likely Benign | 0.328 | Likely Benign | -3.48 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | 3.28 | Benign | 0.03 | Affected | 3.37 | 35 | 0.2545 | 0.3379 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.1555G>C | E519Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a benign effect on protein stability. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -8.693 | Likely Pathogenic | 0.792 | Likely Pathogenic | Ambiguous | -0.35 | Likely Benign | 0.1 | -0.14 | Likely Benign | -0.25 | Likely Benign | -0.21 | Likely Benign | 0.195 | Likely Benign | -2.48 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 3.28 | Benign | 0.14 | Tolerated | 0.1394 | 0.3418 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.1556A>C | E519A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519A missense variant is listed in ClinVar as Pathogenic (ClinVar ID 1029087.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, SIFT, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, ESM1b, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Uncertain predictions from Rosetta and AlphaMissense‑Optimized are treated as unavailable. High‑accuracy results are: AlphaMissense‑Optimized – unavailable; SGM‑Consensus – Pathogenic; Foldetta – Benign. Overall, the predictions are balanced, but the high‑accuracy Foldetta result leans toward benign while the consensus leans toward pathogenic, leaving the assessment inconclusive. Based on the available predictions, the variant is most likely benign, contradicting the ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | Likely Pathogenic | 1 | -8.557 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | -0.05 | Likely Benign | 0.0 | 0.55 | Ambiguous | 0.25 | Likely Benign | 0.00 | Likely Benign | 0.384 | Likely Benign | -5.23 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.33 | Benign | 0.10 | Tolerated | 3.37 | 35 | 0.3544 | 0.3545 | 0 | -1 | 5.3 | -58.04 | 162.4 | 83.5 | -0.1 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | Glu519 is located at the beginning of an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the carboxylate side chain of Glu519 does not make any specific interactions. Accordingly, the Ala residue swap does not show any negative structural effects in the variant simulations. However, it should be noted that Glu519 faces the missing part of the N-terminal in the model, and thus its potential role in maintaining the tertiary structure might be de-emphasized in the current model. | ||||||||||||||||
| c.1556A>G | E519G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519G 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 REVEL, FoldX, FATHMM, and premPS. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments: AlphaMissense‑Optimized is uncertain; SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; Foldetta is uncertain. Overall, the majority of available predictions (7 pathogenic vs. 4 benign) lean toward a pathogenic 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 Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -10.835 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.22 | Likely Benign | 0.1 | 0.92 | Ambiguous | 0.57 | Ambiguous | 0.22 | Likely Benign | 0.458 | Likely Benign | -6.12 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.21 | Benign | 0.01 | Affected | 0.2729 | 0.3471 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1556A>T | E519V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight the discord: 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) indicates benign stability. Overall, the preponderance of evidence points to a pathogenic effect for E519V. This conclusion does not conflict with ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -10.513 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.59 | Ambiguous | 0.0 | -0.40 | Likely Benign | 0.10 | Likely Benign | 0.16 | Likely Benign | 0.400 | Likely Benign | -6.33 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | 3.20 | Benign | 0.00 | Affected | 0.0825 | 0.4369 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1557A>C | E519D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With seven benign predictions versus six pathogenic ones, the overall evidence slightly favors a benign classification. This conclusion does not contradict the ClinVar status, which contains no pathogenic assertion for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -8.009 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 0.24 | Likely Benign | 0.0 | 0.40 | Likely Benign | 0.32 | Likely Benign | 0.05 | Likely Benign | 0.183 | Likely Benign | -2.62 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 3.31 | Benign | 0.07 | Tolerated | 0.2088 | 0.1824 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1557A>T | E519D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E519D is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating a likely pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign effect. Overall, the majority of tools, including the high‑accuracy methods, lean toward a benign interpretation. This consensus does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -8.009 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 0.24 | Likely Benign | 0.0 | 0.40 | Likely Benign | 0.32 | Likely Benign | 0.05 | Likely Benign | 0.182 | Likely Benign | -2.62 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 3.31 | Benign | 0.07 | Tolerated | 0.2088 | 0.1824 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1558T>A | S520T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520T is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from premPS and PROVEAN, while pathogenic predictions are made by SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Four high‑accuracy methods were examined: AlphaMissense‑Optimized returned an uncertain result; 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, was also uncertain. With three of the four high‑accuracy tools indicating pathogenicity and only two tools suggesting benign, the overall evidence points to 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 | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -8.432 | Likely Pathogenic | 0.822 | Likely Pathogenic | Ambiguous | 0.52 | Ambiguous | 0.0 | 0.52 | Ambiguous | 0.52 | Ambiguous | 0.34 | Likely Benign | 0.565 | Likely Pathogenic | -2.41 | Neutral | 0.826 | Possibly Damaging | 0.872 | Possibly Damaging | -1.28 | Pathogenic | 0.02 | Affected | 0.1296 | 0.5199 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1558T>C | S520P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520P 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome, while premPS remains inconclusive. 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, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Overall, the evidence strongly supports a pathogenic impact for S520P, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | Uncertain | 1 | -12.707 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.72 | Destabilizing | 0.8 | 8.86 | Destabilizing | 6.29 | Destabilizing | 0.83 | Ambiguous | 0.855 | Likely Pathogenic | -4.57 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 0.2154 | 0.4776 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||
| c.1558T>G | S520A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S520A missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized, whereas a larger group—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. The premPS score 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. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy consensus is split, but the pathogenic predictions dominate. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -8.417 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | 0.03 | Likely Benign | 0.2 | 0.19 | Likely Benign | 0.11 | Likely Benign | 0.56 | Ambiguous | 0.523 | Likely Pathogenic | -2.55 | Deleterious | 0.944 | Possibly Damaging | 0.987 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 0.4887 | 0.3636 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1559C>A | S520Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520Y 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 algorithms predict pathogenicity: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give inconclusive results: FoldX (Uncertain) and premPS (Uncertain). High‑accuracy assessments further support a mixed signal: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -13.124 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | -0.93 | Ambiguous | 0.4 | 0.16 | Likely Benign | -0.39 | Likely Benign | 0.59 | Ambiguous | 0.814 | Likely Pathogenic | -5.57 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.36 | Pathogenic | 0.00 | Affected | 0.0743 | 0.4563 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.1559C>G | S520C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520C is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX, Foldetta, and ESM1b, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default; Rosetta, premPS, and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -6.947 | Likely Benign | 0.917 | Likely Pathogenic | Ambiguous | 0.05 | Likely Benign | 0.2 | 0.76 | Ambiguous | 0.41 | Likely Benign | 0.53 | Ambiguous | 0.720 | Likely Pathogenic | -4.57 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.36 | Pathogenic | 0.03 | Affected | 0.1029 | 0.4948 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.1559C>T | S520F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include Rosetta, Foldetta, and premPS. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX gives an uncertain result. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign impact. 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 | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | Uncertain | 1 | -12.541 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | -1.20 | Ambiguous | 0.4 | 0.39 | Likely Benign | -0.41 | Likely Benign | 0.25 | Likely Benign | 0.833 | Likely Pathogenic | -5.57 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.36 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.0668 | 0.4779 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||||||
| c.155C>G | S52W 2D  AIThe SynGAP1 missense variant S52W is 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, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Overall, more tools (five) predict pathogenicity than benign (three), and no high‑accuracy consensus or folding‑stability evidence contradicts this trend. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not conflict with 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. | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -8.649 | Likely Pathogenic | 0.909 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.85 | Neutral | 0.986 | Probably Damaging | 0.968 | Probably Damaging | 4.05 | Benign | 0.00 | Affected | 0.0580 | 0.6254 | -2 | -3 | -0.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.155C>T | S52L 2D AISynGAP1 missense variant S52L is listed in ClinVar with an uncertain significance and is present in the gnomAD database (ID 6‑33423564‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the collective evidence points to a likely 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. | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | Uncertain | 1 | 6-33423564-C-T | 1 | 6.20e-7 | -7.199 | In-Between | 0.688 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -1.41 | Neutral | 0.829 | Possibly Damaging | 0.706 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0991 | 0.6100 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||
| c.1561G>A | E521K 2D 3DClick to see structure in 3D Viewer AISynGAP1 E521K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give mixed results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. Overall, the majority of conventional tools lean toward a benign interpretation, while the high‑accuracy methods are split. Thus, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -9.596 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | -0.48 | Likely Benign | 0.2 | 0.14 | Likely Benign | -0.17 | Likely Benign | -0.10 | Likely Benign | 0.379 | Likely Benign | -3.05 | Deleterious | 0.994 | Probably Damaging | 0.994 | Probably Damaging | 3.57 | Benign | 0.45 | Tolerated | 0.2895 | 0.6513 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1561G>C | E521Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E521Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta predicts a benign stability change. Overall, the majority of evidence (9 benign vs. 4 pathogenic predictions) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -8.310 | Likely Pathogenic | 0.777 | Likely Pathogenic | Likely Benign | -0.28 | Likely Benign | 0.2 | 0.19 | Likely Benign | -0.05 | Likely Benign | -0.06 | Likely Benign | 0.262 | Likely Benign | -2.15 | Neutral | 0.992 | Probably Damaging | 0.993 | Probably Damaging | 3.30 | Benign | 0.11 | Tolerated | 0.1580 | 0.6552 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.1562A>C | E521A 2D 3DClick to see structure in 3D Viewer AISynGAP1 E521A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign calls (REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM) and pathogenic calls (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). AlphaMissense‑Optimized is uncertain. High‑accuracy assessments give conflicting results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. No prediction or stability result is missing. Overall, the evidence is evenly split, with six benign and six pathogenic calls, and the two high‑accuracy tools disagree. Therefore, the variant’s impact remains uncertain; it is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -8.997 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.18 | Likely Benign | 0.1 | 0.40 | Likely Benign | 0.29 | Likely Benign | 0.11 | Likely Benign | 0.395 | Likely Benign | -4.12 | Deleterious | 0.998 | Probably Damaging | 0.999 | Probably Damaging | 3.28 | Benign | 0.13 | Tolerated | 0.4041 | 0.5918 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1562A>G | E521G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E521G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it is a 2‑vs‑2 split and is treated as unavailable. Overall, the majority of evidence points to a benign impact. The variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -6.636 | Likely Benign | 0.767 | Likely Pathogenic | Likely Benign | 0.18 | Likely Benign | 0.1 | 0.58 | Ambiguous | 0.38 | Likely Benign | 0.14 | Likely Benign | 0.289 | Likely Benign | -3.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.31 | Benign | 0.07 | Tolerated | 0.2932 | 0.5455 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||
| c.1562A>T | E521V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E521V missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized score is pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the majority of evidence points to a pathogenic impact for E521V, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -10.297 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.31 | Likely Benign | 0.1 | 0.49 | Likely Benign | 0.40 | Likely Benign | 0.21 | Likely Benign | 0.413 | Likely Benign | -5.15 | Deleterious | 0.995 | Probably Damaging | 0.996 | Probably Damaging | 3.26 | Benign | 0.05 | Affected | 0.0913 | 0.7104 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1563G>C | E521D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change E521D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as Benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a Benign effect. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -4.963 | Likely Benign | 0.372 | Ambiguous | Likely Benign | 0.13 | Likely Benign | 0.0 | 0.17 | Likely Benign | 0.15 | Likely Benign | -0.29 | Likely Benign | 0.227 | Likely Benign | 1.07 | Neutral | 0.986 | Probably Damaging | 0.989 | Probably Damaging | 3.40 | Benign | 0.92 | Tolerated | 0.2026 | 0.3721 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1563G>T | E521D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E521D missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. Only two tools—polyPhen‑2 HumDiv and HumVar—predict a pathogenic outcome. The high‑accuracy methods give a consistent benign signal: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -4.963 | Likely Benign | 0.372 | Ambiguous | Likely Benign | 0.13 | Likely Benign | 0.0 | 0.17 | Likely Benign | 0.15 | Likely Benign | -0.29 | Likely Benign | 0.227 | Likely Benign | 1.07 | Neutral | 0.986 | Probably Damaging | 0.989 | Probably Damaging | 3.40 | Benign | 0.92 | Tolerated | 0.2026 | 0.3721 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1564G>A | E522K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E522K has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from Rosetta, Foldetta, premPS, and SIFT, while pathogenic calls are made by REVEL, PROVEAN, both polyPhen‑2 versions, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further indicate AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus also predicts Likely Pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts Benign. No prediction is available from FoldX (Uncertain). Overall, the majority of high‑confidence tools lean toward pathogenicity, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.046216 | Uncertain | 0.823 | 0.376 | 0.000 | -12.637 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | -0.69 | Ambiguous | 0.1 | 0.14 | Likely Benign | -0.28 | Likely Benign | -0.13 | Likely Benign | 0.631 | Likely Pathogenic | -3.81 | Deleterious | 0.994 | Probably Damaging | 0.994 | Probably Damaging | -1.09 | Pathogenic | 0.23 | Tolerated | 0.2019 | 0.4291 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1564G>C | E522Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E522Q is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools show a split: benign predictions come from FoldX, Rosetta, Foldetta, premPS, and SIFT, whereas pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods reinforce this pattern: AlphaMissense‑Optimized classifies the change as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also labels it likely pathogenic, while Foldetta predicts a benign effect on protein stability. Overall, the majority of evidence points to a pathogenic impact. This assessment does not conflict with ClinVar, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.046216 | Uncertain | 0.823 | 0.376 | 0.000 | -10.861 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | -0.13 | Likely Benign | 0.1 | -0.06 | Likely Benign | -0.10 | Likely Benign | 0.03 | Likely Benign | 0.560 | Likely Pathogenic | -2.85 | Deleterious | 0.992 | Probably Damaging | 0.993 | Probably Damaging | -1.33 | Pathogenic | 0.07 | Tolerated | 0.0944 | 0.4130 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1565A>C | E522A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E522A is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the preponderance of evidence (10 pathogenic vs. 4 benign predictions) indicates that E522A is most likely pathogenic, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.046216 | Uncertain | 0.823 | 0.376 | 0.000 | -10.509 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.18 | Likely Benign | 0.1 | 0.01 | Likely Benign | 0.10 | Likely Benign | 0.40 | Likely Benign | 0.739 | Likely Pathogenic | -5.67 | Deleterious | 0.998 | Probably Damaging | 0.999 | Probably Damaging | -1.34 | Pathogenic | 0.02 | Affected | 0.3137 | 0.4128 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1565A>G | E522G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E522G missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as deleterious. No tool reports a benign outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a damaging effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, while Foldetta’s stability analysis is inconclusive. FoldX, Rosetta, and premPS are uncertain and are treated as unavailable evidence. Overall, the computational evidence overwhelmingly points to a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.046216 | Uncertain | 0.823 | 0.376 | 0.000 | -10.053 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.0 | 1.62 | Ambiguous | 1.17 | Ambiguous | 0.58 | Ambiguous | 0.823 | Likely Pathogenic | -6.59 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.34 | Pathogenic | 0.01 | Affected | 0.2672 | 0.3654 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1565A>T | E522V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E522V missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.046216 | Uncertain | 0.823 | 0.376 | 0.000 | -11.985 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.09 | Likely Benign | 0.2 | 0.00 | Likely Benign | 0.05 | Likely Benign | 0.18 | Likely Benign | 0.751 | Likely Pathogenic | -6.59 | Deleterious | 0.995 | Probably Damaging | 0.996 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 0.0537 | 0.4514 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1566A>C | E522D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E522D missense variant is not reported in ClinVar and has no gnomAD entry. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and ESM1b, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, indicates a benign effect. Overall, the balance of evidence points to a likely pathogenic impact for E522D, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.046216 | Uncertain | 0.823 | 0.376 | 0.000 | -5.385 | Likely Benign | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.04 | Likely Benign | 0.1 | -0.02 | Likely Benign | 0.01 | Likely Benign | 0.32 | Likely Benign | 0.494 | Likely Benign | -2.65 | Deleterious | 0.986 | Probably Damaging | 0.989 | Probably Damaging | -1.33 | Pathogenic | 0.10 | Tolerated | 0.1499 | 0.2765 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1566A>T | E522D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E522D missense variant is not reported in ClinVar and has no gnomAD entry. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and ESM1b, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, indicates a benign effect. Overall, the balance of evidence points to a likely pathogenic impact for E522D, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.046216 | Uncertain | 0.823 | 0.376 | 0.000 | -5.385 | Likely Benign | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.04 | Likely Benign | 0.1 | -0.02 | Likely Benign | 0.01 | Likely Benign | 0.32 | Likely Benign | 0.494 | Likely Benign | -2.65 | Deleterious | 0.986 | Probably Damaging | 0.989 | Probably Damaging | -1.33 | Pathogenic | 0.10 | Tolerated | 0.1499 | 0.2765 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1567A>C | N523H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523H is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect are Rosetta and Foldetta, while the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Uncertain results come from FoldX, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta as Benign. Overall, the preponderance of evidence points to a pathogenic effect for this variant, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -9.755 | Likely Pathogenic | 0.815 | Likely Pathogenic | Ambiguous | 0.56 | Ambiguous | 0.2 | 0.09 | Likely Benign | 0.33 | Likely Benign | 0.64 | Ambiguous | 0.694 | Likely Pathogenic | -4.52 | Deleterious | 0.996 | Probably Damaging | 0.941 | Probably Damaging | -1.40 | Pathogenic | 0.02 | Affected | 0.1132 | 0.3461 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.1567A>G | N523D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 N523D missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the predictions are mixed, but the majority of high‑confidence tools lean toward pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -8.955 | Likely Pathogenic | 0.641 | Likely Pathogenic | Likely Benign | 0.14 | Likely Benign | 0.2 | 1.10 | Ambiguous | 0.62 | Ambiguous | 0.56 | Ambiguous | 0.272 | Likely Benign | -3.57 | Deleterious | 0.112 | Benign | 0.079 | Benign | -1.25 | Pathogenic | 0.22 | Tolerated | 0.1553 | 0.1866 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1567A>T | N523Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523Y is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX, premPS, and SIFT. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. With eight tools supporting pathogenicity versus three supporting benign, the overall evidence points to a likely pathogenic impact. This conclusion is consistent with the absence of a ClinVar classification, as no contradictory status exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -11.701 | Likely Pathogenic | 0.836 | Likely Pathogenic | Ambiguous | 0.13 | Likely Benign | 0.3 | -1.36 | Ambiguous | -0.62 | Ambiguous | -0.01 | Likely Benign | 0.624 | Likely Pathogenic | -7.34 | Deleterious | 0.999 | Probably Damaging | 0.972 | Probably Damaging | -1.39 | Pathogenic | 0.10 | Tolerated | 0.0586 | 0.3388 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.1568A>C | N523T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523T is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. Tools that predict pathogenicity are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The premPS score is uncertain and does not contribute to the consensus. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding result is missing or inconclusive. Overall, the majority of tools (10/14) predict pathogenicity, whereas four predict benign. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -10.056 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | 0.47 | Likely Benign | 0.2 | -0.22 | Likely Benign | 0.13 | Likely Benign | 0.65 | Ambiguous | 0.646 | Likely Pathogenic | -5.33 | Deleterious | 0.898 | Possibly Damaging | 0.592 | Possibly Damaging | -1.40 | Pathogenic | 0.02 | Affected | 0.0920 | 0.3780 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.1568A>G | N523S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and FATHMM. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) returned uncertain or inconclusive results. For high‑accuracy assessment, AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports an uncertain folding‑stability change. Taken together, the majority of evidence (five benign versus three pathogenic predictions) points to a benign effect, and this conclusion does not contradict any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -6.188 | Likely Benign | 0.552 | Ambiguous | Likely Benign | 0.64 | Ambiguous | 0.2 | 0.66 | Ambiguous | 0.65 | Ambiguous | 0.17 | Likely Benign | 0.492 | Likely Benign | -4.31 | Deleterious | 0.976 | Probably Damaging | 0.410 | Benign | -1.27 | Pathogenic | 0.27 | Tolerated | 0.2213 | 0.4178 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||
| c.1568A>T | N523I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N523I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools report uncertain results: Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—indicates pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains inconclusive. Overall, the preponderance of evidence (eight pathogenic versus three benign predictions) suggests that the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -12.862 | Likely Pathogenic | 0.761 | Likely Pathogenic | Likely Benign | 0.26 | Likely Benign | 0.2 | -1.53 | Ambiguous | -0.64 | Ambiguous | 0.33 | Likely Benign | 0.726 | Likely Pathogenic | -8.18 | Deleterious | 0.989 | Probably Damaging | 0.946 | Probably Damaging | -1.42 | Pathogenic | 0.00 | Affected | 0.0627 | 0.3714 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.1569C>A | N523K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523K is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX and Foldetta, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome. Uncertain results are reported only by Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Taken together, the preponderance of evidence supports a pathogenic classification for this variant, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -12.276 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | -0.17 | Likely Benign | 0.2 | -0.58 | Ambiguous | -0.38 | Likely Benign | 0.73 | Ambiguous | 0.607 | Likely Pathogenic | -5.35 | Deleterious | 0.972 | Probably Damaging | 0.728 | Possibly Damaging | -1.30 | Pathogenic | 0.04 | Affected | 0.1837 | 0.2866 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1569C>G | N523K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523K is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX and Foldetta, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome. Uncertain results are reported only by Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Taken together, the preponderance of evidence supports a pathogenic classification for this variant, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -12.276 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | -0.17 | Likely Benign | 0.2 | -0.58 | Ambiguous | -0.38 | Likely Benign | 0.73 | Ambiguous | 0.607 | Likely Pathogenic | -5.35 | Deleterious | 0.972 | Probably Damaging | 0.728 | Possibly Damaging | -1.30 | Pathogenic | 0.04 | Affected | 0.1837 | 0.2866 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1570T>A | C524S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524S is listed in gnomAD (variant ID 6‑33438813‑T‑A) but has no ClinVar entry. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome, while FoldX, Rosetta, and Foldetta are uncertain and therefore not counted as evidence. Grouping by agreement yields a benign‑prediction set that is empty and a pathogenic‑prediction set that contains the eleven tools above. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta remains uncertain. Consequently, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.024729 | Uncertain | 0.916 | 0.385 | 0.125 | 6-33438813-T-A | 1 | 6.20e-7 | -11.174 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.1 | 1.55 | Ambiguous | 1.18 | Ambiguous | 1.58 | Destabilizing | 0.915 | Likely Pathogenic | -9.94 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.38 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.5362 | 0.1848 | Weaken | -1 | 0 | -3.3 | -16.06 | |||||||||||||||||||||||
| c.1570T>C | C524R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524R is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Across the evaluated in‑silico tools, all pathogenic‑predicating algorithms—REVEL, SGM‑Consensus, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—return a pathogenic or likely pathogenic verdict. The only tool with an inconclusive result is FoldX, which is treated as unavailable. High‑accuracy predictors reinforce this assessment: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.024729 | Uncertain | 0.916 | 0.385 | 0.125 | -14.337 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | -0.53 | Ambiguous | 0.5 | 9.04 | Destabilizing | 4.26 | Destabilizing | 1.62 | Destabilizing | 0.917 | Likely Pathogenic | -11.93 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.40 | Pathogenic | 0.00 | Affected | 0.2031 | 0.1463 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.1570T>G | C524G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change at residue 524 (C524G) is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while FoldX and Foldetta are uncertain. No tool predicts a benign effect. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, remains uncertain. Overall, the evidence strongly favors a pathogenic impact for C524G, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.024729 | Uncertain | 0.916 | 0.385 | 0.125 | -13.597 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 1.07 | Ambiguous | 0.2 | 2.00 | Destabilizing | 1.54 | Ambiguous | 1.66 | Destabilizing | 0.924 | Likely Pathogenic | -11.93 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.40 | Pathogenic | 0.00 | Affected | 0.3579 | 0.2745 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.1571G>A | C524Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic, while premPS is the sole tool predicting a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. With the overwhelming majority of evidence pointing to a damaging effect and no ClinVar annotation to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.024729 | Uncertain | 0.916 | 0.385 | 0.125 | -11.032 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.20 | Destabilizing | 1.4 | 6.24 | Destabilizing | 4.72 | Destabilizing | 0.18 | Likely Benign | 0.863 | Likely Pathogenic | -10.94 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.36 | Pathogenic | 0.00 | Affected | 0.1496 | 0.3911 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1571G>C | C524S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 C524S variant has no ClinVar entry and is not present in gnomAD. Prediction tools that agree on a benign effect are none; those that predict pathogenicity include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta returned inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.024729 | Uncertain | 0.916 | 0.385 | 0.125 | -11.174 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.1 | 1.55 | Ambiguous | 1.18 | Ambiguous | 1.58 | Destabilizing | 0.904 | Likely Pathogenic | -9.94 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.38 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.5362 | 0.1848 | Weaken | -1 | 0 | -3.3 | -16.06 | ||||||||||||||||||||||||||
| c.1571G>T | C524F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524F is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic, while only premPS predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized reports pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.024729 | Uncertain | 0.916 | 0.385 | 0.125 | -12.145 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.18 | Destabilizing | 1.4 | 5.20 | Destabilizing | 3.69 | Destabilizing | -0.04 | Likely Benign | 0.831 | Likely Pathogenic | -10.94 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.22 | Pathogenic | 0.05 | Affected | 0.1678 | 0.4259 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.1572C>G | C524W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524W is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: benign predictions are absent, while pathogenic predictions are made by REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.024729 | Uncertain | 0.916 | 0.385 | 0.125 | -12.351 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.03 | Destabilizing | 1.2 | 9.88 | Destabilizing | 6.46 | Destabilizing | 0.93 | Ambiguous | 0.675 | Likely Pathogenic | -10.94 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.41 | Pathogenic | 0.00 | Affected | 0.1953 | 0.3920 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1573G>A | E525K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E525K is reported in gnomAD (ID 6‑33438816‑G‑A) but has no ClinVar entry. Functional prediction tools show a split assessment: benign predictions come from FoldX, Rosetta, Foldetta, and FATHMM, whereas pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as pathogenic, the SGM‑Consensus also indicates likely pathogenic, while the Foldetta stability analysis predicts a benign effect. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | 6-33438816-G-A | 1 | 6.20e-7 | -15.628 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | -0.13 | Likely Benign | 0.5 | 0.34 | Likely Benign | 0.11 | Likely Benign | 0.96 | Ambiguous | 0.629 | Likely Pathogenic | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 2.71 | Benign | 0.00 | Affected | 3.37 | 35 | 0.2349 | 0.4293 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.1573G>C | E525Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E525Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely disagree: benign predictions come from Rosetta, Foldetta, and FATHMM, while pathogenic predictions are returned by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta) as benign. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -13.722 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 1.05 | Ambiguous | 0.7 | -0.11 | Likely Benign | 0.47 | Likely Benign | 0.84 | Ambiguous | 0.516 | Likely Pathogenic | -2.98 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 2.68 | Benign | 0.00 | Affected | 0.1173 | 0.3962 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1574A>C | E525A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E525A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Foldetta, premPS, and FATHMM, whereas the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic effect. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the preponderance of evidence from both general and high‑accuracy tools points to a pathogenic classification for E525A, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -12.627 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 1.23 | Ambiguous | 0.6 | -0.62 | Ambiguous | 0.31 | Likely Benign | 0.09 | Likely Benign | 0.680 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.68 | Benign | 0.00 | Affected | 0.3554 | 0.3960 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1574A>G | E525G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E525G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized returns a pathogenic score, the SGM‑Consensus also indicates pathogenicity, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. Taken together, the overwhelming majority of evidence points to a pathogenic impact for E525G. This conclusion is consistent with the absence of ClinVar annotation and gnomAD data, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -13.181 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.71 | Ambiguous | 0.6 | 0.90 | Ambiguous | 1.31 | Ambiguous | 0.78 | Ambiguous | 0.691 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.68 | Benign | 0.00 | Affected | 0.2947 | 0.3886 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1574A>T | E525V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E525V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Foldetta, premPS, and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome; FoldX and Rosetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic effect for E525V, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -13.622 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 1.10 | Ambiguous | 0.7 | -0.69 | Ambiguous | 0.21 | Likely Benign | 0.00 | Likely Benign | 0.683 | Likely Pathogenic | -6.96 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 0.0721 | 0.4946 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1575G>C | E525D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E525D missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and Foldetta, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta provide uncertain results and are therefore not used to weigh the overall assessment. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic, while Foldetta predicts benign. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic effect for E525D. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -11.207 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.78 | Ambiguous | 0.6 | -0.55 | Ambiguous | 0.12 | Likely Benign | 1.00 | Destabilizing | 0.362 | Likely Benign | -2.98 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 2.90 | Benign | 0.00 | Affected | 0.1876 | 0.2197 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1575G>T | E525D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E525D missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and Foldetta, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta provide uncertain results and are not counted as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as benign. Overall, the balance of evidence (nine pathogenic versus three benign predictions) indicates that the variant is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -11.207 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.78 | Ambiguous | 0.6 | -0.55 | Ambiguous | 0.12 | Likely Benign | 1.00 | Destabilizing | 0.362 | Likely Benign | -2.98 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 2.90 | Benign | 0.00 | Affected | 0.1876 | 0.2197 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1576G>A | V526I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V526I variant is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33438819‑G‑A). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of tools (seven benign vs. five pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current predictions, and this assessment does not contradict the ClinVar status, which has no entry for V526I. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.139895 | Structured | 0.023118 | Uncertain | 0.943 | 0.403 | 0.000 | 6-33438819-G-A | -9.962 | Likely Pathogenic | 0.526 | Ambiguous | Likely Benign | 0.07 | Likely Benign | 0.3 | 0.41 | Likely Benign | 0.24 | Likely Benign | 0.02 | Likely Benign | 0.540 | Likely Pathogenic | -0.99 | Neutral | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | -1.34 | Pathogenic | 0.15 | Tolerated | 3.37 | 35 | 0.0630 | 0.3307 | 3 | 4 | 0.3 | 14.03 | |||||||||||||||||||||||||||
| c.1576G>C | V526L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V526L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and SIFT, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for V526L, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.023118 | Uncertain | 0.943 | 0.403 | 0.000 | -9.289 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 1.31 | Ambiguous | 0.5 | 1.74 | Ambiguous | 1.53 | Ambiguous | 0.38 | Likely Benign | 0.643 | Likely Pathogenic | -2.97 | Deleterious | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | -1.16 | Pathogenic | 0.17 | Tolerated | 0.0754 | 0.3894 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1576G>T | V526L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V526L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and SIFT, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for V526L, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.023118 | Uncertain | 0.943 | 0.403 | 0.000 | -9.289 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 1.31 | Ambiguous | 0.5 | 1.74 | Ambiguous | 1.53 | Ambiguous | 0.38 | Likely Benign | 0.643 | Likely Pathogenic | -2.97 | Deleterious | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | -1.16 | Pathogenic | 0.17 | Tolerated | 0.0754 | 0.3894 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1577T>A | V526E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V526E is not listed in ClinVar and has no reported allele in gnomAD. In silico prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Because all available evidence points to a damaging effect and there is no conflicting ClinVar annotation or population frequency data, the variant is most likely pathogenic. This conclusion aligns with the absence of ClinVar status and gnomAD entries, indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.023118 | Uncertain | 0.943 | 0.403 | 0.000 | -16.080 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 5.19 | Destabilizing | 0.3 | 5.12 | Destabilizing | 5.16 | Destabilizing | 2.32 | Destabilizing | 0.962 | Likely Pathogenic | -5.94 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.46 | Pathogenic | 0.00 | Affected | 0.0766 | 0.1326 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.1577T>C | V526A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V526A is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all agree that the variant is deleterious: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify it as pathogenic or likely pathogenic. No tool predicts a benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized is uncertain, SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Based on the overwhelming consensus of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.023118 | Uncertain | 0.943 | 0.403 | 0.000 | -12.055 | Likely Pathogenic | 0.852 | Likely Pathogenic | Ambiguous | 2.30 | Destabilizing | 0.1 | 2.49 | Destabilizing | 2.40 | Destabilizing | 2.05 | Destabilizing | 0.908 | Likely Pathogenic | -3.93 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.44 | Pathogenic | 0.00 | Affected | 0.2224 | 0.1922 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1577T>G | V526G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V526G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on pathogenicity include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; no tool predicts it benign. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. All available evidence points to a deleterious effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.139895 | Structured | 0.023118 | Uncertain | 0.943 | 0.403 | 0.000 | -15.811 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 3.21 | Destabilizing | 0.3 | 4.79 | Destabilizing | 4.00 | Destabilizing | 2.19 | Destabilizing | 0.935 | Likely Pathogenic | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.49 | Pathogenic | 0.00 | Affected | 0.1636 | 0.1837 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1579G>A | D527N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D527N missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas a majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. The high‑accuracy consensus methods give mixed results: AlphaMissense‑Optimized is uncertain, SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign outcome. Overall, the preponderance of evidence points toward a pathogenic effect, and this assessment does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -12.645 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.31 | Likely Benign | 1.0 | 0.09 | Likely Benign | 0.20 | Likely Benign | 0.22 | Likely Benign | 0.730 | Likely Pathogenic | -4.87 | Deleterious | 0.992 | Probably Damaging | 0.990 | Probably Damaging | -2.13 | Pathogenic | 0.01 | Affected | 0.0910 | 0.3754 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1579G>C | D527H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D527H is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX and premPS, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. Uncertain results come from Rosetta and Foldetta. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as pathogenic, and Foldetta as inconclusive. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -13.334 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 1.2 | 1.26 | Ambiguous | 0.83 | Ambiguous | 0.49 | Likely Benign | 0.901 | Likely Pathogenic | -6.80 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -2.39 | Pathogenic | 0.00 | Affected | 0.1092 | 0.4346 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1579G>T | D527Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D527Y is listed in ClinVar with an uncertain significance (ClinVar ID 1698369.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: the single benign prediction from premPS versus a consensus of pathogenic predictions from the remaining 12 tools (REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Protein‑stability calculations from FoldX and Rosetta are also uncertain. Overall, the preponderance of evidence indicates that D527Y is most likely pathogenic, which does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | Uncertain | 1 | -15.386 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | -0.77 | Ambiguous | 0.2 | 1.89 | Ambiguous | 0.56 | Ambiguous | -0.14 | Likely Benign | 0.905 | Likely Pathogenic | -8.79 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -2.41 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.0554 | 0.4229 | -4 | -3 | 2.2 | 48.09 | 270.9 | -45.7 | 0.1 | 0.1 | -0.1 | 0.0 | X | Potentially Pathogenic | Asp527 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the carboxylate group of the Asp527 side chain forms hydrogen bonds with the backbone atoms of loop residues (e.g., Ile529, Lys530) facing the membrane surface. In the variant simulations, Tyr527 is a bulkier residue that faces away from the loop and stacks with Phe646 in a nearby α-helix (res. Ser614-Ser668). Regardless, no negative structural effects are observed during the variant simulations. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||||||||
| c.157G>A | G53R 2D AIThe SynGAP1 missense variant G53R is 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, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic + 2 benign), and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable. Overall, the majority of available predictions (5 pathogenic vs. 3 benign) lean toward a pathogenic impact. Because there is no ClinVar entry to contradict this assessment, 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. | 0.268042 | Structured | 0.460894 | Uncertain | 0.386 | 0.666 | 0.000 | -8.400 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -1.20 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 4.13 | Benign | 0.00 | Affected | 0.0953 | 0.4347 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.157G>C | G53R 2D AIThe SynGAP1 missense variant G53R is 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, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic + 2 benign), and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable. Overall, the majority of tools (5 pathogenic vs. 3 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 the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.268042 | Structured | 0.460894 | Uncertain | 0.386 | 0.666 | 0.000 | -8.400 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -1.20 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 4.13 | Benign | 0.00 | Affected | 0.0953 | 0.4347 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.157G>T | G53W 2D  AIThe SynGAP1 missense variant G53W is 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. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of available predictions (six pathogenic vs. three benign) indicate 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. | 0.268042 | Structured | 0.460894 | Uncertain | 0.386 | 0.666 | 0.000 | -11.012 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.243 | Likely Benign | -1.69 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 4.08 | Benign | 0.00 | Affected | 0.0678 | 0.5071 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.1580A>C | D527A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D527A missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS, while the remaining evaluated methods (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict pathogenicity. FoldX, Rosetta, and Foldetta are inconclusive and are treated as unavailable. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta remains uncertain. Overall, the variant is most likely pathogenic based on the consensus of predictive tools, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -15.473 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.9 | 1.75 | Ambiguous | 1.28 | Ambiguous | -0.24 | Likely Benign | 0.929 | Likely Pathogenic | -7.79 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -2.39 | Pathogenic | 0.00 | Affected | 0.2850 | 0.3799 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1580A>G | D527G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D527G is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools cluster into two groups: the single benign prediction comes from premPS, while all other evaluated algorithms—SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—indicate pathogenicity. FoldX is uncertain and therefore not counted as evidence for either side. High‑accuracy methods reinforce the pathogenic assessment: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No contradictory evidence exists in ClinVar. **Thus, the variant is most likely pathogenic based on the collective predictions, with no ClinVar status to contradict this assessment.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -15.177 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.71 | Ambiguous | 1.0 | 4.22 | Destabilizing | 2.97 | Destabilizing | 0.33 | Likely Benign | 0.933 | Likely Pathogenic | -6.86 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -2.39 | Pathogenic | 0.01 | Affected | 0.2847 | 0.4366 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1580A>T | D527V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D527V missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that are uncertain (FoldX, Rosetta, Foldetta, premPS) provide no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, while Foldetta remains uncertain. Overall, the majority of reliable predictors classify the variant as pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Thus, based on current computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -16.844 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.71 | Ambiguous | 0.7 | 0.84 | Ambiguous | 0.78 | Ambiguous | -0.55 | Ambiguous | 0.938 | Likely Pathogenic | -8.78 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | -2.40 | Pathogenic | 0.00 | Affected | 0.0659 | 0.3984 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1581C>A | D527E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D527E missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a strong bias toward pathogenicity: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a deleterious effect, whereas only FoldX and premPS predict a benign outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain, and the SGM Consensus remains Likely Pathogenic. Overall, the preponderance of evidence points to a pathogenic impact, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -11.125 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.36 | Likely Benign | 0.8 | 2.29 | Destabilizing | 1.33 | Ambiguous | 0.50 | Likely Benign | 0.740 | Likely Pathogenic | -3.74 | Deleterious | 0.929 | Possibly Damaging | 0.938 | Probably Damaging | -2.31 | Pathogenic | 0.02 | Affected | 0.1103 | 0.3428 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1581C>G | D527E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D527E missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a strong bias toward pathogenicity: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a deleterious effect, whereas only FoldX and premPS predict a benign outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain, and the SGM Consensus remains Likely Pathogenic. Overall, the preponderance of evidence points to a pathogenic impact, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -11.125 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.36 | Likely Benign | 0.8 | 2.29 | Destabilizing | 1.33 | Ambiguous | 0.50 | Likely Benign | 0.740 | Likely Pathogenic | -3.74 | Deleterious | 0.929 | Possibly Damaging | 0.938 | Probably Damaging | -2.31 | Pathogenic | 0.02 | Affected | 0.1103 | 0.3428 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1582C>A | P528T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P528T is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tools predict a benign outcome. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic. This conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -13.782 | Likely Pathogenic | 0.798 | Likely Pathogenic | Ambiguous | 2.05 | Destabilizing | 0.3 | 1.01 | Ambiguous | 1.53 | Ambiguous | 0.66 | Ambiguous | 0.673 | Likely Pathogenic | -7.69 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.1367 | 0.4360 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.1582C>G | P528A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized, while the remaining pathogenic‑predicting tools are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; the remaining tools (FoldX, Rosetta, Foldetta, premPS) are uncertain. High‑accuracy methods give AlphaMissense‑Optimized a benign score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) a pathogenic prediction, and Foldetta an uncertain result. Overall, the majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment is not contradicted by ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -11.562 | Likely Pathogenic | 0.607 | Likely Pathogenic | Likely Benign | 1.57 | Ambiguous | 0.1 | 1.49 | Ambiguous | 1.53 | Ambiguous | 0.69 | Ambiguous | 0.548 | Likely Pathogenic | -7.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.52 | Benign | 0.01 | Affected | 0.3146 | 0.3914 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1582C>T | P528S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528S missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Only FATHMM predicts a benign outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) remains Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is inconclusive. No folding‑stability metrics (FoldX, Rosetta, premPS) provide definitive evidence. Overall, the preponderance of pathogenic predictions suggests the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -11.729 | Likely Pathogenic | 0.819 | Likely Pathogenic | Ambiguous | 1.88 | Ambiguous | 0.1 | 1.28 | Ambiguous | 1.58 | Ambiguous | 0.80 | Ambiguous | 0.617 | Likely Pathogenic | -7.65 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.52 | Benign | 0.01 | Affected | 0.3115 | 0.3982 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.1583C>A | P528H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P528H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the change as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely pathogenic. No tool predicts a benign outcome; the remaining predictions (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are uncertain or inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence supports a pathogenic interpretation, and this is consistent with the absence of a ClinVar entry; there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -15.365 | Likely Pathogenic | 0.940 | Likely Pathogenic | Ambiguous | 1.93 | Ambiguous | 0.1 | 0.74 | Ambiguous | 1.34 | Ambiguous | 0.61 | Ambiguous | 0.565 | Likely Pathogenic | -8.61 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.47 | Pathogenic | 0.00 | Affected | 0.1434 | 0.3523 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||
| c.1583C>G | P528R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528R missense variant is not reported in ClinVar and is absent from gnomAD. No in silico predictor classifies it as benign; the following tools predict pathogenicity: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions that are uncertain or inconclusive (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -16.367 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.76 | Ambiguous | 0.4 | 0.67 | Ambiguous | 0.72 | Ambiguous | 0.73 | Ambiguous | 0.615 | Likely Pathogenic | -8.58 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.1261 | 0.2543 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1583C>T | P528L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P528L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only premPS, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Because the majority of evidence points to a deleterious effect and no ClinVar annotation exists to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -13.752 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 1.31 | Ambiguous | 0.1 | 0.61 | Ambiguous | 0.96 | Ambiguous | 0.19 | Likely Benign | 0.555 | Likely Pathogenic | -9.65 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.1975 | 0.5574 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.1585A>C | I529L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529L is listed in gnomAD (variant ID 6‑33438828‑A‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. No prediction or folding result is missing or inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.318242 | Structured | 0.019545 | Uncertain | 0.901 | 0.403 | 0.000 | 6-33438828-A-C | 1 | 6.20e-7 | 0.920 | Likely Benign | 0.066 | Likely Benign | Likely Benign | -0.13 | Likely Benign | 0.0 | -0.11 | Likely Benign | -0.12 | Likely Benign | -0.21 | Likely Benign | 0.309 | Likely Benign | 0.00 | Neutral | 0.001 | Benign | 0.022 | Benign | -1.24 | Pathogenic | 0.48 | Tolerated | 3.37 | 35 | 0.0819 | 0.3789 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||
| c.1585A>G | I529V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529V is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID 6‑33438828‑A‑G). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, the SGM Consensus is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. Based on the collective predictions, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.318242 | Structured | 0.019545 | Uncertain | 0.901 | 0.403 | 0.000 | 6-33438828-A-G | 1 | 6.20e-7 | -2.342 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.18 | Likely Benign | 0.0 | 0.03 | Likely Benign | 0.11 | Likely Benign | 0.36 | Likely Benign | 0.230 | Likely Benign | -0.21 | Neutral | 0.019 | Benign | 0.014 | Benign | -1.24 | Pathogenic | 1.00 | Tolerated | 3.37 | 35 | 0.1043 | 0.3526 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||
| c.1585A>T | I529F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529F is not reported in ClinVar and is present in gnomAD (variant ID 6‑33438828‑A‑T). Consensus from most in‑silico predictors classifies the change as benign: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic effect. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Overall, the preponderance of evidence indicates that I529F is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.318242 | Structured | 0.019545 | Uncertain | 0.901 | 0.403 | 0.000 | 6-33438828-A-T | 4 | 2.48e-6 | -5.669 | Likely Benign | 0.235 | Likely Benign | Likely Benign | -0.21 | Likely Benign | 0.0 | 0.06 | Likely Benign | -0.08 | Likely Benign | 0.06 | Likely Benign | 0.320 | Likely Benign | -0.97 | Neutral | 0.266 | Benign | 0.054 | Benign | -1.30 | Pathogenic | 0.23 | Tolerated | 3.37 | 35 | 0.0522 | 0.2713 | 0 | 1 | -1.7 | 34.02 | ||||||||||||||||||||||||
| c.1586T>A | I529N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all predict a neutral impact. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign effect. Taken together, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.318242 | Structured | 0.019545 | Uncertain | 0.901 | 0.403 | 0.000 | -4.478 | Likely Benign | 0.283 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.2 | -0.05 | Likely Benign | 0.04 | Likely Benign | 0.46 | Likely Benign | 0.378 | Likely Benign | -0.31 | Neutral | 0.997 | Probably Damaging | 0.952 | Probably Damaging | -1.24 | Pathogenic | 0.20 | Tolerated | 0.0722 | 0.0700 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1586T>C | I529T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign” call. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” classification—there is no contradiction between the predictions and the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.318242 | Structured | 0.019545 | Uncertain | 0.901 | 0.403 | 0.000 | Uncertain | 1 | -0.539 | Likely Benign | 0.336 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.2 | 0.16 | Likely Benign | 0.19 | Likely Benign | 0.17 | Likely Benign | 0.343 | Likely Benign | 0.24 | Neutral | 0.872 | Possibly Damaging | 0.820 | Possibly Damaging | -1.23 | Pathogenic | 0.55 | Tolerated | 3.37 | 35 | 0.0897 | 0.0989 | 0 | -1 | -5.2 | -12.05 | 207.2 | 29.8 | 0.2 | 0.0 | 0.2 | 0.1 | X | Potentially Benign | Ile529 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the sec-butyl side chain of Ile529 faces the membrane interface and shows no specific interactions. In the variant simulations, the hydroxyl group of Thr529 forms a hydrogen bond with the carboxylate side chain of Asp527, but no negative structural changes are observed. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||||||||
| c.1586T>G | I529S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict pathogenicity, while Rosetta remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of evidence supports a benign classification and is consistent with the absence of a ClinVar assertion. Therefore, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.318242 | Structured | 0.019545 | Uncertain | 0.901 | 0.403 | 0.000 | -0.171 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.3 | -0.53 | Ambiguous | -0.20 | Likely Benign | 0.00 | Likely Benign | 0.383 | Likely Benign | 1.62 | Neutral | 0.979 | Probably Damaging | 0.820 | Possibly Damaging | -1.14 | Pathogenic | 0.40 | Tolerated | 0.2402 | 0.0887 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1587C>G | I529M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome; Rosetta is uncertain and therefore treated as unavailable. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta outputs)—all uniformly indicate a benign effect. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.318242 | Structured | 0.019545 | Uncertain | 0.901 | 0.403 | 0.000 | 1.489 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.1 | 0.68 | Ambiguous | 0.39 | Likely Benign | -0.17 | Likely Benign | 0.215 | Likely Benign | 0.71 | Neutral | 0.035 | Benign | 0.063 | Benign | -1.27 | Pathogenic | 0.15 | Tolerated | 0.0673 | 0.2876 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.1588A>C | K530Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (13/16) predict pathogenicity, whereas only three predict benign. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | -10.593 | Likely Pathogenic | 0.574 | Likely Pathogenic | Likely Benign | 0.31 | Likely Benign | 0.0 | 0.87 | Ambiguous | 0.59 | Ambiguous | 0.13 | Likely Benign | 0.524 | Likely Pathogenic | -3.18 | Deleterious | 0.698 | Possibly Damaging | 0.694 | Possibly Damaging | -1.61 | Pathogenic | 0.01 | Affected | 0.3001 | 0.0941 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1588A>G | K530E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K530E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and polyPhen‑2 HumVar, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus remains Likely Pathogenic, and Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for K530E. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | -14.450 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.79 | Ambiguous | 0.2 | 1.27 | Ambiguous | 1.03 | Ambiguous | 0.43 | Likely Benign | 0.581 | Likely Pathogenic | -3.45 | Deleterious | 0.703 | Possibly Damaging | 0.276 | Benign | -1.57 | Pathogenic | 0.00 | Affected | 0.2505 | 0.0810 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1589A>C | K530T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530T missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include only premPS, whereas the remaining nine tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of the pathogenic‑predominant tools) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a deleterious impact. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently contains no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | -11.506 | Likely Pathogenic | 0.852 | Likely Pathogenic | Ambiguous | 1.06 | Ambiguous | 0.3 | 1.06 | Ambiguous | 1.06 | Ambiguous | 0.27 | Likely Benign | 0.610 | Likely Pathogenic | -5.17 | Deleterious | 0.921 | Possibly Damaging | 0.950 | Probably Damaging | -1.63 | Pathogenic | 0.00 | Affected | 0.1351 | 0.2780 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1589A>G | K530R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K530R is catalogued in gnomAD (6‑33438832‑A‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | 6-33438832-A-G | 1 | 6.19e-7 | -3.836 | Likely Benign | 0.081 | Likely Benign | Likely Benign | -0.02 | Likely Benign | 0.1 | 0.18 | Likely Benign | 0.08 | Likely Benign | 0.33 | Likely Benign | 0.234 | Likely Benign | -1.39 | Neutral | 0.000 | Benign | 0.002 | Benign | -1.54 | Pathogenic | 0.08 | Tolerated | 3.37 | 35 | 0.3297 | 0.0716 | 2 | 3 | -0.6 | 28.01 | ||||||||||||||||||||||||
| c.1589A>T | K530M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS. Tools that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Based on the predominance of pathogenic predictions and the SGM Consensus result, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | -12.235 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 0.51 | Ambiguous | 0.0 | 1.26 | Ambiguous | 0.89 | Ambiguous | 0.24 | Likely Benign | 0.671 | Likely Pathogenic | -5.17 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | -1.69 | Pathogenic | 0.00 | Affected | 0.0745 | 0.3123 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.158G>A | G53E 2D AIThe SynGAP1 missense variant G53E 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 the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are not available. 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 | 0.268042 | Structured | 0.460894 | Uncertain | 0.386 | 0.666 | 0.000 | -2.061 | Likely Benign | 0.853 | Likely Pathogenic | Ambiguous | 0.198 | Likely Benign | -0.25 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 4.29 | Benign | 0.00 | Affected | 0.1413 | 0.4378 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.158G>C | G53A 2D AIThe SynGAP1 missense variant G53A 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 show AlphaMissense‑Optimized as Benign and the SGM‑Consensus (majority vote) also as 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 because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.268042 | Structured | 0.460894 | Uncertain | 0.386 | 0.666 | 0.000 | -6.329 | Likely Benign | 0.616 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | -1.00 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 4.16 | Benign | 0.00 | Affected | 0.4093 | 0.5550 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.158G>T | G53V 2D AIThe SynGAP1 missense variant G53V is 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. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of predictions (six pathogenic vs. three benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.268042 | Structured | 0.460894 | Uncertain | 0.386 | 0.666 | 0.000 | -8.308 | Likely Pathogenic | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.238 | Likely Benign | -1.71 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 4.11 | Benign | 0.00 | Affected | 0.1193 | 0.4833 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.1590G>C | K530N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530N missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, and Foldetta, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—predict a pathogenic or likely pathogenic outcome; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions (10/13) support pathogenicity, with only three tools indicating benign. Therefore, the variant is most likely pathogenic based on the available computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | -12.459 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.42 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.33 | Likely Benign | 0.56 | Ambiguous | 0.553 | Likely Pathogenic | -4.18 | Deleterious | 0.950 | Possibly Damaging | 0.703 | Possibly Damaging | -1.65 | Pathogenic | 0.00 | Affected | 0.2350 | 0.1086 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1590G>T | K530N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530N missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, and Foldetta, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—predict a pathogenic or likely pathogenic outcome; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions (10/13) support pathogenicity, with only three tools indicating benign. Therefore, the variant is most likely pathogenic based on the available computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | -12.459 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.42 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.33 | Likely Benign | 0.56 | Ambiguous | 0.553 | Likely Pathogenic | -4.18 | Deleterious | 0.950 | Possibly Damaging | 0.703 | Possibly Damaging | -1.65 | Pathogenic | 0.00 | Affected | 0.2350 | 0.1086 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1591T>A | C531S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531S is not reported in ClinVar and has no entries in gnomAD. Prediction tools that assess pathogenicity largely agree on a deleterious effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict pathogenic. In contrast, only three tools predict a benign outcome: FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy methods provide a mixed picture: AlphaMissense‑Optimized reports a benign effect, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta also predicts benign stability. Overall, the preponderance of evidence points to a pathogenic impact for C531S. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.017941 | Uncertain | 0.878 | 0.401 | 0.000 | -8.213 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | -0.02 | Likely Benign | 0.0 | 0.77 | Ambiguous | 0.38 | Likely Benign | 1.23 | Destabilizing | 0.519 | Likely Pathogenic | -8.00 | Deleterious | 0.958 | Probably Damaging | 0.533 | Possibly Damaging | -1.18 | Pathogenic | 0.01 | Affected | 0.3716 | 0.1782 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1591T>C | C531R 2D AIThe SynGAP1 missense variant C531R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and polyPhen‑2 HumVar, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar classification because the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.017941 | Uncertain | 0.878 | 0.401 | 0.000 | -12.600 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 0.31 | Likely Benign | 2.0 | -0.27 | Likely Benign | 0.02 | Likely Benign | 1.40 | Destabilizing | 0.619 | Likely Pathogenic | -9.85 | Deleterious | 0.929 | Possibly Damaging | 0.385 | Benign | -1.24 | Pathogenic | 0.00 | Affected | 0.1322 | 0.1566 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.1591T>G | C531G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX and AlphaMissense‑Optimized, while the majority of other in silico predictors (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) indicate a pathogenic impact. Uncertain results come from Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the balance of evidence leans toward pathogenicity, with no ClinVar entry to contradict this assessment. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.017941 | Uncertain | 0.878 | 0.401 | 0.000 | -10.037 | Likely Pathogenic | 0.577 | Likely Pathogenic | Likely Benign | 0.47 | Likely Benign | 0.3 | 1.49 | Ambiguous | 0.98 | Ambiguous | 1.42 | Destabilizing | 0.545 | Likely Pathogenic | -9.76 | Deleterious | 0.985 | Probably Damaging | 0.832 | Possibly Damaging | -1.24 | Pathogenic | 0.00 | Affected | 0.2653 | 0.2297 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.1592G>A | C531Y 2D AIThe SynGAP1 missense variant C531Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only Rosetta, whereas the remaining tools—REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus—consistently predict a pathogenic impact. Uncertain or inconclusive results come from AlphaMissense‑Optimized, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for C531Y. This prediction does not contradict ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.017941 | Uncertain | 0.878 | 0.401 | 0.000 | -11.667 | Likely Pathogenic | 0.914 | Likely Pathogenic | Ambiguous | 3.09 | Destabilizing | 4.6 | 0.15 | Likely Benign | 1.62 | Ambiguous | 0.65 | Ambiguous | 0.551 | Likely Pathogenic | -8.95 | Deleterious | 0.976 | Probably Damaging | 0.480 | Possibly Damaging | -1.24 | Pathogenic | 0.00 | Affected | 0.0843 | 0.3266 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1592G>C | C531S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Foldetta, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; Rosetta remains uncertain. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized indicates benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic, and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. Overall, the preponderance of evidence points to a pathogenic effect for C531S, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.017941 | Uncertain | 0.878 | 0.401 | 0.000 | -8.213 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | -0.02 | Likely Benign | 0.0 | 0.77 | Ambiguous | 0.38 | Likely Benign | 1.23 | Destabilizing | 0.508 | Likely Pathogenic | -8.00 | Deleterious | 0.958 | Probably Damaging | 0.533 | Possibly Damaging | -1.18 | Pathogenic | 0.01 | Affected | 0.3716 | 0.1782 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1592G>T | C531F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include Rosetta and polyPhen‑2 HumVar, while the majority of tools (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Tools with inconclusive or uncertain results are AlphaMissense‑Optimized, Foldetta, and premPS. High‑accuracy assessments show SGM‑Consensus as “Likely Pathogenic”; AlphaMissense‑Optimized is uncertain; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also uncertain. Taken together, the preponderance of evidence from multiple pathogenic‑predicting algorithms and the SGM‑Consensus score indicates that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.017941 | Uncertain | 0.878 | 0.401 | 0.000 | -10.428 | Likely Pathogenic | 0.842 | Likely Pathogenic | Ambiguous | 2.47 | Destabilizing | 1.6 | 0.26 | Likely Benign | 1.37 | Ambiguous | 0.59 | Ambiguous | 0.519 | Likely Pathogenic | -8.89 | Deleterious | 0.866 | Possibly Damaging | 0.244 | Benign | -1.23 | Pathogenic | 0.01 | Affected | 0.1103 | 0.3784 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.1593C>G | C531W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a deleterious effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, all of which classify the change as pathogenic. Tools with uncertain or mixed outputs are Rosetta (uncertain) and premPS (uncertain). High‑accuracy assessments further support a damaging impact: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports pathogenic. Based on the overwhelming agreement among pathogenic predictions and the corroborating high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.017941 | Uncertain | 0.878 | 0.401 | 0.000 | -14.107 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 5.27 | Destabilizing | 3.4 | 0.63 | Ambiguous | 2.95 | Destabilizing | 0.70 | Ambiguous | 0.510 | Likely Pathogenic | -9.12 | Deleterious | 0.998 | Probably Damaging | 0.871 | Possibly Damaging | -1.25 | Pathogenic | 0.00 | Affected | 0.1234 | 0.3074 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1594A>C | T532P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532P is listed in ClinVar as Benign (ClinVar ID 1598909.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM Consensus, and Foldetta (combining FoldX‑MD and Rosetta outputs)—all indicate a benign impact. No prediction or folding‑stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.275179 | Structured | 0.021478 | Uncertain | 0.889 | 0.385 | 0.000 | Benign | 1 | -2.143 | Likely Benign | 0.061 | Likely Benign | Likely Benign | -0.30 | Likely Benign | 0.2 | 0.06 | Likely Benign | -0.12 | Likely Benign | 0.08 | Likely Benign | 0.201 | Likely Benign | -0.90 | Neutral | 0.005 | Benign | 0.008 | Benign | -1.28 | Pathogenic | 0.18 | Tolerated | 3.37 | 35 | 0.1850 | 0.3811 | 0 | -1 | -0.9 | -3.99 | 174.2 | 35.1 | 0.4 | 0.0 | 0.1 | 0.0 | X | Potentially Benign | Thr532 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560) facing the membrane. In the WT simulations, the hydroxyl group of Thr532 occasionally forms hydrogen bonds with the backbone atoms of other loop residues without any specific interaction. In the variant simulations, the Pro532 residue swap does not cause structural changes. Although hydrophilic residues seem more favorable in the loop, the pyrrolidine side chain of proline is well suited for unstructured protein regions such as loops. However, due to its location at the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||||||||
| c.1594A>G | T532A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome. Grouping by consensus, the benign‑predicting tools outnumber the single pathogenic prediction. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.275179 | Structured | 0.021478 | Uncertain | 0.889 | 0.385 | 0.000 | -2.907 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.16 | Likely Benign | 0.0 | 0.13 | Likely Benign | 0.15 | Likely Benign | 0.11 | Likely Benign | 0.165 | Likely Benign | -0.80 | Neutral | 0.032 | Benign | 0.023 | Benign | -1.15 | Pathogenic | 0.14 | Tolerated | 0.3573 | 0.3114 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1594A>T | T532S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. When high‑accuracy methods are considered separately, AlphaMissense‑Optimized remains benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a benign effect. No prediction or stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.275179 | Structured | 0.021478 | Uncertain | 0.889 | 0.385 | 0.000 | 0.616 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.15 | Likely Benign | 0.1 | -0.23 | Likely Benign | -0.04 | Likely Benign | -0.10 | Likely Benign | 0.160 | Likely Benign | 0.53 | Neutral | 0.005 | Benign | 0.013 | Benign | -1.22 | Pathogenic | 1.00 | Tolerated | 0.2988 | 0.2866 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1595C>A | T532K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T532K missense variant is not reported in ClinVar and has no entries in gnomAD. Prediction tools that classify the change as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With ten benign versus four pathogenic predictions and two of the three high‑accuracy tools supporting a benign outcome, the variant is most likely benign. This assessment does not contradict the ClinVar status, which currently has no classification for T532K. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.021478 | Uncertain | 0.889 | 0.385 | 0.000 | -8.460 | Likely Pathogenic | 0.644 | Likely Pathogenic | Likely Benign | -0.44 | Likely Benign | 0.2 | 0.24 | Likely Benign | -0.10 | Likely Benign | 0.34 | Likely Benign | 0.376 | Likely Benign | -1.97 | Neutral | 0.259 | Benign | 0.033 | Benign | -1.21 | Pathogenic | 0.29 | Tolerated | 0.0943 | 0.1992 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||
| c.1595C>G | T532R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T532R missense variant is not listed in ClinVar and has no reported allele in gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, FATHMM, and AlphaMissense‑Default. FoldX and Rosetta provide uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling it likely pathogenic, and Foldetta predicting a benign effect. Overall, the balance of evidence (seven benign versus five pathogenic predictions) indicates that the variant is most likely benign, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.021478 | Uncertain | 0.889 | 0.385 | 0.000 | -6.564 | Likely Benign | 0.608 | Likely Pathogenic | Likely Benign | -0.57 | Ambiguous | 0.2 | 0.68 | Ambiguous | 0.06 | Likely Benign | 0.48 | Likely Benign | 0.495 | Likely Benign | -2.62 | Deleterious | 0.694 | Possibly Damaging | 0.230 | Benign | -1.20 | Pathogenic | 0.06 | Tolerated | 0.0841 | 0.1755 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||
| c.1595C>T | T532I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized classifies the variant as benign, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) reports a benign effect. Overall, the balance of evidence leans toward pathogenicity, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.021478 | Uncertain | 0.889 | 0.385 | 0.000 | -9.031 | Likely Pathogenic | 0.591 | Likely Pathogenic | Likely Benign | -0.11 | Likely Benign | 0.2 | 0.87 | Ambiguous | 0.38 | Likely Benign | 0.22 | Likely Benign | 0.428 | Likely Benign | -3.31 | Deleterious | 0.633 | Possibly Damaging | 0.202 | Benign | -1.31 | Pathogenic | 0.03 | Affected | 0.0713 | 0.4983 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1597G>A | A533T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533T is catalogued in gnomAD (6-33438840‑G‑A) but has no ClinVar entry. In silico predictors overwhelmingly favor a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes, whereas only FATHMM predicts pathogenicity. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, the SGM Consensus is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) predicts a benign stability change. Overall, the evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | 6-33438840-G-A | 2 | 1.24e-6 | -5.396 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.1 | 0.31 | Likely Benign | 0.31 | Likely Benign | 0.19 | Likely Benign | 0.147 | Likely Benign | -0.48 | Neutral | 0.002 | Benign | 0.001 | Benign | -1.26 | Pathogenic | 0.11 | Tolerated | 3.37 | 35 | 0.1413 | 0.6541 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||
| c.1597G>C | A533P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict benign. Only FATHMM predicts pathogenic. Stability‑based methods are inconclusive: FoldX, Rosetta, and the combined Foldetta output are listed as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as unavailable. Overall, the consensus of the majority of tools indicates a benign impact. This prediction does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -3.951 | Likely Benign | 0.081 | Likely Benign | Likely Benign | -0.93 | Ambiguous | 0.3 | -0.92 | Ambiguous | -0.93 | Ambiguous | -0.18 | Likely Benign | 0.187 | Likely Benign | -0.48 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.26 | Pathogenic | 0.09 | Tolerated | 0.1925 | 0.5299 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1597G>T | A533S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. When predictions are grouped by consensus, the benign group contains all tools except FATHMM, which stands alone in the pathogenic group. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates a benign effect. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -3.740 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.24 | Likely Benign | 0.0 | -0.05 | Likely Benign | 0.10 | Likely Benign | -0.14 | Likely Benign | 0.193 | Likely Benign | 0.33 | Neutral | 0.009 | Benign | 0.039 | Benign | -1.14 | Pathogenic | 0.45 | Tolerated | 0.2612 | 0.5334 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1598C>A | A533E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -10.810 | Likely Pathogenic | 0.553 | Ambiguous | Likely Benign | -0.13 | Likely Benign | 0.0 | -0.26 | Likely Benign | -0.20 | Likely Benign | 0.43 | Likely Benign | 0.314 | Likely Benign | -1.89 | Neutral | 0.259 | Benign | 0.107 | Benign | -1.18 | Pathogenic | 0.18 | Tolerated | 0.1147 | 0.1498 | 0 | -1 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||
| c.1598C>G | A533G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533G resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome; Rosetta is uncertain and therefore not counted as evidence. High‑accuracy assessments—all of which are available—show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Benign, reinforcing the benign consensus. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -3.412 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.32 | Likely Benign | 0.1 | 0.64 | Ambiguous | 0.48 | Likely Benign | 0.33 | Likely Benign | 0.185 | Likely Benign | -1.94 | Neutral | 0.258 | Benign | 0.099 | Benign | -1.23 | Pathogenic | 0.23 | Tolerated | 0.2348 | 0.4737 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1598C>T | A533V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are SIFT and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as benign, all supporting a non‑pathogenic interpretation. No prediction or folding‑stability result is missing or inconclusive. Based on the overall consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar evidence exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -6.948 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.23 | Likely Benign | 0.0 | 0.51 | Ambiguous | 0.37 | Likely Benign | 0.25 | Likely Benign | 0.170 | Likely Benign | -2.41 | Neutral | 0.149 | Benign | 0.024 | Benign | -1.28 | Pathogenic | 0.05 | Affected | 0.1243 | 0.6205 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.1600T>A | S534T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Thus, the overall evidence strongly supports a benign classification, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -4.925 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.28 | Likely Benign | 0.19 | Likely Benign | 0.200 | Likely Benign | -2.42 | Neutral | 0.676 | Possibly Damaging | 0.933 | Probably Damaging | 3.32 | Benign | 0.07 | Tolerated | 0.1238 | 0.5064 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1600T>C | S534P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534P is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438843‑T‑C). Functional prediction tools that report a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy assessments are consistent with a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the aggregate predictions, the variant is most likely benign, which does not contradict the ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | Uncertain | 1 | 6-33438843-T-C | 3 | 1.86e-6 | -5.056 | Likely Benign | 0.265 | Likely Benign | Likely Benign | -0.40 | Likely Benign | 0.2 | 0.35 | Likely Benign | -0.03 | Likely Benign | 0.47 | Likely Benign | 0.203 | Likely Benign | -3.81 | Deleterious | 0.993 | Probably Damaging | 0.993 | Probably Damaging | 3.32 | Benign | 0.05 | Affected | 3.37 | 35 | 0.2071 | 0.4650 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||
| c.1600T>G | S534A 2D 3DClick to see structure in 3D Viewer AISynGAP1 S534A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenicity. High‑accuracy methods reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. No evidence suggests a deleterious effect. Therefore, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -4.691 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.01 | Likely Benign | 0.0 | -0.01 | Likely Benign | 0.00 | Likely Benign | 0.11 | Likely Benign | 0.163 | Likely Benign | -1.70 | Neutral | 0.880 | Possibly Damaging | 0.994 | Probably Damaging | 3.36 | Benign | 0.42 | Tolerated | 0.5042 | 0.3131 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.1601C>A | S534Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534Y has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, FATHMM, premPS, AlphaMissense‑Optimized, and Foldetta, while those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of tools (seven versus six) lean toward a pathogenic effect, and the high‑accuracy consensus is split, leaving the variant’s impact uncertain. Based on the aggregate predictions, the variant is most likely pathogenic, which does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -11.540 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | -0.01 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.33 | Likely Benign | 0.46 | Likely Benign | 0.314 | Likely Benign | -5.02 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | 3.27 | Benign | 0.00 | Affected | 0.0629 | 0.5073 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.1601C>G | S534C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is uncertain, so both are treated as unavailable. No other high‑accuracy predictions are available. Overall, the evidence is evenly split between benign and pathogenic predictions, leaving the variant’s clinical significance inconclusive. There is no ClinVar status to contradict this balanced prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -8.077 | Likely Pathogenic | 0.247 | Likely Benign | Likely Benign | 0.18 | Likely Benign | 0.1 | 0.90 | Ambiguous | 0.54 | Ambiguous | 0.56 | Ambiguous | 0.308 | Likely Benign | -4.05 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 3.25 | Benign | 0.00 | Affected | 0.0984 | 0.4861 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.1601C>T | S534F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FoldX, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Tools with uncertain results are AlphaMissense‑Default and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this is consistent with the lack of ClinVar evidence; thus the variant is most likely benign and does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -10.948 | Likely Pathogenic | 0.492 | Ambiguous | Likely Benign | -0.03 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.43 | Likely Benign | 0.43 | Likely Benign | 0.313 | Likely Benign | -5.09 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.0621 | 0.5379 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||
| c.1603A>C | S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R is not reported in ClinVar and is present in gnomAD (ID 6‑33438846‑A‑C). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results come from AlphaMissense‑Optimized, Foldetta, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the balance of evidence, especially the SGM Consensus, points to a pathogenic interpretation. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | 6-33438846-A-C | 3 | 1.86e-6 | -9.363 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.0 | -0.97 | Ambiguous | -0.67 | Ambiguous | 0.64 | Ambiguous | 0.390 | Likely Benign | -1.99 | Neutral | 0.830 | Possibly Damaging | 0.274 | Benign | -1.23 | Pathogenic | 0.19 | Tolerated | 3.37 | 35 | 0.1086 | 0.3743 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||
| c.1603A>G | S535G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for S535G, and this conclusion does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -4.619 | Likely Benign | 0.143 | Likely Benign | Likely Benign | 0.19 | Likely Benign | 0.0 | 0.93 | Ambiguous | 0.56 | Ambiguous | 0.64 | Ambiguous | 0.247 | Likely Benign | -1.75 | Neutral | 0.606 | Possibly Damaging | 0.114 | Benign | -1.30 | Pathogenic | 0.19 | Tolerated | 0.2858 | 0.4644 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.1603A>T | S535C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. Two tools, FoldX and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -7.526 | In-Between | 0.165 | Likely Benign | Likely Benign | 0.57 | Ambiguous | 0.1 | 0.25 | Likely Benign | 0.41 | Likely Benign | 0.47 | Likely Benign | 0.500 | Likely Pathogenic | -2.96 | Deleterious | 0.933 | Possibly Damaging | 0.419 | Benign | -1.33 | Pathogenic | 0.02 | Affected | 0.1139 | 0.5633 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.1604G>A | S535N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Across the broad panel of in‑silico predictors, 13 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign”) uniformly predict a benign effect, whereas only FATHMM assigns a pathogenic label. High‑accuracy assessments corroborate the benign consensus: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Thus, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -4.957 | Likely Benign | 0.196 | Likely Benign | Likely Benign | -0.46 | Likely Benign | 0.2 | -0.26 | Likely Benign | -0.36 | Likely Benign | 0.18 | Likely Benign | 0.176 | Likely Benign | -0.05 | Neutral | 0.070 | Benign | 0.032 | Benign | -1.25 | Pathogenic | 0.29 | Tolerated | 0.1390 | 0.4784 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||
| c.1604G>C | S535T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535T is catalogued in ClinVar as benign (ClinVar ID 537005.0) and is observed in gnomAD (variant ID 6‑33438847‑G‑C). In silico prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. Only FATHMM predicts a pathogenic outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign; the SGM Consensus is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Overall, the consensus of predictive tools and high‑accuracy methods indicates that the variant is most likely benign, consistent with its ClinVar classification and presence in gnomAD. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | Benign | 1 | 6-33438847-G-C | 14 | 8.67e-6 | -3.886 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.1 | -0.27 | Likely Benign | 0.09 | Likely Benign | 0.17 | Likely Benign | 0.177 | Likely Benign | -0.81 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.25 | Pathogenic | 0.25 | Tolerated | 3.37 | 35 | 0.1456 | 0.6291 | 1 | 1 | 0.1 | 14.03 | 201.3 | -17.3 | -0.1 | 0.7 | -0.2 | 0.1 | X | Potentially Benign | Ser535 is located near the terminal end of an α-helix (res. Ala533-Val560) close to the membrane interface. In the WT simulations, the hydroxyl side chain of Ser535 forms hydrogen bonds with nearby residues (e.g., His539, Glu538) without any specific interactions. These hydrogen bonds disrupt the structure of the terminal end of the α-helix (Ala533-Ser535), causing it to weaken or unfold during the WT simulations. In the variant simulations, Thr535, a hydrophilic residue with a hydroxyl group of almost the same size as Ser, interacts more frequently with the preceding loop residues (e.g., Thr532, Cys531) due to its longer side chain. Regardless, the residue swap is tolerated in the simulations with no negative effects. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||
| c.1604G>T | S535I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the preponderance of evidence points to a benign impact for S535I, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -8.073 | Likely Pathogenic | 0.330 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.0 | -0.42 | Likely Benign | 0.04 | Likely Benign | 0.14 | Likely Benign | 0.246 | Likely Benign | -2.49 | Neutral | 0.004 | Benign | 0.004 | Benign | -1.25 | Pathogenic | 0.07 | Tolerated | 0.1123 | 0.5571 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||
| c.1605T>A | S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, and SIFT, while pathogenic calls come from polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is also inconclusive. Overall, the balance of evidence, particularly the SGM Consensus, points to a pathogenic effect. This conclusion does not conflict with ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -9.363 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.0 | -0.97 | Ambiguous | -0.67 | Ambiguous | 0.64 | Ambiguous | 0.432 | Likely Benign | -1.99 | Neutral | 0.830 | Possibly Damaging | 0.274 | Benign | -1.23 | Pathogenic | 0.19 | Tolerated | 3.37 | 35 | 0.1086 | 0.3743 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||
| c.1605T>G | S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, and SIFT, while pathogenic calls come from polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is also inconclusive. Overall, the balance of evidence, particularly the SGM Consensus, points to a pathogenic effect. This conclusion does not conflict with ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -9.363 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.0 | -0.97 | Ambiguous | -0.67 | Ambiguous | 0.64 | Ambiguous | 0.432 | Likely Benign | -1.99 | Neutral | 0.830 | Possibly Damaging | 0.274 | Benign | -1.23 | Pathogenic | 0.19 | Tolerated | 3.37 | 35 | 0.1086 | 0.3743 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||
| c.1606T>A | L536M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L536M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | -10.124 | Likely Pathogenic | 0.462 | Ambiguous | Likely Benign | 0.37 | Likely Benign | 0.1 | 1.18 | Ambiguous | 0.78 | Ambiguous | 0.93 | Ambiguous | 0.571 | Likely Pathogenic | -1.94 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 0.0937 | 0.3299 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1606T>G | L536V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L536V is listed in ClinVar (ID 1690714.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic verdict. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. No evidence from FoldX or Rosetta alone is available. Overall, the majority of evidence points toward a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | Uncertain | 1 | -9.014 | Likely Pathogenic | 0.269 | Likely Benign | Likely Benign | 1.25 | Ambiguous | 0.3 | 1.22 | Ambiguous | 1.24 | Ambiguous | 1.20 | Destabilizing | 0.586 | Likely Pathogenic | -2.81 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.34 | Pathogenic | 0.09 | Tolerated | 3.37 | 34 | 0.1591 | 0.3565 | 2 | 1 | 0.4 | -14.03 | 204.7 | 26.4 | 0.2 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | Leu536 is located on an α-helix (res. Ala533-Val560) at the membrane interface. The iso-butyl group of Leu536 interacts with nearby hydrophobic residues in the preceding loop (e.g., Val526, Pro528, Cys531). In the variant simulations, the iso-propyl side chain of Val536 forms similar hydrophobic interactions as Leu536 in the WT, causing no negative structural effects. | ||||||||||||||||
| c.1607T>C | L536S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L536S is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. The only inconclusive result is from FoldX, which is listed as uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | -12.996 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 1.45 | Ambiguous | 0.3 | 3.08 | Destabilizing | 2.27 | Destabilizing | 1.51 | Destabilizing | 0.909 | Likely Pathogenic | -5.78 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.47 | Pathogenic | 0.00 | Affected | 0.2849 | 0.0577 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||
| c.1607T>G | L536W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L536W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a deleterious effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; all of these classify the variant as pathogenic. Tools that are inconclusive (FoldX, Rosetta, Foldetta) do not provide evidence for or against pathogenicity. High‑accuracy assessments further support a damaging impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta’s stability analysis is uncertain. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | -14.169 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 1.07 | Ambiguous | 0.6 | 1.31 | Ambiguous | 1.19 | Ambiguous | 1.33 | Destabilizing | 0.897 | Likely Pathogenic | -5.92 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | 0.0843 | 0.2577 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.1608G>C | L536F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L536F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only Rosetta. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus. Predictions that are uncertain or inconclusive are FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of reliable tools predict a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | -10.316 | Likely Pathogenic | 0.851 | Likely Pathogenic | Ambiguous | 1.31 | Ambiguous | 0.5 | 0.40 | Likely Benign | 0.86 | Ambiguous | 0.70 | Ambiguous | 0.724 | Likely Pathogenic | -3.90 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 0.0874 | 0.2804 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1608G>T | L536F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L536F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only Rosetta. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus. Predictions that are uncertain or inconclusive are FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of reliable tools predict a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | -10.316 | Likely Pathogenic | 0.851 | Likely Pathogenic | Ambiguous | 1.31 | Ambiguous | 0.5 | 0.40 | Likely Benign | 0.86 | Ambiguous | 0.70 | Ambiguous | 0.722 | Likely Pathogenic | -3.90 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 0.0874 | 0.2804 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1609G>A | A537T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537T is catalogued in gnomAD (6‑33438852‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus (majority vote) is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts Benign. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | 6-33438852-G-A | 2 | 1.24e-6 | -4.704 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.35 | Likely Benign | 0.0 | 0.29 | Likely Benign | 0.32 | Likely Benign | 0.37 | Likely Benign | 0.210 | Likely Benign | -1.41 | Neutral | 0.953 | Possibly Damaging | 0.602 | Possibly Damaging | -1.27 | Pathogenic | 0.44 | Tolerated | 3.37 | 35 | 0.1520 | 0.5440 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||
| c.1609G>C | A537P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FATHMM and Rosetta; FoldX and Foldetta are inconclusive. The high‑accuracy consensus (SGM‑Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN indicates a likely benign outcome, while AlphaMissense‑Optimized also predicts benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the majority of evidence points to a benign impact for A537P, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | 0.404 | Likely Benign | 0.102 | Likely Benign | Likely Benign | -0.61 | Ambiguous | 0.6 | 2.43 | Destabilizing | 0.91 | Ambiguous | -0.18 | Likely Benign | 0.218 | Likely Benign | 0.67 | Neutral | 0.020 | Benign | 0.022 | Benign | -1.29 | Pathogenic | 0.35 | Tolerated | 0.2152 | 0.3807 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1609G>T | A537S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537S is reported in gnomAD (6-33438852-G-T) and has no ClinVar entry. Consensus from multiple in silico predictors indicates a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while polyPhen‑2 (HumDiv and HumVar) and FATHMM predict pathogenicity. When predictions are grouped, the majority of tools (ten) support benign, whereas three tools support pathogenic. High‑accuracy assessments further reinforce the benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Consequently, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | 6-33438852-G-T | 1 | 6.20e-7 | -3.602 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.28 | Likely Benign | 0.0 | 0.46 | Likely Benign | 0.37 | Likely Benign | 0.28 | Likely Benign | 0.206 | Likely Benign | -0.66 | Neutral | 0.528 | Possibly Damaging | 0.592 | Possibly Damaging | -1.25 | Pathogenic | 0.60 | Tolerated | 3.37 | 35 | 0.2729 | 0.4431 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||
| c.160A>C | N54H 2D AISynGAP1 missense variant N54H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is 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 show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for the variant, 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 | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -7.646 | In-Between | 0.236 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -1.18 | Neutral | 0.943 | Possibly Damaging | 0.924 | Probably Damaging | 4.14 | Benign | 0.00 | Affected | 0.1377 | 0.7334 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.160A>G | N54D 2D AIThe SynGAP1 missense variant N54D 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 (which is labeled “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 (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -6.980 | Likely Benign | 0.325 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -0.75 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 4.22 | Benign | 0.00 | Affected | 0.1826 | 0.4496 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.160A>T | N54Y 2D AIThe SynGAP1 missense variant N54Y is 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2). High‑accuracy methods show AlphaMissense‑Optimized as benign; the SGM Consensus is unavailable, and Foldetta results are not provided, so its stability prediction is also unavailable. Overall, more tools (five) predict pathogenicity than benign (four), and the high‑accuracy benign prediction is outweighed by the majority of pathogenic calls. Thus, the variant is most likely pathogenic based on current computational 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. | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -9.313 | Likely Pathogenic | 0.640 | Likely Pathogenic | Likely Benign | 0.183 | Likely Benign | -1.57 | Neutral | 0.943 | Possibly Damaging | 0.924 | Probably Damaging | 4.16 | Benign | 0.00 | Affected | 0.0512 | 0.6687 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||||||||||||
| c.1610C>A | A537E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or stability result is missing or inconclusive. Based on the overall consensus of the available tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | -5.120 | Likely Benign | 0.450 | Ambiguous | Likely Benign | -0.14 | Likely Benign | 0.1 | 0.00 | Likely Benign | -0.07 | Likely Benign | 0.23 | Likely Benign | 0.378 | Likely Benign | -1.78 | Neutral | 0.987 | Probably Damaging | 0.838 | Possibly Damaging | -1.04 | Pathogenic | 1.00 | Tolerated | 0.1347 | 0.1566 | 0 | -1 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||
| c.1610C>G | A537G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict pathogenic. Uncertain results come from Rosetta, Foldetta, and premPS. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized reports benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Benign, and Foldetta’s stability prediction is inconclusive. Overall, the majority of evidence supports a benign impact for A537G, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | -4.302 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.40 | Likely Benign | 0.0 | 0.88 | Ambiguous | 0.64 | Ambiguous | 0.68 | Ambiguous | 0.290 | Likely Benign | -1.85 | Neutral | 0.977 | Probably Damaging | 0.672 | Possibly Damaging | -1.30 | Pathogenic | 0.36 | Tolerated | 0.2289 | 0.3387 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1610C>T | A537V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A537V is listed in ClinVar as Benign (ClinVar ID 766762.0) and is present in gnomAD (ID 6‑33438853‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is benign. FoldX alone is uncertain and therefore not considered evidence. Overall, the consensus of available predictions indicates that the variant is most likely benign, in agreement with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | Likely Benign | 1 | 6-33438853-C-T | 7 | 4.34e-6 | -6.888 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.54 | Ambiguous | 0.0 | -0.05 | Likely Benign | 0.25 | Likely Benign | 0.41 | Likely Benign | 0.382 | Likely Benign | -1.97 | Neutral | 0.977 | Probably Damaging | 0.469 | Possibly Damaging | -1.26 | Pathogenic | 0.24 | Tolerated | 3.37 | 35 | 0.1328 | 0.4748 | 0 | 0 | 2.4 | 28.05 | 220.3 | -45.1 | 0.0 | 0.0 | -0.7 | 0.1 | X | Potentially Benign | Ala537 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala537 is on the surface and does not form any interactions. In the variant simulations, the iso-propyl side chain of Val537 is also on the surface, similar to Ala537 in the WT, causing no negative structural effects. | |||||||||||||
| c.1612G>A | E538K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E538K has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment indicates that AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) supports a pathogenic outcome, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Overall, the majority of tools lean toward a benign effect, but the consensus of high‑accuracy predictors and several individual pathogenic scores suggest uncertainty. The variant is most likely benign based on the bulk of evidence, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.033501 | Uncertain | 0.938 | 0.359 | 0.000 | -11.345 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | -0.03 | Likely Benign | 0.0 | -0.16 | Likely Benign | -0.10 | Likely Benign | -0.22 | Likely Benign | 0.215 | Likely Benign | -2.97 | Deleterious | 0.848 | Possibly Damaging | 0.294 | Benign | 3.46 | Benign | 0.16 | Tolerated | 0.2257 | 0.3818 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1612G>C | E538Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E538Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of evidence supports a benign impact. This conclusion does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.122885 | Structured | 0.033501 | Uncertain | 0.938 | 0.359 | 0.000 | -10.380 | Likely Pathogenic | 0.733 | Likely Pathogenic | Likely Benign | 0.07 | Likely Benign | 0.0 | 0.07 | Likely Benign | 0.07 | Likely Benign | -0.08 | Likely Benign | 0.188 | Likely Benign | -2.14 | Neutral | 0.890 | Possibly Damaging | 0.436 | Benign | 3.37 | Benign | 0.11 | Tolerated | 0.1127 | 0.3952 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.1613A>C | E538A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E538A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote). High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts likely pathogenic, and Foldetta predicts benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of tools (7 pathogenic vs 6 benign) lean toward a pathogenic interpretation, and this does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.033501 | Uncertain | 0.938 | 0.359 | 0.000 | -9.888 | Likely Pathogenic | 0.770 | Likely Pathogenic | Likely Benign | 0.33 | Likely Benign | 0.0 | -0.06 | Likely Benign | 0.14 | Likely Benign | 0.16 | Likely Benign | 0.269 | Likely Benign | -4.66 | Deleterious | 0.944 | Possibly Damaging | 0.761 | Possibly Damaging | 3.36 | Benign | 0.05 | Affected | 0.3995 | 0.4187 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1613A>G | E538G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E538G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No folding‑stability result is definitive. Overall, the balance of evidence, including the majority‑vote SGM Consensus and the higher number of pathogenic predictions, points to a pathogenic effect for E538G. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.033501 | Uncertain | 0.938 | 0.359 | 0.000 | -9.258 | Likely Pathogenic | 0.701 | Likely Pathogenic | Likely Benign | 0.91 | Ambiguous | 0.0 | 1.07 | Ambiguous | 0.99 | Ambiguous | 0.31 | Likely Benign | 0.285 | Likely Benign | -5.10 | Deleterious | 0.993 | Probably Damaging | 0.700 | Possibly Damaging | 3.33 | Benign | 0.03 | Affected | 0.3173 | 0.3713 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1613A>T | E538V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E538V missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, premPS, and FATHMM. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized and FoldX give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of evidence points to a pathogenic effect. Based on the aggregate predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.033501 | Uncertain | 0.938 | 0.359 | 0.000 | -11.537 | Likely Pathogenic | 0.885 | Likely Pathogenic | Ambiguous | 0.67 | Ambiguous | 0.0 | -0.49 | Likely Benign | 0.09 | Likely Benign | 0.23 | Likely Benign | 0.310 | Likely Benign | -5.53 | Deleterious | 0.929 | Possibly Damaging | 0.641 | Possibly Damaging | 3.30 | Benign | 0.04 | Affected | 0.0722 | 0.4436 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1614G>C | E538D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E538D is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and FATHMM. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports benign. Consequently, the variant is most likely benign, and this prediction does not contradict the ClinVar status (no ClinVar entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.122885 | Structured | 0.033501 | Uncertain | 0.938 | 0.359 | 0.000 | -2.355 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.32 | Likely Benign | 0.0 | 0.09 | Likely Benign | 0.21 | Likely Benign | 0.16 | Likely Benign | 0.122 | Likely Benign | -0.88 | Neutral | 0.002 | Benign | 0.005 | Benign | 3.35 | Benign | 0.30 | Tolerated | 0.1801 | 0.2352 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1614G>T | E538D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E538D is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and FATHMM. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports benign. Consequently, the variant is most likely benign, and this prediction does not contradict the ClinVar status (no ClinVar entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.122885 | Structured | 0.033501 | Uncertain | 0.938 | 0.359 | 0.000 | -2.355 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.32 | Likely Benign | 0.0 | 0.09 | Likely Benign | 0.21 | Likely Benign | 0.16 | Likely Benign | 0.122 | Likely Benign | -0.88 | Neutral | 0.002 | Benign | 0.005 | Benign | 3.35 | Benign | 0.30 | Tolerated | 0.1801 | 0.2352 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1615C>A | H539N 2D 3DClick to see structure in 3D Viewer AISynGAP1 H539N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Foldetta, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further clarify the variant’s impact: AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a benign change. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence points toward a pathogenic effect, which does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.031398 | Uncertain | 0.948 | 0.360 | 0.000 | -8.685 | Likely Pathogenic | 0.751 | Likely Pathogenic | Likely Benign | 0.12 | Likely Benign | 0.1 | 0.78 | Ambiguous | 0.45 | Likely Benign | 0.72 | Ambiguous | 0.647 | Likely Pathogenic | -5.93 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.89 | Pathogenic | 0.26 | Tolerated | 0.1234 | 0.1281 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| c.1615C>G | H539D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H539D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the only inconclusive result is FoldX, which is listed as uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is consistent with the absence of any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.031398 | Uncertain | 0.948 | 0.360 | 0.000 | -16.450 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 1.22 | Ambiguous | 0.2 | 3.27 | Destabilizing | 2.25 | Destabilizing | 1.08 | Destabilizing | 0.889 | Likely Pathogenic | -8.05 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.25 | Pathogenic | 0.02 | Affected | 0.2008 | 0.0708 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.1615C>T | H539Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H539Y has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include only premPS, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default) all predict a pathogenic impact. Predictions marked as uncertain are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for H539Y. This conclusion is not contradicted by ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.031398 | Uncertain | 0.948 | 0.360 | 0.000 | -13.177 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | -1.22 | Ambiguous | 0.0 | -1.12 | Ambiguous | -1.17 | Ambiguous | 0.34 | Likely Benign | 0.906 | Likely Pathogenic | -5.60 | Deleterious | 0.998 | Probably Damaging | 0.990 | Probably Damaging | -1.26 | Pathogenic | 0.01 | Affected | 0.0776 | 0.2552 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||
| c.1616A>C | H539P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H539P missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include only FoldX, whereas all other evaluated algorithms—REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Taken together, the overwhelming majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.031398 | Uncertain | 0.948 | 0.360 | 0.000 | -15.182 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.22 | Likely Benign | 0.3 | 9.08 | Destabilizing | 4.65 | Destabilizing | 1.03 | Destabilizing | 0.913 | Likely Pathogenic | -9.18 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 0.1900 | 0.2794 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.1616A>G | H539R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H539R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from SIFT and the protein‑folding stability method Foldetta, whereas the remaining tools (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) suggests a benign impact. Overall, the preponderance of evidence points to a pathogenic effect for H539R, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.031398 | Uncertain | 0.948 | 0.360 | 0.000 | -14.979 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | -0.83 | Ambiguous | 0.1 | 0.66 | Ambiguous | -0.09 | Likely Benign | 1.02 | Destabilizing | 0.832 | Likely Pathogenic | -7.19 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | -1.16 | Pathogenic | 0.07 | Tolerated | 0.1497 | 0.1112 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||
| c.1616A>T | H539L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H539L is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, the SGM Consensus is likely pathogenic, and Foldetta’s stability prediction is uncertain. No evidence from the available data contradicts the ClinVar status, which is currently unreported. Overall, the preponderance of computational evidence indicates that H539L is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.031398 | Uncertain | 0.948 | 0.360 | 0.000 | -14.161 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | -1.76 | Ambiguous | 0.1 | -0.17 | Likely Benign | -0.97 | Ambiguous | 0.35 | Likely Benign | 0.879 | Likely Pathogenic | -10.17 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 0.0758 | 0.3680 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||
| c.1617C>A | H539Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H539Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SIFT, FoldX, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain predictions come from AlphaMissense‑Optimized, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of tools (nine pathogenic vs. three benign) indicate a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.031398 | Uncertain | 0.948 | 0.360 | 0.000 | -9.133 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | -0.42 | Likely Benign | 0.0 | 0.92 | Ambiguous | 0.25 | Likely Benign | 0.89 | Ambiguous | 0.597 | Likely Pathogenic | -7.05 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.21 | Pathogenic | 0.07 | Tolerated | 0.1052 | 0.2008 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.1617C>G | H539Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H539Q missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include SIFT, FoldX, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain predictions come from AlphaMissense‑Optimized, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of tools (nine pathogenic vs. three benign) and the SGM‑Consensus result support a pathogenic classification, while Foldetta suggests benign. No ClinVar entry exists to contradict these predictions, so the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.031398 | Uncertain | 0.948 | 0.360 | 0.000 | -9.133 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | -0.42 | Likely Benign | 0.0 | 0.92 | Ambiguous | 0.25 | Likely Benign | 0.89 | Ambiguous | 0.597 | Likely Pathogenic | -7.05 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.21 | Pathogenic | 0.07 | Tolerated | 0.1052 | 0.2008 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.1618C>A | Q540K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q540K is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions (10 pathogenic vs. 5 benign) indicate a likely pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.029522 | Uncertain | 0.958 | 0.371 | 0.000 | -11.418 | Likely Pathogenic | 0.638 | Likely Pathogenic | Likely Benign | -0.37 | Likely Benign | 0.0 | -0.03 | Likely Benign | -0.20 | Likely Benign | 0.76 | Ambiguous | 0.808 | Likely Pathogenic | -3.98 | Deleterious | 0.985 | Probably Damaging | 0.965 | Probably Damaging | -1.31 | Pathogenic | 0.06 | Tolerated | 0.1508 | 0.2472 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.1618C>G | Q540E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q540E is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated tools—REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus majority vote—predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX and Rosetta individually also returned uncertain results. Based on the overall consensus of the majority of prediction algorithms, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.029522 | Uncertain | 0.958 | 0.371 | 0.000 | -14.417 | Likely Pathogenic | 0.622 | Likely Pathogenic | Likely Benign | 0.69 | Ambiguous | 0.1 | 0.85 | Ambiguous | 0.77 | Ambiguous | 0.80 | Ambiguous | 0.747 | Likely Pathogenic | -2.98 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | -1.32 | Pathogenic | 0.04 | Affected | 0.1171 | 0.1337 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1619A>C | Q540P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q540P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic, while premPS is uncertain. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a pathogenic effect. No tool predicts a benign outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.029522 | Uncertain | 0.958 | 0.371 | 0.000 | -16.096 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.95 | Destabilizing | 0.3 | 10.06 | Destabilizing | 7.01 | Destabilizing | 0.73 | Ambiguous | 0.922 | Likely Pathogenic | -5.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 0.1882 | 0.3654 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.1619A>G | Q540R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q540R has no ClinVar entry and is present in gnomAD (ID 6‑33438862‑A‑G). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools report uncertainty: premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. Overall, the majority of evidence points to a benign impact, with only a minority of tools indicating pathogenicity. This conclusion does not contradict ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.029522 | Uncertain | 0.958 | 0.371 | 0.000 | 6-33438862-A-G | 1 | 6.19e-7 | -13.312 | Likely Pathogenic | 0.540 | Ambiguous | Likely Benign | -0.06 | Likely Benign | 0.0 | -0.07 | Likely Benign | -0.07 | Likely Benign | 0.88 | Ambiguous | 0.795 | Likely Pathogenic | -3.98 | Deleterious | 0.991 | Probably Damaging | 0.985 | Probably Damaging | -1.28 | Pathogenic | 0.08 | Tolerated | 3.37 | 35 | 0.1328 | 0.1886 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||
| c.1619A>T | Q540L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q540L has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from Rosetta, Foldetta, premPS, and SIFT, while pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX is uncertain and therefore not considered. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of evidence points to a pathogenic impact for Q540L, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.029522 | Uncertain | 0.958 | 0.371 | 0.000 | -14.266 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | -0.71 | Ambiguous | 0.1 | 0.44 | Likely Benign | -0.14 | Likely Benign | 0.50 | Likely Benign | 0.756 | Likely Pathogenic | -6.96 | Deleterious | 0.994 | Probably Damaging | 0.977 | Probably Damaging | -1.06 | Pathogenic | 0.08 | Tolerated | 0.0654 | 0.3601 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||
| c.161A>C | N54T 2D AIThe SynGAP1 missense variant N54T 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, and SIFT. 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 computational evidence points to a benign impact, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -5.808 | Likely Benign | 0.386 | Ambiguous | Likely Benign | 0.070 | Likely Benign | -0.47 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.20 | Benign | 0.00 | Affected | 0.1268 | 0.7498 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||||||
| c.161A>G | N54S 2D AIThe SynGAP1 missense variant N54S 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, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect 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 | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -5.358 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -0.17 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 4.31 | Benign | 0.00 | Affected | 0.3740 | 0.7048 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.161A>T | N54I 2D AIThe SynGAP1 missense variant N54I 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, and FATHMM. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward pathogenicity. Thus, 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. | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -9.919 | Likely Pathogenic | 0.890 | Likely Pathogenic | Ambiguous | 0.201 | Likely Benign | -1.70 | Neutral | 0.943 | Possibly Damaging | 0.924 | Probably Damaging | 4.15 | Benign | 0.00 | Affected | 0.0637 | 0.6793 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.1620G>C | Q540H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q540H is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool predicts a benign effect. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a damaging effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the evidence strongly favors a pathogenic impact for Q540H, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.029522 | Uncertain | 0.958 | 0.371 | 0.000 | -12.730 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 1.79 | Ambiguous | 0.6 | 1.46 | Ambiguous | 1.63 | Ambiguous | 0.72 | Ambiguous | 0.832 | Likely Pathogenic | -4.97 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.30 | Pathogenic | 0.03 | Affected | 0.1179 | 0.2072 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.1620G>T | Q540H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q540H is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool predicts a benign effect. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a damaging effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the evidence strongly favors a pathogenic impact for Q540H, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.029522 | Uncertain | 0.958 | 0.371 | 0.000 | -12.730 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 1.79 | Ambiguous | 0.6 | 1.46 | Ambiguous | 1.63 | Ambiguous | 0.72 | Ambiguous | 0.832 | Likely Pathogenic | -4.97 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.30 | Pathogenic | 0.03 | Affected | 0.1179 | 0.2072 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.1621G>A | A541T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A541T missense variant is not listed in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that report a benign effect include Rosetta, Foldetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools (FoldX and AlphaMissense‑Default) returned uncertain results. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized predicts benign; Foldetta predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic. Overall, the majority of tools (six benign vs. five pathogenic) suggest a benign impact, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | -8.555 | Likely Pathogenic | 0.541 | Ambiguous | Likely Benign | 0.52 | Ambiguous | 0.0 | -0.07 | Likely Benign | 0.23 | Likely Benign | 0.45 | Likely Benign | 0.500 | Likely Pathogenic | -2.02 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.28 | Pathogenic | 0.15 | Tolerated | 0.1088 | 0.4164 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.1621G>C | A541P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. No predictions are inconclusive or missing. Overall, the collective evidence points to a pathogenic effect for A541P, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | Uncertain | 1 | -14.733 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.47 | Destabilizing | 0.3 | 7.26 | Destabilizing | 4.87 | Destabilizing | 0.86 | Ambiguous | 0.594 | Likely Pathogenic | -3.16 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.34 | Pathogenic | 0.07 | Tolerated | 3.37 | 35 | 0.1706 | 0.2707 | 1 | -1 | -3.4 | 26.04 | 170.4 | -11.2 | 0.1 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | Ala541 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala541 is on the surface and does not form any interactions. Proline lacks a free backbone amide group, and thus, Pro541 is unable to form a hydrogen bond with the carbonyl group of Ala537 in the variant simulations. Consequently, Pro541 disrupts the continuity of the secondary structure element, causing the α-helix to bend slightly in the variant simulations. | ||||||||||||||||
| c.1621G>T | A541S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541S is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools overwhelmingly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all classify the change as tolerated. In contrast, only three tools—polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM—predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized reports Benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | -5.941 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.15 | Likely Benign | 0.0 | 0.18 | Likely Benign | 0.17 | Likely Benign | 0.35 | Likely Benign | 0.347 | Likely Benign | -0.45 | Neutral | 0.983 | Probably Damaging | 0.993 | Probably Damaging | -1.27 | Pathogenic | 0.44 | Tolerated | 0.2182 | 0.3340 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1622C>A | A541D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SIFT and FoldX, whereas a larger group—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | -11.510 | Likely Pathogenic | 0.864 | Likely Pathogenic | Ambiguous | 0.36 | Likely Benign | 0.0 | 0.65 | Ambiguous | 0.51 | Ambiguous | 0.65 | Ambiguous | 0.571 | Likely Pathogenic | -3.18 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.15 | Pathogenic | 0.14 | Tolerated | 0.1581 | 0.1902 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1622C>G | A541G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A541G is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438865‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, and ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, the balance of evidence leans toward a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | Uncertain | 1 | 6-33438865-C-G | 2 | 1.24e-6 | -7.233 | In-Between | 0.341 | Ambiguous | Likely Benign | 0.67 | Ambiguous | 0.0 | 0.94 | Ambiguous | 0.81 | Ambiguous | 0.76 | Ambiguous | 0.421 | Likely Benign | -1.48 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.31 | Pathogenic | 0.57 | Tolerated | 3.37 | 35 | 0.1787 | 0.2428 | 1 | 0 | -2.2 | -14.03 | 170.1 | 23.6 | 0.0 | 0.0 | 0.0 | 0.0 | X | Potentially Pathogenic | Ala541 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala541 is on the surface and does not form any interactions. Glycine, known as an “α-helix breaker,” weakens the integrity of the helix. Indeed, in the variant simulations, the hydrogen bond formation between Gly541 and the backbone carbonyl of Ala537 is disrupted. | ||||||||||||||
| c.1622C>T | A541V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541V is not reported in ClinVar and is absent from gnomAD. Benign predictions come from REVEL, Foldetta, premPS, SIFT, Rosetta, and AlphaMissense‑Optimized, whereas pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy tools give mixed results: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. FoldX is uncertain and therefore not considered. Overall, the majority of tools predict pathogenicity, and this assessment is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | -9.777 | Likely Pathogenic | 0.762 | Likely Pathogenic | Likely Benign | 0.63 | Ambiguous | 0.1 | 0.06 | Likely Benign | 0.35 | Likely Benign | 0.43 | Likely Benign | 0.497 | Likely Benign | -3.09 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | -1.33 | Pathogenic | 0.06 | Tolerated | 0.0985 | 0.3648 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.1624A>C | N542H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N542H is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of evidence supports a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | -10.983 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.06 | Likely Benign | 0.1 | -0.12 | Likely Benign | -0.03 | Likely Benign | 0.46 | Likely Benign | 0.791 | Likely Pathogenic | -3.91 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.44 | Pathogenic | 0.05 | Affected | 0.1137 | 0.5368 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.1624A>G | N542D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N542D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the majority of tools (REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact; Rosetta and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | -13.269 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 2.13 | Destabilizing | 0.3 | 1.75 | Ambiguous | 1.94 | Ambiguous | 1.05 | Destabilizing | 0.796 | Likely Pathogenic | -4.51 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.40 | Pathogenic | 0.08 | Tolerated | 0.1664 | 0.3176 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1624A>T | N542Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N542Y is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS, while the 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, Rosetta, and Foldetta are inconclusive. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts likely pathogenic; Foldetta, a protein‑folding stability approach combining FoldX‑MD and Rosetta, remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for the variant, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | -14.488 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | -0.66 | Ambiguous | 0.0 | -0.56 | Ambiguous | -0.61 | Ambiguous | 0.42 | Likely Benign | 0.872 | Likely Pathogenic | -6.86 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.46 | Pathogenic | 0.02 | Affected | 0.0578 | 0.5480 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.1625A>C | N542T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N542T 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 SIFT and Rosetta. Tools that predict a pathogenic effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. 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 | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | -9.918 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 1.13 | Ambiguous | 0.1 | 0.20 | Likely Benign | 0.67 | Ambiguous | 0.75 | Ambiguous | 0.784 | Likely Pathogenic | -5.37 | Deleterious | 0.997 | Probably Damaging | 0.990 | Probably Damaging | -1.41 | Pathogenic | 0.12 | Tolerated | 0.1120 | 0.5872 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.1625A>G | N542S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N542S is listed in ClinVar as benign (ClinVar ID 833567.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include SIFT and AlphaMissense‑Optimized, whereas the majority of tools predict pathogenicity: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (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 preponderance of evidence points to a pathogenic effect, which is in conflict with the ClinVar benign designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | Likely Benign | 1 | -9.675 | Likely Pathogenic | 0.767 | Likely Pathogenic | Likely Benign | 0.98 | Ambiguous | 0.1 | 0.99 | Ambiguous | 0.99 | Ambiguous | 0.91 | Ambiguous | 0.752 | Likely Pathogenic | -4.40 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | -1.36 | Pathogenic | 0.13 | Tolerated | 3.37 | 35 | 0.3054 | 0.5719 | 1 | 1 | 2.7 | -27.03 | 212.5 | 32.1 | 0.0 | 0.0 | -0.6 | 0.3 | X | Potentially Pathogenic | Asn542 is located in an α-helix (res. Ala533-Val560) next to an α-α loop between two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the carboxamide group of the Asn542 side chain forms a hydrogen bond with the backbone carbonyl group of Asn523 and packs favourably against Glu522 from the loop. In contrast, in the variant simulations, the hydroxyl group of the Ser542 side chain is unable to maintain either the hydrogen bond with Asn523 or the packing against the Glu522 side chain. Instead, the hydroxyl group of Ser542 occasionally forms a hydrogen bond with the backbone carbonyl group of Glu538.Altogether, the residue swap results in a looser helix-loop association, which is especially evident in the third replica simulation, where Asn523 moves away from its initial placement next to the α-helix. In short, based on the simulations, the residue swap weakens the GAP domain tertiary structure assembly, which in turn could negatively affect protein folding. | ||||||||||||||||
| c.1625A>T | N542I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N542I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from FoldX, Rosetta, Foldetta, and premPS, whereas pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. High‑accuracy assessments give AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta) as benign. Thus, the majority of evidence points to a deleterious effect, with only a minority of tools predicting benign stability. The variant is most likely pathogenic, and this assessment does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | -14.975 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.14 | Likely Benign | 0.4 | -0.38 | Likely Benign | -0.12 | Likely Benign | 0.42 | Likely Benign | 0.829 | Likely Pathogenic | -7.99 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.37 | Pathogenic | 0.02 | Affected | 0.0638 | 0.5427 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.1626C>A | N542K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N542K is not reported in ClinVar and has no entries in gnomAD. Prediction tools largely disagree: benign calls come from FoldX, SIFT, and Foldetta; pathogenic calls come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (Rosetta and premPS) give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, whereas Foldetta predicts benign. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence (nine pathogenic vs three benign) points to a pathogenic effect. 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 | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | -11.967 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.36 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.09 | Likely Benign | 0.75 | Ambiguous | 0.610 | Likely Pathogenic | -5.33 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.23 | Pathogenic | 0.10 | Tolerated | 0.1870 | 0.4349 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1626C>G | N542K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N542K 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, SIFT, and Foldetta. Those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (Rosetta and premPS) returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also pathogenic, while Foldetta predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the majority of evidence (nine pathogenic vs. three benign) indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | -11.967 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.36 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.09 | Likely Benign | 0.75 | Ambiguous | 0.610 | Likely Pathogenic | -5.33 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.23 | Pathogenic | 0.10 | Tolerated | 0.1870 | 0.4349 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1627C>A | L543M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L543M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and PROVEAN, whereas pathogenic calls are made by polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Rosetta. Predictions that are uncertain (FoldX, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments give AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of available tools predict a deleterious effect, indicating that the variant is most likely pathogenic. 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 Pathogenic | GAP | 0.048328 | Structured | 0.020918 | Uncertain | 0.963 | 0.314 | 0.000 | -11.452 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.68 | Ambiguous | 0.2 | 2.53 | Destabilizing | 1.61 | Ambiguous | 0.99 | Ambiguous | 0.382 | Likely Benign | -1.99 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.93 | Pathogenic | 0.01 | Affected | 0.0788 | 0.2172 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1627C>G | L543V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L543V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—classify the variant as pathogenic. AlphaMissense‑Optimized is inconclusive (uncertain). High‑accuracy assessments further support pathogenicity: the SGM‑Consensus predicts “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. AlphaMissense‑Optimized remains uncertain. Based on the overwhelming majority of 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 | GAP | 0.048328 | Structured | 0.020918 | Uncertain | 0.963 | 0.314 | 0.000 | -11.561 | Likely Pathogenic | 0.908 | Likely Pathogenic | Ambiguous | 3.09 | Destabilizing | 0.3 | 2.03 | Destabilizing | 2.56 | Destabilizing | 1.28 | Destabilizing | 0.398 | Likely Benign | -2.99 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 1.99 | Pathogenic | 0.01 | Affected | 0.1334 | 0.2028 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1628T>A | L543Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L543Q 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 predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.020918 | Uncertain | 0.963 | 0.314 | 0.000 | -14.851 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.03 | Destabilizing | 0.2 | 3.48 | Destabilizing | 3.26 | Destabilizing | 2.25 | Destabilizing | 0.746 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.89 | Pathogenic | 0.00 | Affected | 0.0983 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1628T>C | L543P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L543P 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, 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 the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.020918 | Uncertain | 0.963 | 0.314 | 0.000 | -15.958 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 8.56 | Destabilizing | 0.6 | 13.44 | Destabilizing | 11.00 | Destabilizing | 1.54 | Destabilizing | 0.770 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.89 | Pathogenic | 0.00 | Affected | 0.3457 | 0.0992 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1628T>G | L543R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L543R is not reported in ClinVar (ClinVar status: 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 pathogenic impact. 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 | GAP | 0.048328 | Structured | 0.020918 | Uncertain | 0.963 | 0.314 | 0.000 | -18.563 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.47 | Destabilizing | 1.2 | 8.02 | Destabilizing | 5.75 | Destabilizing | 1.64 | Destabilizing | 0.739 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.89 | Pathogenic | 0.00 | Affected | 0.1229 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.162C>A | N54K 2D AIThe SynGAP1 missense variant N54K is 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign) and is treated as unavailable. High‑accuracy methods show AlphaMissense‑Optimized as benign; Foldetta results are not provided, so its stability prediction is unavailable. Overall, the balance of evidence (five pathogenic vs. four benign predictions) suggests the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -8.252 | Likely Pathogenic | 0.779 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | -0.82 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.23 | Benign | 0.00 | Affected | 0.2010 | 0.5987 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||||
| c.162C>G | N54K 2D AIThe SynGAP1 missense variant N54K is 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign) and is treated as unavailable. High‑accuracy methods show AlphaMissense‑Optimized as benign; Foldetta results are not provided, so its stability prediction is unavailable. Overall, the balance of evidence (five pathogenic vs. four benign predictions) suggests the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -8.252 | Likely Pathogenic | 0.779 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | -0.82 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.23 | Benign | 0.00 | Affected | 0.2010 | 0.5987 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||||
| c.1630C>G | R544G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R544G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from SIFT, while the remaining eleven tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. Taken together, the consensus of the majority of tools and the high‑accuracy methods indicates that R544G is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038858 | Structured | 0.016004 | Uncertain | 0.967 | 0.333 | 0.000 | -12.971 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 2.58 | Destabilizing | 0.2 | 2.18 | Destabilizing | 2.38 | Destabilizing | 0.74 | Ambiguous | 0.714 | Likely Pathogenic | -5.33 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.48 | Pathogenic | 0.09 | Tolerated | 0.2711 | 0.2123 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1631G>A | R544Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R544Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438874‑G‑A). Prediction tools that classify the change as benign include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Foldetta and Rosetta 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 remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, which is not contradictory to the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038858 | Structured | 0.016004 | Uncertain | 0.967 | 0.333 | 0.000 | Uncertain | 1 | 6-33438874-G-A | 1 | 6.20e-7 | -10.281 | Likely Pathogenic | 0.596 | Likely Pathogenic | Likely Benign | 0.19 | Likely Benign | 0.2 | 0.87 | Ambiguous | 0.53 | Ambiguous | 1.40 | Destabilizing | 0.542 | Likely Pathogenic | -2.41 | Neutral | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.40 | Pathogenic | 0.09 | Tolerated | 3.37 | 35 | 0.2103 | 0.1959 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||
| c.1631G>C | R544P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R544P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Across the available in‑silico predictors, none indicate a benign effect; all 13 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized 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. Consequently, the variant is most likely pathogenic based on current predictions, which contradicts the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038858 | Structured | 0.016004 | Uncertain | 0.967 | 0.333 | 0.000 | Uncertain | 2 | -16.905 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.70 | Destabilizing | 0.1 | 4.19 | Destabilizing | 4.45 | Destabilizing | 1.14 | Destabilizing | 0.762 | Likely Pathogenic | -4.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.48 | Pathogenic | 0.05 | Affected | 3.37 | 35 | 0.2024 | 0.3038 | 0 | -2 | 2.9 | -59.07 | 192.0 | 123.8 | 0.1 | 0.0 | -0.3 | 0.0 | X | X | Potentially Pathogenic | Arg544 is located in the middle of an α-helix (res. Ala533-Val560). In the WT simulations, the guanidinium side chain of Arg544 forms a salt bridge with the carboxylate groups of Glu548 on the same α-helix, and with Glu651 and Glu656 on an opposing α-helix (res. Glu666-Asp644). In the variant simulations, the pyrrolidine side chain of Pro544 cannot form any of the salt bridges that Arg544 does in the WT, potentially weakening the tertiary structure assembly. Additionally, Pro544 lacks the amide group, and thus, unlike Arg544 in the WT, is unable to form a hydrogen bond with the carbonyl of Gln540. This disruption breaks the continuity of the secondary structure element, causing the α-helix to bend slightly in the variant simulations. These negative structural effects could be more pronounced during protein folding and are likely to be undermined in the MD simulations. | |||||||||||||||
| c.1631G>T | R544L 2D AIThe SynGAP1 R544L missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and SIFT, whereas tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default; 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 predictions are mixed, with a slight majority leaning toward pathogenicity, and there is no ClinVar entry to contradict these findings. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038858 | Structured | 0.016004 | Uncertain | 0.967 | 0.333 | 0.000 | -13.159 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | -0.34 | Likely Benign | 0.6 | 0.08 | Likely Benign | -0.13 | Likely Benign | 0.29 | Likely Benign | 0.573 | Likely Pathogenic | -5.43 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.42 | Pathogenic | 0.24 | Tolerated | 0.1478 | 0.3191 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1633A>C | M545L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545L 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, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are AlphaMissense‑Optimized, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of available predictions lean toward pathogenicity, 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 | GAP | 0.025762 | Structured | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | -7.163 | In-Between | 0.914 | Likely Pathogenic | Ambiguous | 0.06 | Likely Benign | 0.1 | 0.26 | Likely Benign | 0.16 | Likely Benign | 0.79 | Ambiguous | 0.638 | Likely Pathogenic | -2.72 | Deleterious | 0.732 | Possibly Damaging | 0.795 | Possibly Damaging | -1.26 | Pathogenic | 0.40 | Tolerated | 0.1239 | 0.2802 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1633A>G | M545V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545V is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include SIFT and Rosetta, while a majority of tools predict a pathogenic outcome: PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus. Tools with inconclusive results (FoldX, Foldetta, premPS, ESM1b) are considered unavailable for interpretation. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for M545V. This conclusion is not contradicted by ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | -7.481 | In-Between | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.91 | Ambiguous | 0.1 | 0.33 | Likely Benign | 0.62 | Ambiguous | 0.94 | Ambiguous | 0.688 | Likely Pathogenic | -3.54 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.26 | Pathogenic | 0.34 | Tolerated | 0.2454 | 0.2953 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||
| c.1633A>T | M545L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545L has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, and SIFT, while pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Uncertain results are reported by premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, seven tools predict pathogenicity versus four predicting benign, with three uncertain. Therefore, 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 | GAP | 0.025762 | Structured | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | -7.163 | In-Between | 0.914 | Likely Pathogenic | Ambiguous | 0.06 | Likely Benign | 0.1 | 0.26 | Likely Benign | 0.16 | Likely Benign | 0.79 | Ambiguous | 0.639 | Likely Pathogenic | -2.72 | Deleterious | 0.732 | Possibly Damaging | 0.795 | Possibly Damaging | -1.26 | Pathogenic | 0.40 | Tolerated | 0.1239 | 0.2802 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1634T>A | M545K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from SIFT, FoldX, and Rosetta, while pathogenic predictions are made by REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and PROVEAN. 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 show AlphaMissense‑Optimized as Pathogenic, SGM Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of evidence points toward a pathogenic 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 | GAP | 0.025762 | Structured | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | -11.723 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.02 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.24 | Likely Benign | 1.07 | Destabilizing | 0.809 | Likely Pathogenic | -4.80 | Deleterious | 0.972 | Probably Damaging | 0.960 | Probably Damaging | -1.17 | Pathogenic | 0.43 | Tolerated | 0.1144 | 0.0488 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.1634T>C | M545T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) uniformly predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta’s protein‑folding stability analysis is inconclusive. Taken together, the preponderance of evidence points to a pathogenic effect for M545T. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | -8.070 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.94 | Ambiguous | 0.2 | 0.78 | Ambiguous | 0.86 | Ambiguous | 0.97 | Ambiguous | 0.722 | Likely Pathogenic | -5.03 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.24 | Pathogenic | 0.36 | Tolerated | 0.1727 | 0.1847 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||
| c.1634T>G | M545R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that classify the variant as benign include SIFT, FoldX, and Foldetta, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta’s assessment is uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenicity; the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign. Overall, the preponderance of evidence from both general and high‑accuracy predictors 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. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | -9.223 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | -0.27 | Likely Benign | 0.1 | 0.95 | Ambiguous | 0.34 | Likely Benign | 1.07 | Destabilizing | 0.773 | Likely Pathogenic | -4.76 | Deleterious | 0.987 | Probably Damaging | 0.971 | Probably Damaging | -1.23 | Pathogenic | 0.36 | Tolerated | 0.1345 | 0.0837 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||
| c.1635G>A | M545I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545I is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions arise from FoldX, Rosetta, and SIFT, whereas pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default; premPS remains inconclusive. High‑accuracy methods provide mixed evidence: AlphaMissense‑Optimized indicates pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also suggests likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the preponderance of conventional tools and the SGM Consensus lean toward pathogenicity, whereas the Foldetta result is an outlier. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict its ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | Uncertain | 1 | -8.348 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.47 | Likely Benign | 0.1 | 0.14 | Likely Benign | 0.31 | Likely Benign | 0.63 | Ambiguous | 0.592 | Likely Pathogenic | -3.61 | Deleterious | 0.935 | Possibly Damaging | 0.941 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 3.37 | 35 | 0.1091 | 0.2114 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||
| c.1635G>C | M545I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545I has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, and SIFT, whereas pathogenic predictions are reported by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus result is a majority vote of four pathogenic predictors (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), confirming its pathogenic label. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign; no other high‑accuracy tools are available. Overall, the majority of predictions support a pathogenic effect, with only a minority indicating benign. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | -8.348 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.47 | Likely Benign | 0.1 | 0.14 | Likely Benign | 0.31 | Likely Benign | 0.63 | Ambiguous | 0.592 | Likely Pathogenic | -3.61 | Deleterious | 0.935 | Possibly Damaging | 0.941 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 3.37 | 35 | 0.1091 | 0.2114 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1635G>T | M545I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and SIFT, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The premPS score is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | -8.348 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.47 | Likely Benign | 0.1 | 0.14 | Likely Benign | 0.31 | Likely Benign | 0.63 | Ambiguous | 0.592 | Likely Pathogenic | -3.61 | Deleterious | 0.935 | Possibly Damaging | 0.941 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 3.37 | 35 | 0.1091 | 0.2114 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1636T>A | C546S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C546S is reported in gnomAD (ID 6‑33438879‑T‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from FoldX and SIFT; pathogenic predictions from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give uncertain results: Rosetta and Foldetta. High‑accuracy assessments reinforce a pathogenic signal: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains inconclusive. Overall, the preponderance of evidence, including the high‑accuracy tools, indicates that C546S is most likely pathogenic, and this assessment does not conflict with any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | 6-33438879-T-A | 1 | 6.20e-7 | -8.079 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.44 | Likely Benign | 0.1 | 1.39 | Ambiguous | 0.92 | Ambiguous | 1.65 | Destabilizing | 0.836 | Likely Pathogenic | -8.04 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.21 | Pathogenic | 0.17 | Tolerated | 3.37 | 35 | 0.4343 | 0.1950 | -1 | 0 | -3.3 | -16.06 | ||||||||||||||||||||||||
| c.1636T>C | C546R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C546R is 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 SIFT, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta return uncertain results and are therefore not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | -15.237 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | -0.70 | Ambiguous | 0.3 | 2.04 | Destabilizing | 0.67 | Ambiguous | 1.70 | Destabilizing | 0.894 | Likely Pathogenic | -9.73 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.26 | Pathogenic | 0.06 | Tolerated | 0.1808 | 0.1685 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.1636T>G | C546G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant C546G is not reported in ClinVar and is present in gnomAD (ID 6‑33438879‑T‑G). Prediction tools that indicate a benign effect include only SIFT, whereas the remaining tools—REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—predict a pathogenic outcome. 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 is inconclusive and therefore not considered evidence. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | 6-33438879-T-G | 1 | 6.20e-7 | -14.026 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 1.55 | Ambiguous | 0.0 | 2.43 | Destabilizing | 1.99 | Ambiguous | 1.53 | Destabilizing | 0.877 | Likely Pathogenic | -9.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.26 | Pathogenic | 0.06 | Tolerated | 3.37 | 35 | 0.3135 | 0.2513 | -3 | -3 | -2.9 | -46.09 | ||||||||||||||||||||||||
| c.1637G>A | C546Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C546Y is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include FoldX, premPS, and SIFT, whereas the remaining tools—SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports a pathogenic effect; 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 impact. Based on the collective evidence, 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 | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | -10.771 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | -0.08 | Likely Benign | 1.8 | 4.75 | Destabilizing | 2.34 | Destabilizing | 0.09 | Likely Benign | 0.794 | Likely Pathogenic | -8.74 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.07 | Pathogenic | 0.29 | Tolerated | 0.1433 | 0.3015 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1637G>C | C546S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C546S 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 and SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta and Foldetta are uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for C546S, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | -8.079 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.44 | Likely Benign | 0.1 | 1.39 | Ambiguous | 0.92 | Ambiguous | 1.65 | Destabilizing | 0.788 | Likely Pathogenic | -8.04 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.21 | Pathogenic | 0.17 | Tolerated | 3.37 | 35 | 0.4343 | 0.1950 | -1 | 0 | -3.3 | -16.06 | |||||||||||||||||||||||||||
| c.1637G>T | C546F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant C546F is not reported in ClinVar and is absent from gnomAD. In silico predictors that classify the variant as benign include premPS and SIFT, whereas the majority of tools predict pathogenicity: REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus score (Likely Pathogenic). High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, SGM Consensus also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for C546F, and this assessment does not conflict with 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 | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | -13.479 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | -1.21 | Ambiguous | 0.9 | 3.98 | Destabilizing | 1.39 | Ambiguous | 0.34 | Likely Benign | 0.800 | Likely Pathogenic | -8.99 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.20 | Pathogenic | 0.12 | Tolerated | 0.1622 | 0.3533 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.1638C>G | C546W 2D 3DClick to see structure in 3D Viewer AIClinVar has no entry for this SynGAP1 missense variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, which scores the substitution as tolerated. The majority of other in silico predictors classify the change as pathogenic: REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) report a likely pathogenic outcome. Predictions that are inconclusive or unavailable are FoldX, Foldetta, and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, while Foldetta’s stability analysis is uncertain. Overall, the consensus of the available evidence points to a pathogenic effect for the variant, and this conclusion 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 | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | -14.685 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | -0.79 | Ambiguous | 1.2 | 3.60 | Destabilizing | 1.41 | Ambiguous | 0.56 | Ambiguous | 0.703 | Likely Pathogenic | -9.09 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.24 | Pathogenic | 0.08 | Tolerated | 0.1855 | 0.2904 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1639T>A | C547S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547S 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, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tools predict a benign outcome. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | -11.888 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.85 | Ambiguous | 0.0 | 1.73 | Ambiguous | 1.29 | Ambiguous | 1.76 | Destabilizing | 0.884 | Likely Pathogenic | -9.64 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.27 | Pathogenic | 0.04 | Affected | 0.4542 | 0.1792 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1639T>C | C547R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547R 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, while 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, also predicts pathogenicity. 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 | GAP | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | Uncertain | 1 | -16.967 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 7.76 | Destabilizing | 0.8 | 5.83 | Destabilizing | 6.80 | Destabilizing | 1.69 | Destabilizing | 0.900 | Likely Pathogenic | -11.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.33 | Pathogenic | 0.02 | Affected | 3.37 | 35 | 0.1802 | 0.1408 | -4 | -3 | -7.0 | 53.05 | 267.4 | -90.3 | 0.0 | 0.0 | -0.1 | 0.1 | X | X | X | X | Potentially Pathogenic | Cys547 is located in an α-helix (res. Ala533-Val560). The thiol side chain of Cys is situated in a hydrophobic inter-helix space, where it packs hydrophobically with other residues such as Ile626, Leu551, and Phe652. Additionally, the thiol side chain of Cys547 weakly hydrogen bonds with the carbonyl group of Leu543 in the same α-helix. In the variant simulations, the bulkier, positively charged guanidinium group of Arg547 must rotate out of the hydrophobic space. Consequently, it forms ionic interactions with the carboxylate groups of Glu548 in the same helix and Glu656 in the neighboring α-helix (res. Glu666-Asp644). This causes the two helices to slightly separate, significantly affecting the secondary structure integrity of the latter helix. These negative structural effects could be more pronounced during protein folding and are likely to be undermined in the MD simulations. | |||||||||||||
| c.1639T>G | C547G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict pathogenic. No tool predicts a benign outcome. AlphaMissense‑Optimized is uncertain, providing no definitive direction. High‑accuracy assessments further support a harmful impact: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a pathogenic effect. Taken together, the evidence overwhelmingly points to a pathogenic classification for this variant, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | -14.182 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | 2.21 | Destabilizing | 0.0 | 2.99 | Destabilizing | 2.60 | Destabilizing | 1.83 | Destabilizing | 0.902 | Likely Pathogenic | -11.60 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.30 | Pathogenic | 0.05 | Affected | 0.3201 | 0.2502 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.163C>A | Q55K 2D AIThe SynGAP1 missense variant Q55K is listed in ClinVar (ID 520688.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33423572‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The 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, and this is not in conflict with the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.332115 | Structured | 0.470108 | Uncertain | 0.461 | 0.657 | 0.000 | Uncertain | 2 | 6-33423572-C-A | 24 | 1.49e-5 | -5.840 | Likely Benign | 0.612 | Likely Pathogenic | Likely Benign | 0.085 | Likely Benign | -1.21 | Neutral | 0.140 | Benign | 0.184 | Benign | 3.91 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2047 | 0.4129 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||||
| c.163C>G | Q55E 2D AIThe SynGAP1 missense variant Q55E 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), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while SIFT uniquely predicts pathogenic. ESM1b is 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 reinforce this: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also indicates likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign impact, 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 | 0.332115 | Structured | 0.470108 | Uncertain | 0.461 | 0.657 | 0.000 | -7.361 | In-Between | 0.265 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.98 | Neutral | 0.064 | Benign | 0.184 | Benign | 3.89 | Benign | 0.00 | Affected | 0.1380 | 0.2632 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.1640G>A | C547Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547Y (ClinVar ID 1404191.0) is listed as Pathogenic in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Taken together, the overwhelming majority of computational evidence indicates a pathogenic effect, which is in agreement with the ClinVar classification. Thus, the variant is most likely pathogenic and does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | Pathogenic | 1 | -15.871 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 8.53 | Destabilizing | 1.8 | 6.20 | Destabilizing | 7.37 | Destabilizing | 0.62 | Ambiguous | 0.874 | Likely Pathogenic | -10.57 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.33 | Pathogenic | 0.06 | Tolerated | 3.37 | 35 | 0.1393 | 0.2742 | 0 | -2 | -3.8 | 60.04 | 280.1 | -54.8 | 0.0 | 0.0 | 0.0 | 0.0 | X | X | X | Potentially Pathogenic | Cys547 is located in an α-helix (res. Ala533-Val560). The thiol side chain of Cys547 is situated in a hydrophobic inter-helix space, where it packs hydrophobically with other residues such as Ile626, Leu551, and Phe652. Additionally, the thiol side chain of Cys weakly hydrogen bonds with the carbonyl group of Leu543 in the same α-helix. In the variant simulations, the bulkier phenol ring of Tyr547, with its polar hydroxyl group, is less suited for the hydrophobic space. Consequently, it moves outside and forms a hydrogen bond with the carbonyl group of Phe652 in the neighboring α-helix (res. Glu666-Asp644). This causes the two helices to slightly separate, negatively affecting the secondary structure integrity of the latter helix. These negative structural effects could be more pronounced during protein folding and are likely to be undermined in the MD simulations. | ||||||||||||||
| c.1640G>C | C547S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547S 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, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tools predict a benign outcome. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | -11.888 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.85 | Ambiguous | 0.0 | 1.73 | Ambiguous | 1.29 | Ambiguous | 1.76 | Destabilizing | 0.825 | Likely Pathogenic | -9.64 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.27 | Pathogenic | 0.04 | Affected | 0.4542 | 0.1792 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1640G>T | C547F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547F is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect fall into two groups: the single benign prediction comes from premPS, while all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify it as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a destabilizing, pathogenic effect. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions and the absence of any ClinVar annotation, the variant is most likely pathogenic, with no contradiction from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | -15.404 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 5.63 | Destabilizing | 1.2 | 5.82 | Destabilizing | 5.73 | Destabilizing | 0.49 | Likely Benign | 0.828 | Likely Pathogenic | -10.57 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.29 | Pathogenic | 0.05 | Affected | 0.1603 | 0.3260 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.1641T>G | C547W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547W is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact 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 variant 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, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenic. Taken together, the overwhelming consensus from both general and high‑accuracy predictors is that C547W is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | -15.788 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 11.03 | Destabilizing | 0.3 | 2.63 | Destabilizing | 6.83 | Destabilizing | 0.54 | Ambiguous | 0.764 | Likely Pathogenic | -10.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.34 | Pathogenic | 0.01 | Affected | 0.1854 | 0.2750 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1642G>A | E548K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E548K missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic impact are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicting likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicating a benign effect on protein stability. Overall, the balance of evidence leans toward a pathogenic interpretation, with no conflict with 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 | GAP | 0.054297 | Structured | 0.008632 | Uncertain | 0.965 | 0.288 | 0.000 | -13.734 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.34 | Likely Benign | 0.0 | -0.19 | Likely Benign | -0.27 | Likely Benign | 0.13 | Likely Benign | 0.348 | Likely Benign | -3.85 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.33 | Benign | 0.09 | Tolerated | 0.1990 | 0.4491 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1642G>C | E548Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 E548Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. 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. Because the predictions are split evenly and the high‑accuracy tools give opposing results, the variant’s functional impact remains ambiguous. Thus, the variant is most likely benign based on the majority of evidence, and this does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.008632 | Uncertain | 0.965 | 0.288 | 0.000 | -11.006 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | -0.15 | Likely Benign | 0.0 | 0.16 | Likely Benign | 0.01 | Likely Benign | 0.05 | Likely Benign | 0.310 | Likely Benign | -2.88 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.37 | Benign | 0.06 | Tolerated | 0.0957 | 0.4330 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1643A>C | E548A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E548A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, FATHMM, premPS, and Foldetta, whereas pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a pathogenic call from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and a benign result from Foldetta. Overall, the majority of evidence points to a pathogenic effect, so the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.008632 | Uncertain | 0.965 | 0.288 | 0.000 | -13.543 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.18 | Likely Benign | 0.1 | 0.56 | Ambiguous | 0.37 | Likely Benign | 0.48 | Likely Benign | 0.499 | Likely Benign | -5.83 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.27 | Benign | 0.05 | Affected | 0.3035 | 0.4328 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1643A>G | E548G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E548G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SIFT and FATHMM, while the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact; SGM‑Consensus also classifies the variant as likely pathogenic. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized predicting pathogenicity, SGM‑Consensus confirming a likely pathogenic status, and Foldetta yielding an inconclusive stability change. Overall, the consensus of the available predictions points to a pathogenic effect for E548G, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.008632 | Uncertain | 0.965 | 0.288 | 0.000 | -12.010 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.97 | Ambiguous | 0.1 | 1.66 | Ambiguous | 1.32 | Ambiguous | 0.59 | Ambiguous | 0.521 | Likely Pathogenic | -6.73 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.32 | Benign | 0.06 | Tolerated | 0.2638 | 0.3654 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1643A>T | E548V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E548V missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, premPS, and FATHMM. In contrast, tools predicting a pathogenic impact are 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, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions (10 pathogenic vs. 5 benign) 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. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.008632 | Uncertain | 0.965 | 0.288 | 0.000 | -15.029 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.29 | Likely Benign | 0.0 | -0.18 | Likely Benign | 0.06 | Likely Benign | 0.36 | Likely Benign | 0.578 | Likely Pathogenic | -6.83 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.24 | Benign | 0.02 | Affected | 0.0569 | 0.4714 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1644G>C | E548D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E548D variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, premPS, SIFT, and FATHMM, whereas a separate group predicts pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are uncertain or unavailable are FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a pathogenic verdict (2 pathogenic, 1 benign, 1 uncertain). Foldetta’s stability prediction is unavailable. Overall, the majority of evidence points to 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. | GAP | 0.054297 | Structured | 0.008632 | Uncertain | 0.965 | 0.288 | 0.000 | -7.359 | In-Between | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.74 | Ambiguous | 0.1 | 1.29 | Ambiguous | 1.02 | Ambiguous | 0.32 | Likely Benign | 0.254 | Likely Benign | -2.85 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | 3.51 | Benign | 0.09 | Tolerated | 0.1374 | 0.2524 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1644G>T | E548D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E548D variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, premPS, SIFT, and FATHMM, whereas a separate group predicts a pathogenic effect: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are uncertain or unavailable are FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a pathogenic verdict (2 pathogenic, 1 benign, 1 uncertain). Foldetta’s stability prediction is unavailable. Overall, the majority of evidence points to a pathogenic impact for E548D, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.054297 | Structured | 0.008632 | Uncertain | 0.965 | 0.288 | 0.000 | -7.359 | In-Between | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.74 | Ambiguous | 0.1 | 1.29 | Ambiguous | 1.02 | Ambiguous | 0.32 | Likely Benign | 0.254 | Likely Benign | -2.85 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | 3.51 | Benign | 0.09 | Tolerated | 0.1374 | 0.2524 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1645T>A | L549M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L549M has no ClinVar assertion and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, PROVEAN, and SIFT; pathogenic predictions come from SGM‑Consensus, REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.007921 | Uncertain | 0.955 | 0.281 | 0.000 | -8.115 | Likely Pathogenic | 0.855 | Likely Pathogenic | Ambiguous | 0.34 | Likely Benign | 0.1 | 0.28 | Likely Benign | 0.31 | Likely Benign | 0.64 | Ambiguous | 0.546 | Likely Pathogenic | -1.49 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.26 | Pathogenic | 0.08 | Tolerated | 0.0811 | 0.2004 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1645T>G | L549V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L549V is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include Rosetta, PROVEAN, and SIFT, whereas a majority of tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default) predict a pathogenic impact. Four tools (FoldX, Foldetta, premPS, and AlphaMissense‑Optimized) give uncertain or inconclusive results. 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 uncertain, SGM Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic interpretation. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.007921 | Uncertain | 0.955 | 0.281 | 0.000 | -9.379 | Likely Pathogenic | 0.847 | Likely Pathogenic | Ambiguous | 1.22 | Ambiguous | 0.3 | 0.27 | Likely Benign | 0.75 | Ambiguous | 0.88 | Ambiguous | 0.544 | Likely Pathogenic | -2.32 | Neutral | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.23 | Pathogenic | 0.21 | Tolerated | 0.1400 | 0.1860 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1646T>C | L549S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L549S is catalogued in gnomAD (ID 6‑33438889‑T‑C) but has no ClinVar entry. Functional prediction tools largely converge on a deleterious effect: SIFT reports a benign change, whereas the remaining 10 evaluated algorithms (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. The high‑accuracy predictors reinforce this trend: AlphaMissense‑Optimized returns a pathogenic score, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. No evidence from FoldX or Rosetta alone is available. Consequently, the variant is most likely pathogenic, and this assessment does not conflict with ClinVar, which contains no classification for this allele. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.007921 | Uncertain | 0.955 | 0.281 | 0.000 | 6-33438889-T-C | 1 | 6.20e-7 | -13.018 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.76 | Ambiguous | 0.4 | 1.03 | Ambiguous | 1.40 | Ambiguous | 1.01 | Destabilizing | 0.801 | Likely Pathogenic | -4.85 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.14 | Pathogenic | 0.34 | Tolerated | 3.37 | 35 | 0.2965 | 0.0305 | -2 | -3 | -4.6 | -26.08 | ||||||||||||||||||||||||
| c.1646T>G | L549W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L549W is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta and Foldetta, whereas the remaining tools—REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM Consensus, and premPS—consistently predict a pathogenic or likely pathogenic impact. 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 as benign. Overall, the preponderance of evidence points to a pathogenic effect for L549W. 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 | GAP | 0.025762 | Structured | 0.007921 | Uncertain | 0.955 | 0.281 | 0.000 | -14.277 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.76 | Ambiguous | 0.4 | -0.19 | Likely Benign | 0.29 | Likely Benign | 1.06 | Destabilizing | 0.763 | Likely Pathogenic | -5.23 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.30 | Pathogenic | 0.04 | Affected | 0.0699 | 0.1632 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.1647G>C | L549F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L549F is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include Rosetta, premPS, and SIFT, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, which is consistent with its ClinVar “Uncertain” classification and does not contradict the available data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.007921 | Uncertain | 0.955 | 0.281 | 0.000 | Uncertain | 1 | -11.634 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.3 | 0.27 | Likely Benign | 0.54 | Ambiguous | 0.49 | Likely Benign | 0.514 | Likely Pathogenic | -3.42 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.29 | Pathogenic | 0.14 | Tolerated | 0.0724 | 0.1859 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||
| c.1647G>T | L549F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L549F is not reported in ClinVar and is absent from gnomAD. Benign predictions come from Rosetta, premPS, and SIFT, whereas pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score indicates likely pathogenic, while FoldX and Foldetta are uncertain. High‑accuracy tools specifically: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic; Foldetta, which integrates 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 currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.007921 | Uncertain | 0.955 | 0.281 | 0.000 | -11.634 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.3 | 0.27 | Likely Benign | 0.54 | Ambiguous | 0.49 | Likely Benign | 0.514 | Likely Pathogenic | -3.42 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.29 | Pathogenic | 0.14 | Tolerated | 0.0724 | 0.1859 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1648G>A | A550T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A550T 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 SIFT, Rosetta, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Foldetta, and premPS are inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta’s stability analysis is uncertain. Overall, the majority of reliable predictors (8/11) indicate a pathogenic impact, whereas only three suggest benign. Therefore, the variant is most likely pathogenic based on current 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 | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | -10.555 | Likely Pathogenic | 0.621 | Likely Pathogenic | Likely Benign | 1.68 | Ambiguous | 0.3 | -0.05 | Likely Benign | 0.82 | Ambiguous | 0.73 | Ambiguous | 0.627 | Likely Pathogenic | -3.19 | Deleterious | 0.991 | Probably Damaging | 0.872 | Possibly Damaging | -1.25 | Pathogenic | 0.10 | Tolerated | 0.0931 | 0.4465 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1648G>C | A550P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A550P is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar or gnomAD evidence to the contrary, the variant is most likely pathogenic and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | -18.578 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 6.15 | Destabilizing | 0.3 | 6.75 | Destabilizing | 6.45 | Destabilizing | 0.67 | Ambiguous | 0.872 | Likely Pathogenic | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.971 | Probably Damaging | -1.32 | Pathogenic | 0.02 | Affected | 0.1476 | 0.3417 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1648G>T | A550S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A550S missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated predictors—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently classify the variant as pathogenic. FoldX, Rosetta, Foldetta, and premPS yield uncertain or inconclusive results and are therefore not considered evidence for either side. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for A550S. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | -12.166 | Likely Pathogenic | 0.569 | Likely Pathogenic | Likely Benign | 1.00 | Ambiguous | 0.1 | 1.08 | Ambiguous | 1.04 | Ambiguous | 0.80 | Ambiguous | 0.753 | Likely Pathogenic | -2.69 | Deleterious | 0.976 | Probably Damaging | 0.907 | Possibly Damaging | -1.29 | Pathogenic | 0.02 | Affected | 0.1739 | 0.3615 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1649C>A | A550D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A550D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect. Benign predictions: none. Pathogenic predictions: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized. Uncertain predictions: Rosetta and Foldetta. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the overwhelming majority of evidence indicates a pathogenic effect. Based on the aggregate predictions, the variant is most likely pathogenic, and this is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | -18.844 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.51 | Destabilizing | 0.1 | 1.46 | Ambiguous | 1.99 | Ambiguous | 1.01 | Destabilizing | 0.879 | Likely Pathogenic | -5.43 | Deleterious | 0.999 | Probably Damaging | 0.971 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 0.1333 | 0.1783 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1649C>G | A550G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A550G 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 AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and premPS are inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of reliable predictors indicate 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. | Likely Pathogenic | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | -15.086 | Likely Pathogenic | 0.776 | Likely Pathogenic | Likely Benign | 1.73 | Ambiguous | 0.0 | 1.82 | Ambiguous | 1.78 | Ambiguous | 0.85 | Ambiguous | 0.769 | Likely Pathogenic | -3.79 | Deleterious | 0.999 | Probably Damaging | 0.932 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 0.1595 | 0.2758 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1649C>T | A550V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A550V variant has no ClinVar entry and is catalogued in gnomAD (ID 6‑33438892‑C‑T). Prediction tools that agree on a benign effect include Foldetta, premPS, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain results come from FoldX and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as pathogenic, and Foldetta as benign. Overall, the majority of tools (seven versus four) favor a pathogenic interpretation, and this does not contradict any ClinVar classification because none is available. Thus, based on the current predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | 6-33438892-C-T | 1 | 6.20e-7 | -10.461 | Likely Pathogenic | 0.441 | Ambiguous | Likely Benign | 0.77 | Ambiguous | 0.2 | -0.05 | Likely Benign | 0.36 | Likely Benign | 0.48 | Likely Benign | 0.540 | Likely Pathogenic | -2.93 | Deleterious | 0.984 | Probably Damaging | 0.494 | Possibly Damaging | -1.05 | Pathogenic | 0.39 | Tolerated | 3.37 | 33 | 0.0874 | 0.4370 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||
| c.164A>C | Q55P 2D AIThe SynGAP1 missense variant Q55P is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33423573‑A‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs two benign), and Foldetta results are unavailable. Overall, more tools predict pathogenicity than benignity, and no ClinVar entry 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. | 0.332115 | Structured | 0.470108 | Uncertain | 0.461 | 0.657 | 0.000 | 6-33423573-A-C | 1 | 6.20e-7 | -13.163 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 0.260 | Likely Benign | -2.06 | Neutral | 0.462 | Possibly Damaging | 0.480 | Possibly Damaging | 3.83 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2557 | 0.5508 | -1 | 0 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.164A>G | Q55R 2D AIThe SynGAP1 missense variant Q55R 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from 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 benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that 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 | 0.332115 | Structured | 0.470108 | Uncertain | 0.461 | 0.657 | 0.000 | -6.626 | Likely Benign | 0.578 | Likely Pathogenic | Likely Benign | 0.166 | Likely Benign | -1.15 | Neutral | 0.140 | Benign | 0.275 | Benign | 3.87 | Benign | 0.00 | Affected | 0.1607 | 0.1558 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.164A>T | Q55L 2D AIThe SynGAP1 missense variant Q55L 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, 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, and PROVEAN) reports the variant as 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 assessment 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 | 0.332115 | Structured | 0.470108 | Uncertain | 0.461 | 0.657 | 0.000 | -5.823 | Likely Benign | 0.844 | Likely Pathogenic | Ambiguous | 0.173 | Likely Benign | -1.99 | Neutral | 0.273 | Benign | 0.275 | Benign | 3.83 | Benign | 0.00 | Affected | 0.0776 | 0.5982 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.1651C>A | L551M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L551M is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438894‑C‑A). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, while those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Two tools report an uncertain outcome: premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this does not contradict the ClinVar “Uncertain” classification. Thus, the variant is most likely benign based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.009977 | Structured | 0.006653 | Uncertain | 0.960 | 0.254 | 0.000 | Uncertain | 1 | 6-33438894-C-A | 7 | 4.34e-6 | -9.937 | Likely Pathogenic | 0.480 | Ambiguous | Likely Benign | -0.07 | Likely Benign | 0.1 | 0.13 | Likely Benign | 0.03 | Likely Benign | 0.71 | Ambiguous | 0.544 | Likely Pathogenic | -0.56 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.48 | Pathogenic | 0.06 | Tolerated | 3.37 | 35 | 0.0838 | 0.2701 | 4 | 2 | -1.9 | 18.03 | 246.5 | -18.6 | 0.0 | 0.0 | 0.3 | 0.0 | X | Potentially Benign | L551 is located on an α-helix (res. Ala533-Val560). The iso-butyl side chain of Leu551 hydrophobically packs with nearby hydrophobic residues such as Cys547, Phe652, Leu633, and Ile630 in the inter-helix space. In the variant simulations, the thioether side chain of Met551 can maintain similar hydrophobic interactions as Leu551 in the WT, thus causing no negative effect on the protein structure during the simulations. | ||||||||||||||
| c.1651C>G | L551V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L551V is 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 predict a pathogenic effect are REVEL, FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Two tools give uncertain results: AlphaMissense‑Default and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic. Foldetta’s stability prediction is uncertain. Overall, the majority of evidence points to a pathogenic impact for L551V. 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. | GAP | 0.009977 | Structured | 0.006653 | Uncertain | 0.960 | 0.254 | 0.000 | -10.154 | Likely Pathogenic | 0.556 | Ambiguous | Likely Benign | 2.04 | Destabilizing | 0.0 | 1.41 | Ambiguous | 1.73 | Ambiguous | 1.03 | Destabilizing | 0.575 | Likely Pathogenic | -1.39 | Neutral | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.48 | Pathogenic | 0.22 | Tolerated | 0.1376 | 0.2778 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.1652T>A | L551Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L551Q is not reported in ClinVar and is present in gnomAD (allele ID 6‑33438895‑T‑A). In silico prediction tools uniformly indicate a deleterious effect: benign‑predicting tools: none; pathogenic‑predicting tools: 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. No predictions are inconclusive or missing. **Thus, the variant is most likely pathogenic based on the available predictions, and this conclusion does not contradict the ClinVar status (no entry).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009977 | Structured | 0.006653 | Uncertain | 0.960 | 0.254 | 0.000 | 6-33438895-T-A | 1 | 6.20e-7 | -13.632 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 2.48 | Destabilizing | 0.1 | 2.19 | Destabilizing | 2.34 | Destabilizing | 2.37 | Destabilizing | 0.936 | Likely Pathogenic | -3.68 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.60 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.0983 | 0.0688 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||
| c.1652T>C | L551P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L551P (ClinVar ID 547942.0) 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. No tool in the dataset predicts a benign outcome. 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 predictions, is Pathogenic. 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 | GAP | 0.009977 | Structured | 0.006653 | Uncertain | 0.960 | 0.254 | 0.000 | Likely Pathogenic | 1 | -14.620 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.66 | Destabilizing | 0.1 | 6.58 | Destabilizing | 6.62 | Destabilizing | 2.66 | Destabilizing | 0.953 | Likely Pathogenic | -4.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.60 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.3377 | 0.1353 | -3 | -3 | -5.4 | -16.04 | 208.6 | 60.9 | 0.1 | 0.0 | -0.3 | 0.0 | X | Potentially Pathogenic | L551 is located on an α-helix (res. Ala533-Val560). The iso-butyl side chain of Leu551 hydrophobically packs with nearby hydrophobic residues such as Cys547, Phe652, Leu633, and Ile630 in the inter-helix space. In the variant simulations, the pyrrolidine side chain of Pro551 is not as optimal as leucine for hydrophobic packing with the nearby residues. Moreover, Pro551 lacks the amide group, and thus, it cannot form a hydrogen bond with the backbone carbonyl group of Cys547, which disrupts the continuity of the secondary structure element. | ||||||||||||||||
| c.1652T>G | L551R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L551R 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 REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the only tool with an uncertain outcome is FoldX. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Based on the concordant predictions from multiple independent algorithms and the absence of benign evidence, 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 | GAP | 0.009977 | Structured | 0.006653 | Uncertain | 0.960 | 0.254 | 0.000 | -15.420 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.81 | Ambiguous | 0.2 | 2.35 | Destabilizing | 2.08 | Destabilizing | 2.09 | Destabilizing | 0.949 | Likely Pathogenic | -3.85 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.60 | Pathogenic | 0.01 | Affected | 0.1278 | 0.0530 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1654T>A | C552S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C552S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and SIFT, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). The high‑accuracy assessments are mixed: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus also indicates a likely pathogenic outcome, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, reports a benign effect. premPS is inconclusive. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for C552S. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.005714 | Uncertain | 0.955 | 0.256 | 0.000 | -9.309 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | -0.27 | Likely Benign | 0.0 | -0.34 | Likely Benign | -0.31 | Likely Benign | 0.97 | Ambiguous | 0.748 | Likely Pathogenic | -8.21 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.15 | Pathogenic | 0.69 | Tolerated | 0.3469 | 0.1415 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1654T>C | C552R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C552R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. 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 pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) yields an uncertain result, which is treated as unavailable evidence. Overall, the preponderance of predictions supports a pathogenic 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 Pathogenic | GAP | 0.013265 | Structured | 0.005714 | Uncertain | 0.955 | 0.256 | 0.000 | -14.315 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | -1.18 | Ambiguous | 0.1 | -0.51 | Ambiguous | -0.85 | Ambiguous | 1.10 | Destabilizing | 0.809 | Likely Pathogenic | -9.93 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.19 | Pathogenic | 0.48 | Tolerated | 0.1449 | 0.1366 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.1654T>G | C552G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C552G is not reported in ClinVar and is absent from gnomAD. In silico predictors that classify the change as benign include FoldX, Rosetta, Foldetta, and SIFT, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy subset shows AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With six pathogenic versus four benign predictions overall, the evidence leans toward a deleterious effect. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.005714 | Uncertain | 0.955 | 0.256 | 0.000 | -11.570 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.27 | Likely Benign | 0.0 | 0.29 | Likely Benign | 0.28 | Likely Benign | 1.06 | Destabilizing | 0.745 | Likely Pathogenic | -10.20 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.21 | Pathogenic | 0.35 | Tolerated | 0.2338 | 0.1930 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.1655G>A | C552Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C552Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from premPS and SIFT, and pathogenic predictions from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a pathogenic impact for C552Y. This conclusion is consistent with the absence of ClinVar annotation and does not contradict any existing database status. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.005714 | Uncertain | 0.955 | 0.256 | 0.000 | -13.195 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | -0.96 | Ambiguous | 0.1 | -0.57 | Ambiguous | -0.77 | Ambiguous | 0.41 | Likely Benign | 0.750 | Likely Pathogenic | -9.37 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.23 | Pathogenic | 0.07 | Tolerated | 0.0988 | 0.2563 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1655G>C | C552S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C552S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and SIFT, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). The high‑accuracy assessments are mixed: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus also indicates a likely pathogenic outcome, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, reports a benign effect. premPS is inconclusive. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for C552S. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.005714 | Uncertain | 0.955 | 0.256 | 0.000 | -9.309 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | -0.27 | Likely Benign | 0.0 | -0.34 | Likely Benign | -0.31 | Likely Benign | 0.97 | Ambiguous | 0.684 | Likely Pathogenic | -8.21 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.15 | Pathogenic | 0.69 | Tolerated | 0.3469 | 0.1415 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1655G>T | C552F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C552F is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include Rosetta, premPS, and SIFT, whereas the majority of tools predict it to be pathogenic: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. FoldX and Foldetta give uncertain results. High‑accuracy methods specifically report AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the consensus of the available predictions indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.005714 | Uncertain | 0.955 | 0.256 | 0.000 | -14.979 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | -1.01 | Ambiguous | 0.1 | -0.35 | Likely Benign | -0.68 | Ambiguous | 0.40 | Likely Benign | 0.759 | Likely Pathogenic | -9.51 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.25 | Pathogenic | 0.07 | Tolerated | 0.1209 | 0.3081 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.1656C>G | C552W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C552W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only premPS, whereas the majority of in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all classify the variant as pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability assessments. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.005714 | Uncertain | 0.955 | 0.256 | 0.000 | -15.723 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | -1.19 | Ambiguous | 0.1 | -0.66 | Ambiguous | -0.93 | Ambiguous | 0.50 | Likely Benign | 0.830 | Likely Pathogenic | -9.51 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.26 | Pathogenic | 0.02 | Affected | 0.1397 | 0.2371 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1657A>C | K553Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K553Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Foldetta, and SIFT, whereas the majority of tools (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict it to be pathogenic; Rosetta is inconclusive and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, all pathogenic) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence (10 pathogenic vs. 3 benign predictions) indicates that K553Q is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.012270 | Structured | 0.006539 | Uncertain | 0.949 | 0.246 | 0.000 | -13.476 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.44 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.49 | Likely Benign | 1.01 | Destabilizing | 0.783 | Likely Pathogenic | -3.78 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.37 | Pathogenic | 0.07 | Tolerated | 0.3477 | 0.0830 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1657A>G | K553E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K553E missense variant is not reported in ClinVar (status: None) and has no entries in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict pathogenicity. FoldX and Rosetta give uncertain results, and Foldetta also reports an uncertain stability change. 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 evidence points to a deleterious effect. Thus, the variant is most likely pathogenic based on current 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 | GAP | 0.012270 | Structured | 0.006539 | Uncertain | 0.949 | 0.246 | 0.000 | -17.415 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.08 | Ambiguous | 0.3 | 1.15 | Ambiguous | 1.12 | Ambiguous | 1.04 | Destabilizing | 0.828 | Likely Pathogenic | -3.85 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.35 | Pathogenic | 0.12 | Tolerated | 0.2890 | 0.0650 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1658A>C | K553T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K553T is listed in ClinVar with an uncertain significance (ClinVar ID 2007142.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include Rosetta and SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, both polyPhen‑2 HumDiv and HumVar, 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 inconclusive. Overall, the consensus of the available predictions indicates that K553T is most likely pathogenic, which 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 | GAP | 0.012270 | Structured | 0.006539 | Uncertain | 0.949 | 0.246 | 0.000 | Uncertain | 1 | -15.328 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.06 | Ambiguous | 0.2 | 0.48 | Likely Benign | 0.77 | Ambiguous | 0.79 | Ambiguous | 0.761 | Likely Pathogenic | -5.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.34 | Pathogenic | 0.14 | Tolerated | 3.37 | 35 | 0.1733 | 0.2619 | 0 | -1 | 3.2 | -27.07 | 218.2 | -10.7 | 0.0 | 0.0 | -0.2 | 0.5 | X | Potentially Pathogenic | Lys533 is located on an α-helix (res. Ala533-Val560). In the WT simulations, Lys533 packs against Phe513, and its amino side chain occasionally forms an ionic interaction with the carboxylate group of Glu512 from an opposing α-helix (res. Gln503-Tyr518). In the variant simulations, Thr533 is unable to reproduce these interactions, potentially weakening the integrity of the tertiary structure. Additionally, Thr533 forms a hydrogen bond with the backbone carbonyl group of Leu549 in the same helix, which could potentially weaken the secondary structure. Regardless, the residue swap does not cause significant structural effects based on the simulations. | ||||||||||||||||
| c.1658A>G | K553R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K553R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta’s output is uncertain and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability calculations) predicting a benign outcome. Overall, the majority of tools (nine pathogenic vs. five benign) lean toward a pathogenic interpretation, while the high‑accuracy consensus is split. Because ClinVar has no classification, there is no contradiction with existing clinical data. Based on the preponderance of predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.012270 | Structured | 0.006539 | Uncertain | 0.949 | 0.246 | 0.000 | -8.182 | Likely Pathogenic | 0.644 | Likely Pathogenic | Likely Benign | -0.14 | Likely Benign | 0.2 | 0.63 | Ambiguous | 0.25 | Likely Benign | 0.38 | Likely Benign | 0.641 | Likely Pathogenic | -2.58 | Deleterious | 0.996 | Probably Damaging | 0.990 | Probably Damaging | -1.31 | Pathogenic | 0.13 | Tolerated | 0.3762 | 0.0835 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.1658A>T | K553M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K553M is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and premPS, whereas the majority of tools predict it to be pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.012270 | Structured | 0.006539 | Uncertain | 0.949 | 0.246 | 0.000 | -16.086 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | -0.08 | Likely Benign | 0.0 | -0.06 | Likely Benign | -0.07 | Likely Benign | 0.32 | Likely Benign | 0.854 | Likely Pathogenic | -5.76 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.39 | Pathogenic | 0.01 | Affected | 0.0921 | 0.2756 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1659G>C | K553N 2D 3DClick to see structure in 3D Viewer AISynGAP1 K553N is not reported in ClinVar and is present in gnomAD (6-33438902-G-C). Functional prediction tools largely agree on a deleterious effect: SIFT is the sole benign predictor, whereas REVEL, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. FoldX, Rosetta, and Foldetta return uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta remains uncertain. Overall, the consensus of the majority of tools indicates that K553N is most likely pathogenic, and this conclusion 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 | GAP | 0.012270 | Structured | 0.006539 | Uncertain | 0.949 | 0.246 | 0.000 | 6-33438902-G-C | 1 | 6.20e-7 | -13.664 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.63 | Ambiguous | 0.0 | 0.62 | Ambiguous | 0.63 | Ambiguous | 1.11 | Destabilizing | 0.566 | Likely Pathogenic | -4.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.24 | Pathogenic | 0.11 | Tolerated | 3.37 | 35 | 0.2758 | 0.0926 | 0 | 1 | 0.4 | -14.07 | ||||||||||||||||||||||||
| c.1659G>T | K553N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K553N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the majority of algorithms (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, Rosetta, and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.012270 | Structured | 0.006539 | Uncertain | 0.949 | 0.246 | 0.000 | -13.664 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.63 | Ambiguous | 0.0 | 0.62 | Ambiguous | 0.63 | Ambiguous | 1.11 | Destabilizing | 0.566 | Likely Pathogenic | -4.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.24 | Pathogenic | 0.11 | Tolerated | 3.37 | 35 | 0.2758 | 0.0926 | 0 | 1 | 0.4 | -14.07 | |||||||||||||||||||||||||||
| c.165G>C | Q55H 2D AIThe SynGAP1 missense variant Q55H is not reported in ClinVar and is absent from gnomAD. 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, SIFT, and AlphaMissense‑Default. 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 consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.332115 | Structured | 0.470108 | Uncertain | 0.461 | 0.657 | 0.000 | -5.624 | Likely Benign | 0.678 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | -1.76 | Neutral | 0.676 | Possibly Damaging | 0.585 | Possibly Damaging | 3.81 | Benign | 0.00 | Affected | 0.1352 | 0.4143 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.165G>T | Q55H 2D AIThe SynGAP1 missense variant Q55H is not reported in ClinVar and is absent from 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 classifying the variant as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicating a likely benign outcome; the Foldetta protein‑folding stability analysis is unavailable. 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 | 0.332115 | Structured | 0.470108 | Uncertain | 0.461 | 0.657 | 0.000 | -5.624 | Likely Benign | 0.678 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | -1.76 | Neutral | 0.676 | Possibly Damaging | 0.585 | Possibly Damaging | 3.81 | Benign | 0.00 | Affected | 0.1352 | 0.4143 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.1660G>A | V554M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V554M is not reported in ClinVar but is present in gnomAD (ID 6‑33438903‑G‑A). Functional prediction tools show a split opinion: benign calls come from REVEL, Rosetta, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessment focuses on AlphaMissense‑Optimized, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. AlphaMissense‑Optimized predicts benign, the SGM Consensus is a tie and thus unavailable, and Foldetta is uncertain, so it is treated as unavailable. Overall, the available evidence leans toward a benign effect, and this 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. | GAP | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | 6-33438903-G-A | 1 | 6.20e-7 | -8.118 | Likely Pathogenic | 0.671 | Likely Pathogenic | Likely Benign | -1.11 | Ambiguous | 0.0 | -0.20 | Likely Benign | -0.66 | Ambiguous | 0.73 | Ambiguous | 0.217 | Likely Benign | -2.26 | Neutral | 0.994 | Probably Damaging | 0.867 | Possibly Damaging | 3.22 | Benign | 0.00 | Affected | 3.37 | 35 | 0.0743 | 0.2810 | 1 | 2 | -2.3 | 32.06 | |||||||||||||||||||||||||
| c.1660G>C | V554L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V554L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome, while FoldX, premPS, and ESM1b are uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the variant is most likely benign based on the available computational evidence, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | -7.884 | In-Between | 0.645 | Likely Pathogenic | Likely Benign | -1.14 | Ambiguous | 0.0 | 0.29 | Likely Benign | -0.43 | Likely Benign | 0.56 | Ambiguous | 0.162 | Likely Benign | -1.54 | Neutral | 0.204 | Benign | 0.053 | Benign | 3.49 | Benign | 0.08 | Tolerated | 0.0991 | 0.2998 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.1660G>T | V554L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V554L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome, while FoldX, premPS, and ESM1b are uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the variant is most likely benign based on the available computational evidence, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | -7.884 | In-Between | 0.645 | Likely Pathogenic | Likely Benign | -1.14 | Ambiguous | 0.0 | 0.29 | Likely Benign | -0.43 | Likely Benign | 0.56 | Ambiguous | 0.162 | Likely Benign | -1.54 | Neutral | 0.204 | Benign | 0.053 | Benign | 3.49 | Benign | 0.08 | Tolerated | 0.0991 | 0.2998 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.1661T>A | V554E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V554E is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: all evaluated algorithms except FATHMM classify the variant as pathogenic (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default). FATHMM is the sole benign prediction. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | -12.813 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.51 | Destabilizing | 0.1 | 2.05 | Destabilizing | 2.28 | Destabilizing | 2.42 | Destabilizing | 0.590 | Likely Pathogenic | -5.96 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 0.0862 | 0.1180 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.1661T>C | V554A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V554A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated predictors—SGM‑Consensus, 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 is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | -9.730 | Likely Pathogenic | 0.870 | Likely Pathogenic | Ambiguous | 2.07 | Destabilizing | 0.1 | 2.34 | Destabilizing | 2.21 | Destabilizing | 2.00 | Destabilizing | 0.419 | Likely Benign | -3.97 | Deleterious | 0.998 | Probably Damaging | 0.981 | Probably Damaging | 3.22 | Benign | 0.02 | Affected | 0.2131 | 0.1633 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1661T>G | V554G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V554G 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, while the remaining eleven tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as pathogenic. No predictions are missing or inconclusive. Overall, the variant is most likely pathogenic based on the collective evidence, 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. | GAP | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | -13.879 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | 3.31 | Destabilizing | 0.1 | 4.13 | Destabilizing | 3.72 | Destabilizing | 2.40 | Destabilizing | 0.594 | Likely Pathogenic | -6.96 | Deleterious | 0.997 | Probably Damaging | 1.000 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 0.1619 | 0.1548 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1663G>A | V555I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V555I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, Rosetta, 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, while FoldX, Foldetta, and premPS 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, 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 | GAP | 0.013265 | Structured | 0.008218 | Uncertain | 0.943 | 0.225 | 0.000 | Uncertain | 1 | -4.544 | Likely Benign | 0.084 | Likely Benign | Likely Benign | -0.82 | Ambiguous | 0.0 | -0.41 | Likely Benign | -0.62 | Ambiguous | -0.55 | Ambiguous | 0.253 | Likely Benign | 0.45 | Neutral | 0.002 | Benign | 0.002 | Benign | -1.26 | Pathogenic | 1.00 | Tolerated | 0.0844 | 0.2590 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||
| c.1663G>C | V555L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V555L is 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, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The remaining tools—FoldX, Foldetta, ESM1b, 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) is unavailable due to a tie between pathogenic and benign calls, and Foldetta is uncertain. Overall, the preponderance of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.013265 | Structured | 0.008218 | Uncertain | 0.943 | 0.225 | 0.000 | -7.816 | In-Between | 0.521 | Ambiguous | Likely Benign | -1.43 | Ambiguous | 0.1 | -0.14 | Likely Benign | -0.79 | Ambiguous | 0.16 | Likely Benign | 0.260 | Likely Benign | -0.97 | Neutral | 0.025 | Benign | 0.015 | Benign | -1.22 | Pathogenic | 0.14 | Tolerated | 0.1036 | 0.2958 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.1663G>T | V555F 2D 3DClick to see structure in 3D Viewer AISynGAP1 V555F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.008218 | Uncertain | 0.943 | 0.225 | 0.000 | -10.965 | Likely Pathogenic | 0.599 | Likely Pathogenic | Likely Benign | 0.17 | Likely Benign | 0.3 | -2.01 | Stabilizing | -0.92 | Ambiguous | 0.16 | Likely Benign | 0.440 | Likely Benign | -2.85 | Deleterious | 0.011 | Benign | 0.013 | Benign | -1.20 | Pathogenic | 0.16 | Tolerated | 0.0727 | 0.2366 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||
| c.1664T>A | V555D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V555D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are none, while a majority of algorithms predict a pathogenic impact: REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain results. High‑accuracy methods reinforce the pathogenic prediction: AlphaMissense‑Optimized is 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, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.008218 | Uncertain | 0.943 | 0.225 | 0.000 | -16.413 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.84 | Ambiguous | 0.1 | 1.70 | Ambiguous | 1.77 | Ambiguous | 1.25 | Destabilizing | 0.896 | Likely Pathogenic | -5.71 | Deleterious | 1.000 | Probably Damaging | 0.987 | Probably Damaging | -1.39 | Pathogenic | 0.00 | Affected | 0.1411 | 0.0541 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||
| c.1664T>C | V555A 2D 3DClick to see structure in 3D Viewer AISynGAP1 V555A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess sequence conservation and structural impact uniformly indicate a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all classify the variant as pathogenic. No tool predicts a benign outcome. Predictions that are inconclusive—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—are listed as uncertain and do not alter the overall assessment. High‑accuracy methods give a pathogenic consensus from SGM and an uncertain result from AlphaMissense‑Optimized and Foldetta. 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 | GAP | 0.013265 | Structured | 0.008218 | Uncertain | 0.943 | 0.225 | 0.000 | -8.781 | Likely Pathogenic | 0.857 | Likely Pathogenic | Ambiguous | 0.91 | Ambiguous | 0.0 | 0.90 | Ambiguous | 0.91 | Ambiguous | 1.04 | Destabilizing | 0.633 | Likely Pathogenic | -3.48 | Deleterious | 0.979 | Probably Damaging | 0.956 | Probably Damaging | -1.34 | Pathogenic | 0.01 | Affected | 0.2602 | 0.1761 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1664T>G | V555G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V555G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on pathogenicity include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; no tool predicts it benign. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. No predictions are inconclusive or missing. 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. | GAP | 0.013265 | Structured | 0.008218 | Uncertain | 0.943 | 0.225 | 0.000 | -13.327 | Likely Pathogenic | 0.899 | Likely Pathogenic | Ambiguous | 2.07 | Destabilizing | 0.1 | 2.22 | Destabilizing | 2.15 | Destabilizing | 1.07 | Destabilizing | 0.798 | Likely Pathogenic | -6.35 | Deleterious | 0.984 | Probably Damaging | 1.000 | Probably Damaging | -1.39 | Pathogenic | 0.01 | Affected | 0.1994 | 0.1677 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1666A>C | N556H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N556H is not reported in ClinVar and has no entries in gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, premPS, SIFT, and AlphaMissense‑Optimized. Tools that predict pathogenicity are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting benign stability. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the absence of a ClinVar classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.015078 | Structured | 0.008655 | Uncertain | 0.925 | 0.225 | 0.000 | -8.877 | Likely Pathogenic | 0.570 | Likely Pathogenic | Likely Benign | 0.33 | Likely Benign | 0.0 | 0.12 | Likely Benign | 0.23 | Likely Benign | 0.08 | Likely Benign | 0.744 | Likely Pathogenic | -4.06 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.39 | Pathogenic | 0.10 | Tolerated | 0.1177 | 0.2940 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.1666A>G | N556D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N556D is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, premPS, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With two of the three high‑accuracy tools indicating benign and an equal split among the broader set of predictors, the variant is most likely benign. This conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.015078 | Structured | 0.008655 | Uncertain | 0.925 | 0.225 | 0.000 | -6.787 | Likely Benign | 0.704 | Likely Pathogenic | Likely Benign | 0.41 | Likely Benign | 0.0 | 0.39 | Likely Benign | 0.40 | Likely Benign | 0.33 | Likely Benign | 0.546 | Likely Pathogenic | -3.19 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.33 | Pathogenic | 0.08 | Tolerated | 0.1817 | 0.1625 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1666A>T | N556Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N556Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized, whereas tools that predict a pathogenic impact are REVEL, 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, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus as pathogenic. Taken together, the majority of evidence (8 pathogenic vs 5 benign) points to a pathogenic effect, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.015078 | Structured | 0.008655 | Uncertain | 0.925 | 0.225 | 0.000 | -12.533 | Likely Pathogenic | 0.730 | Likely Pathogenic | Likely Benign | -0.01 | Likely Benign | 0.1 | -0.40 | Likely Benign | -0.21 | Likely Benign | 0.28 | Likely Benign | 0.743 | Likely Pathogenic | -6.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.40 | Pathogenic | 0.01 | Affected | 0.0690 | 0.3157 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.1667A>C | N556T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N556T 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, premPS, AlphaMissense‑Optimized, and Rosetta. Tools that predict a pathogenic effect are REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta reporting an uncertain stability change. FoldX‑MD and Foldetta results are inconclusive and are treated as unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.015078 | Structured | 0.008655 | Uncertain | 0.925 | 0.225 | 0.000 | -8.636 | Likely Pathogenic | 0.642 | Likely Pathogenic | Likely Benign | 1.03 | Ambiguous | 0.1 | 0.08 | Likely Benign | 0.56 | Ambiguous | 0.06 | Likely Benign | 0.695 | Likely Pathogenic | -4.73 | Deleterious | 0.996 | Probably Damaging | 0.990 | Probably Damaging | -1.36 | Pathogenic | 0.09 | Tolerated | 0.1189 | 0.3171 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
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