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.990C>G | D330E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D330E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are Rosetta and FATHMM. The remaining tools—FoldX, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -3.427 | Likely Benign | 0.407 | Ambiguous | Likely Benign | 0.98 | Ambiguous | 0.2 | 2.31 | Destabilizing | 1.65 | Ambiguous | 0.39 | Likely Benign | 0.075 | Likely Benign | -1.38 | Neutral | 0.122 | Benign | 0.030 | Benign | 0.97 | Pathogenic | 0.67 | Tolerated | 0.1464 | 0.4416 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.118G>A | D40N 2D  AIThe SynGAP1 missense variant D40N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The predictions do not contradict ClinVar status, as ClinVar contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.384043 | Structured | 0.432002 | Uncertain | 0.319 | 0.769 | 0.375 | -3.841 | Likely Benign | 0.210 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -0.81 | Neutral | 0.028 | Benign | 0.032 | Benign | 4.05 | Benign | 0.00 | Affected | 0.2676 | 0.8761 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.118G>C | D40H 2D  AIThe SynGAP1 missense variant D40H is reported in ClinVar as “Not submitted” and is not present in 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 a likely benign outcome. 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. Overall, the consensus of available predictions 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 | 0.384043 | Structured | 0.432002 | Uncertain | 0.319 | 0.769 | 0.375 | -4.108 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.147 | Likely Benign | -1.28 | Neutral | 0.172 | Benign | 0.248 | Benign | 3.99 | Benign | 0.00 | Affected | 0.3123 | 0.9007 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.118G>T | D40Y 2D  AIThe SynGAP1 D40Y missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus indicates Likely Benign, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for D40Y, 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 Benign | 0.384043 | Structured | 0.432002 | Uncertain | 0.319 | 0.769 | 0.375 | -4.313 | Likely Benign | 0.483 | Ambiguous | Likely Benign | 0.182 | Likely Benign | -1.72 | Neutral | 0.388 | Benign | 0.328 | Benign | 3.98 | Benign | 0.00 | Affected | 0.1173 | 0.7918 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.119A>C | D40A 2D  AIThe SynGAP1 missense variant D40A 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 call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are not available. Taken together, the majority of evidence supports a benign interpretation, 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 | 0.384043 | Structured | 0.432002 | Uncertain | 0.319 | 0.769 | 0.375 | -3.630 | Likely Benign | 0.339 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.22 | Neutral | 0.006 | Benign | 0.023 | Benign | 4.05 | Benign | 0.00 | Affected | 0.4299 | 0.7993 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.119A>G | D40G 2D  AIThe SynGAP1 D40G missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this 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 | 0.384043 | Structured | 0.432002 | Uncertain | 0.319 | 0.769 | 0.375 | -2.777 | Likely Benign | 0.287 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -1.43 | Neutral | 0.012 | Benign | 0.032 | Benign | 4.01 | Benign | 0.00 | Affected | 0.4110 | 0.7949 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.119A>T | D40V 2D  AIThe SynGAP1 missense variant D40V is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence points to a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.384043 | Structured | 0.432002 | Uncertain | 0.319 | 0.769 | 0.375 | -3.350 | Likely Benign | 0.431 | Ambiguous | Likely Benign | 0.222 | Likely Benign | -1.16 | Neutral | 0.028 | Benign | 0.088 | Benign | 4.00 | Benign | 0.00 | Affected | 0.1679 | 0.8357 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.120T>A | D40E 2D AIThe SynGAP1 missense variant D40E 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 call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.384043 | Structured | 0.432002 | Uncertain | 0.319 | 0.769 | 0.375 | -3.520 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -0.21 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.20 | Benign | 0.00 | Affected | 0.2764 | 0.8141 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.120T>G | D40E 2D AIThe SynGAP1 missense variant D40E 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 call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this assessment does not contradict the ClinVar record, which contains no pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.384043 | Structured | 0.432002 | Uncertain | 0.319 | 0.769 | 0.375 | -3.520 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -0.21 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.20 | Benign | 0.00 | Affected | 0.2764 | 0.8141 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2155A>C | N719H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only two tools—polyPhen‑2 HumDiv and polyPhen‑2 HumVar—predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports Benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates Benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -6.310 | Likely Benign | 0.130 | Likely Benign | Likely Benign | -0.04 | Likely Benign | 0.0 | -0.36 | Likely Benign | -0.20 | Likely Benign | 0.12 | Likely Benign | 0.095 | Likely Benign | -2.22 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.71 | Benign | 0.19 | Tolerated | 0.0782 | 0.4209 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.2155A>G | N719D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools give uncertain results: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of individual predictors (seven benign vs. four pathogenic) support a benign effect, and this conclusion does not contradict the lack of ClinVar annotation. Thus, based on the available predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -9.016 | Likely Pathogenic | 0.416 | Ambiguous | Likely Benign | -0.03 | Likely Benign | 0.0 | 0.64 | Ambiguous | 0.31 | Likely Benign | 0.46 | Likely Benign | 0.106 | Likely Benign | -2.56 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.75 | Benign | 0.84 | Tolerated | 0.1581 | 0.2345 | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.2155A>T | N719Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Rosetta and Foldetta provide uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is also uncertain. Overall, the majority of evaluated tools (7 benign vs 4 pathogenic) support a benign classification. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -11.005 | Likely Pathogenic | 0.302 | Likely Benign | Likely Benign | -0.38 | Likely Benign | 0.0 | -0.62 | Ambiguous | -0.50 | Ambiguous | 0.33 | Likely Benign | 0.187 | Likely Benign | -4.15 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.70 | Benign | 0.09 | Tolerated | 0.0412 | 0.3951 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||
| c.2156A>C | N719T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all predict a neutral impact. In contrast, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar predict a pathogenic effect, while Rosetta remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -6.251 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.0 | -0.59 | Ambiguous | -0.10 | Likely Benign | 0.44 | Likely Benign | 0.078 | Likely Benign | -2.60 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.76 | Benign | 0.38 | Tolerated | 0.0851 | 0.4620 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.2156A>G | N719S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719S is reported in gnomAD (variant ID 6‑33441621‑A‑G) but has no ClinVar entry. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign status: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus itself is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts Benign. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | 6-33441621-A-G | 2 | 1.24e-6 | -5.190 | Likely Benign | 0.072 | Likely Benign | Likely Benign | -0.06 | Likely Benign | 0.0 | -0.29 | Likely Benign | -0.18 | Likely Benign | 0.46 | Likely Benign | 0.087 | Likely Benign | -1.83 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.85 | Benign | 0.40 | Tolerated | 3.50 | 9 | 0.2611 | 0.4653 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||
| c.2156A>T | N719I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools report uncertainty: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of predictions lean toward a benign impact, with no conflict with ClinVar status. Thus, the variant is most likely benign based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -10.794 | Likely Pathogenic | 0.399 | Ambiguous | Likely Benign | -0.19 | Likely Benign | 0.0 | -0.74 | Ambiguous | -0.47 | Likely Benign | 0.40 | Likely Benign | 0.146 | Likely Benign | -4.88 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.71 | Benign | 0.10 | Tolerated | 0.0408 | 0.4493 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||
| c.2157C>A | N719K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, ESM1b, and Foldetta) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of reliable predictions indicate a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -7.454 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | -0.64 | Ambiguous | 0.0 | -0.62 | Ambiguous | -0.63 | Ambiguous | 0.42 | Likely Benign | 0.250 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.80 | Benign | 0.55 | Tolerated | 0.1424 | 0.3112 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2157C>G | N719K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719K is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors shows a predominance of benign calls: REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized all predict a neutral effect, whereas polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict pathogenicity. FoldX, Rosetta, ESM1b, and Foldetta are inconclusive. High‑accuracy assessment further supports a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign outcome; Foldetta remains uncertain. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -7.454 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | -0.64 | Ambiguous | 0.0 | -0.62 | Ambiguous | -0.63 | Ambiguous | 0.42 | Likely Benign | 0.244 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.80 | Benign | 0.55 | Tolerated | 0.1424 | 0.3112 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.769A>C | S257R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta and Foldetta are uncertain. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for S257R. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.746 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.18 | Likely Benign | 0.0 | -1.33 | Ambiguous | -0.76 | Ambiguous | 0.29 | Likely Benign | 0.754 | Likely Pathogenic | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 5.81 | Benign | 0.13 | Tolerated | 0.0762 | 0.3068 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.769A>G | S257G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257G is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD status: None). Prediction tools that agree on a benign effect include SIFT, FATHMM, and AlphaMissense‑Optimized. In contrast, a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support this view: AlphaMissense‑Optimized indicates a benign change, whereas the SGM‑Consensus (majority vote) indicates likely pathogenic. The Foldetta stability prediction is unavailable and therefore does not influence the overall assessment. Based on the preponderance of pathogenic predictions and the lack of any ClinVar annotation, the variant is most likely pathogenic, with no contradiction from existing ClinVar data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.206 | Likely Pathogenic | 0.624 | Likely Pathogenic | Likely Benign | 0.61 | Ambiguous | 0.3 | 0.60 | Ambiguous | 0.61 | Ambiguous | 0.62 | Ambiguous | 0.703 | Likely Pathogenic | -2.95 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 5.79 | Benign | 0.11 | Tolerated | 0.2087 | 0.3589 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.769A>T | S257C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, Rosetta) and pathogenic predictions (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar). The high‑accuracy consensus methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta—each indicate a benign effect. No folding‑stability assessment is available beyond the benign Foldetta result. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar assertion. Thus, the variant is most likely benign, and this is not contradicted by ClinVar status, which has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -3.553 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.4 | -0.33 | Likely Benign | 0.09 | Likely Benign | -0.46 | Likely Benign | 0.611 | Likely Pathogenic | 0.02 | Neutral | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 5.76 | Benign | 0.18 | Tolerated | 0.0880 | 0.5151 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.770G>A | S257N 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant S257N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split consensus: benign calls come from FoldX, Rosetta, Foldetta, PROVEAN, SIFT, and FATHMM, while pathogenic calls come from REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments give an inconclusive SGM Consensus (a tie between AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), an uncertain AlphaMissense‑Optimized result, and a benign Foldetta prediction. No evidence of pathogenicity is supported by the protein‑stability analysis, which indicates a benign effect. Overall, the predictions are mixed, but the majority of high‑accuracy tools lean toward a benign interpretation. This assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -10.508 | Likely Pathogenic | 0.820 | Likely Pathogenic | Ambiguous | 0.25 | Likely Benign | 0.1 | -0.18 | Likely Benign | 0.04 | Likely Benign | 0.85 | Ambiguous | 0.533 | Likely Pathogenic | -2.30 | Neutral | 0.993 | Probably Damaging | 0.968 | Probably Damaging | 5.82 | Benign | 0.16 | Tolerated | 0.0985 | 0.3596 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
| c.770G>C | S257T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority benign) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that S257T is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -8.603 | Likely Pathogenic | 0.243 | Likely Benign | Likely Benign | 0.42 | Likely Benign | 0.1 | -0.16 | Likely Benign | 0.13 | Likely Benign | 0.06 | Likely Benign | 0.472 | Likely Benign | -1.58 | Neutral | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 5.83 | Benign | 0.48 | Tolerated | 0.1073 | 0.4898 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.770G>T | S257I 2D  AIThe SynGAP1 missense variant S257I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating likely pathogenic, and Foldetta predicting a benign outcome. FoldX and Rosetta results are uncertain and therefore not considered. Overall, the balance of evidence leans toward a pathogenic interpretation, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -12.126 | Likely Pathogenic | 0.595 | Likely Pathogenic | Likely Benign | 0.78 | Ambiguous | 1.0 | -1.17 | Ambiguous | -0.20 | Likely Benign | 0.30 | Likely Benign | 0.739 | Likely Pathogenic | -2.97 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.81 | Benign | 0.07 | Tolerated | 0.0681 | 0.5209 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.771C>A | S257R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools show a split: benign calls come from FoldX, premPS, SIFT, and FATHMM, whereas pathogenic calls are made by REVEL, PROVEAN, both polyPhen‑2 versions, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain outcomes include Rosetta and Foldetta. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta’s stability analysis is inconclusive. Overall, the majority of reliable predictors indicate a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Therefore, the variant is most likely pathogenic, and this assessment is consistent with its lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.746 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.18 | Likely Benign | 0.0 | -1.33 | Ambiguous | -0.76 | Ambiguous | 0.29 | Likely Benign | 0.707 | Likely Pathogenic | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 5.81 | Benign | 0.13 | Tolerated | 0.0762 | 0.3068 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.771C>G | S257R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, whereas those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (7 pathogenic vs. 4 benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.746 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.18 | Likely Benign | 0.0 | -1.33 | Ambiguous | -0.76 | Ambiguous | 0.29 | Likely Benign | 0.707 | Likely Pathogenic | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 5.81 | Benign | 0.13 | Tolerated | 0.0762 | 0.3068 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.985C>A | R329S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R329S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the majority of available predictions support a pathogenic impact. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.376086 | Uncertain | 0.887 | 0.479 | 0.250 | -10.731 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 1.80 | Ambiguous | 0.3 | 0.78 | Ambiguous | 1.29 | Ambiguous | 0.78 | Ambiguous | 0.192 | Likely Benign | -3.36 | Deleterious | 0.653 | Possibly Damaging | 0.226 | Benign | 4.07 | Benign | 0.04 | Affected | 0.2886 | 0.3625 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||
| c.985C>G | R329G 2D  3DClick to see structure in 3D Viewer AISynGAP1 R329G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls are made by FoldX, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments give an overall pathogenic signal: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta is inconclusive. Taken together, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.376086 | Uncertain | 0.887 | 0.479 | 0.250 | -12.426 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 2.21 | Destabilizing | 0.3 | 1.58 | Ambiguous | 1.90 | Ambiguous | 0.92 | Ambiguous | 0.204 | Likely Benign | -4.78 | Deleterious | 0.653 | Possibly Damaging | 0.293 | Benign | 4.03 | Benign | 0.04 | Affected | 0.3147 | 0.3037 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.985C>T | R329C 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R329C is reported in gnomAD (ID 6‑33437890‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, Rosetta, Foldetta, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools remain inconclusive: premPS and AlphaMissense‑Optimized. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta) as benign. Overall, six tools favor pathogenicity versus five favor benign, with one uncertain. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.376086 | Uncertain | 0.887 | 0.479 | 0.250 | 6-33437890-C-T | 2 | 1.24e-6 | -9.433 | Likely Pathogenic | 0.865 | Likely Pathogenic | Ambiguous | 0.44 | Likely Benign | 0.1 | 0.40 | Likely Benign | 0.42 | Likely Benign | 0.69 | Ambiguous | 0.313 | Likely Benign | -5.70 | Deleterious | 0.999 | Probably Damaging | 0.825 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 3.41 | 15 | 0.3553 | 0.2921 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||||
| c.986G>A | R329H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R329H is listed in ClinVar with an uncertain significance (ClinVar ID 2074400.0) and is present in gnomAD (ID 6‑33437891‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the balance of predictions favors a pathogenic impact, which does not contradict the ClinVar uncertain status but suggests the variant is more likely deleterious. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.376086 | Uncertain | 0.887 | 0.479 | 0.250 | Uncertain | 1 | 6-33437891-G-A | 2 | 1.24e-6 | -10.154 | Likely Pathogenic | 0.769 | Likely Pathogenic | Likely Benign | 2.53 | Destabilizing | 0.7 | 0.71 | Ambiguous | 1.62 | Ambiguous | 0.82 | Ambiguous | 0.155 | Likely Benign | -3.17 | Deleterious | 0.995 | Probably Damaging | 0.778 | Possibly Damaging | 4.04 | Benign | 0.05 | Affected | 3.41 | 15 | 0.2955 | 0.1961 | 2 | 0 | 1.3 | -19.05 | 220.4 | 81.4 | 0.1 | 0.1 | 0.2 | 0.3 | Uncertain | The guanidinium group of Arg329, located at the end of an anti-parallel β sheet strand (res. Ala322-Asp330), faces the negatively charged lipid bilayer surface. While the residue swap does not cause any apparent negative effects on the protein structure in the variant simulations, it could adversely affect the SynGAP-membrane association in reality. The positively charged Arg329 side chain forms hydrogen bonds with other loop residues (e.g., Ser371, Asp338) that are expected to dynamically interact with the membrane head group region. However, this phenomenon is beyond the scope of the solvent-only simulations to unravel. Notably, histidine can also be double protonated and positively charged, but this alternative protonation state was not considered in the variant simulations. | ||||||||||||||
| c.986G>C | R329P 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R329P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of algorithms predict a pathogenic outcome: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic,” and premPS is uncertain. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. Overall, the evidence overwhelmingly points to a pathogenic effect for R329P, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.376086 | Uncertain | 0.887 | 0.479 | 0.250 | -14.528 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 3.06 | Destabilizing | 0.2 | 4.99 | Destabilizing | 4.03 | Destabilizing | 0.73 | Ambiguous | 0.350 | Likely Benign | -4.28 | Deleterious | 0.902 | Possibly Damaging | 0.544 | Possibly Damaging | 4.00 | Benign | 0.01 | Affected | 0.2215 | 0.4099 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.986G>T | R329L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R329L has no ClinVar entry and is not reported in gnomAD. Consensus from standard prediction tools shows a split: benign calls come from REVEL, FoldX, FATHMM, and polyPhen‑2 HumVar, while pathogenic calls arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Predictions marked uncertain (Rosetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of tools lean toward pathogenicity, but the folding‑stability evidence suggests a benign effect. Given the lack of ClinVar annotation, there is no contradiction. The variant is most likely pathogenic based on the preponderance of pathogenic predictions, though the benign folding‑stability result introduces uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.376086 | Uncertain | 0.887 | 0.479 | 0.250 | -10.186 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | -0.09 | Likely Benign | 0.4 | 0.53 | Ambiguous | 0.22 | Likely Benign | 0.54 | Ambiguous | 0.219 | Likely Benign | -4.81 | Deleterious | 0.653 | Possibly Damaging | 0.361 | Benign | 4.02 | Benign | 0.01 | Affected | 0.1827 | 0.4121 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1018G>A | A340T 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant A340T is reported in gnomAD (ID 6‑33437923‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus all classify the change as benign or likely benign. Only two tools predict pathogenicity—polyPhen‑2 HumDiv and FATHMM—while stability‑based methods (FoldX, Rosetta, premPS, Foldetta) return uncertain or inconclusive results. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign, and Foldetta provides no definitive stability change. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.390993 | Structured | 0.410781 | Uncertain | 0.558 | 0.485 | 0.250 | 6-33437923-G-A | -3.286 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.84 | Ambiguous | 0.2 | 0.96 | Ambiguous | 0.90 | Ambiguous | -0.54 | Ambiguous | 0.105 | Likely Benign | 0.62 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 1.93 | Pathogenic | 0.47 | Tolerated | 3.42 | 13 | 0.1740 | 0.7297 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||
| c.1018G>C | A340P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A340P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The high‑accuracy predictors—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta—each report a benign outcome. No prediction or folding‑stability result is missing or inconclusive; all available evidence points to a benign impact. Consequently, the variant is most likely benign based on the aggregate predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.390993 | Structured | 0.410781 | Uncertain | 0.558 | 0.485 | 0.250 | -4.983 | Likely Benign | 0.264 | Likely Benign | Likely Benign | 0.32 | Likely Benign | 0.5 | -0.58 | Ambiguous | -0.13 | Likely Benign | 0.46 | Likely Benign | 0.279 | Likely Benign | -1.48 | Neutral | 0.891 | Possibly Damaging | 0.575 | Possibly Damaging | 1.91 | Pathogenic | 0.25 | Tolerated | 0.2178 | 0.5468 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1018G>T | A340S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A340S is reported in gnomAD (variant ID 6‑33437923‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only FATHMM predicts pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign majority (3 benign vs. 1 pathogenic). High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign; the SGM‑Consensus is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.390993 | Structured | 0.410781 | Uncertain | 0.558 | 0.485 | 0.250 | 6-33437923-G-T | 1 | 6.20e-7 | -0.705 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.15 | Likely Benign | 0.0 | 0.27 | Likely Benign | 0.21 | Likely Benign | -0.46 | Likely Benign | 0.083 | Likely Benign | 1.62 | Neutral | 0.007 | Benign | 0.008 | Benign | 1.93 | Pathogenic | 0.51 | Tolerated | 3.42 | 13 | 0.2852 | 0.6309 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||
| c.1019C>A | A340E 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant A340E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic outcome, while the protein‑folding stability method Foldetta is uncertain. AlphaMissense‑Optimized also yields an uncertain result. Overall, the majority of evidence points toward a pathogenic impact, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.390993 | Structured | 0.410781 | Uncertain | 0.558 | 0.485 | 0.250 | -8.225 | Likely Pathogenic | 0.803 | Likely Pathogenic | Ambiguous | 0.63 | Ambiguous | 0.4 | 1.55 | Ambiguous | 1.09 | Ambiguous | 0.06 | Likely Benign | 0.138 | Likely Benign | -0.33 | Neutral | 0.625 | Possibly Damaging | 0.252 | Benign | 1.91 | Pathogenic | 0.39 | Tolerated | 0.1418 | 0.2160 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||
| c.1019C>G | A340G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A340G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictors indicate a benign effect, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.390993 | Structured | 0.410781 | Uncertain | 0.558 | 0.485 | 0.250 | -3.763 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.66 | Ambiguous | 0.2 | 1.44 | Ambiguous | 1.05 | Ambiguous | 0.50 | Likely Benign | 0.044 | Likely Benign | -0.34 | Neutral | 0.267 | Benign | 0.127 | Benign | 1.92 | Pathogenic | 0.42 | Tolerated | 0.2355 | 0.4470 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1019C>T | A340V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 A340V variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) is uncertain and therefore unavailable for interpretation. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.390993 | Structured | 0.410781 | Uncertain | 0.558 | 0.485 | 0.250 | -6.427 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.69 | Ambiguous | 0.3 | 0.32 | Likely Benign | 0.51 | Ambiguous | 0.40 | Likely Benign | 0.102 | Likely Benign | -1.81 | Neutral | 0.801 | Possibly Damaging | 0.315 | Benign | 2.09 | Pathogenic | 0.57 | Tolerated | 0.1197 | 0.5780 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.1090C>A | P364T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P364T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Four tools (FoldX, Foldetta, premPS, ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (five benign versus four pathogenic) lean toward a benign classification, and this assessment does not contradict any ClinVar annotation because no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.390993 | Structured | 0.439474 | Uncertain | 0.942 | 0.590 | 0.250 | -7.951 | In-Between | 0.230 | Likely Benign | Likely Benign | 1.18 | Ambiguous | 0.6 | 0.47 | Likely Benign | 0.83 | Ambiguous | 0.53 | Ambiguous | 0.342 | Likely Benign | -5.60 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.60 | Pathogenic | 0.09 | Tolerated | 0.1660 | 0.5726 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
| c.1090C>G | P364A 2D  3DClick to see structure in 3D Viewer AISynGAP1 P364A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Stability‑based methods (FoldX, Rosetta, premPS) give uncertain outcomes, and Foldetta is unavailable. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, does not provide a definitive result. Overall, the predictions are discordant; the majority of tools lean toward pathogenicity, but a substantial subset suggests benign. Based on the predictions, the variant is most likely pathogenic, and this does not contradict ClinVar status because there is no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.390993 | Structured | 0.439474 | Uncertain | 0.942 | 0.590 | 0.250 | -8.077 | Likely Pathogenic | 0.135 | Likely Benign | Likely Benign | 0.79 | Ambiguous | 0.0 | 0.69 | Ambiguous | 0.74 | Ambiguous | 0.60 | Ambiguous | 0.320 | Likely Benign | -6.10 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.56 | Pathogenic | 0.06 | Tolerated | 0.3496 | 0.5186 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1090C>T | P364S 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant P364S resides in the C2 domain. It is not reported in ClinVar and is present in gnomAD (ID 6‑33437995‑C‑T). Prediction tools that classify the variant as benign include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM; the SGM‑Consensus score is also 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 prediction or stability result is missing or inconclusive beyond the Uncertain labels. Based on the majority of 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 | C2 | 0.390993 | Structured | 0.439474 | Uncertain | 0.942 | 0.590 | 0.250 | 6-33437995-C-T | 1 | 6.20e-7 | -8.318 | Likely Pathogenic | 0.214 | Likely Benign | Likely Benign | 1.34 | Ambiguous | 0.3 | 0.68 | Ambiguous | 1.01 | Ambiguous | 0.83 | Ambiguous | 0.307 | Likely Benign | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.62 | Pathogenic | 0.05 | Affected | 3.39 | 20 | 0.3390 | 0.5512 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||
| c.1091C>A | P364H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant P364H is reported in gnomAD (ID 6‑33437996‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support this dichotomy: AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it pathogenic. The protein‑folding stability predictor Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with ClinVar status, which currently lacks an entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.390993 | Structured | 0.439474 | Uncertain | 0.942 | 0.590 | 0.250 | 6-33437996-C-A | -10.744 | Likely Pathogenic | 0.632 | Likely Pathogenic | Likely Benign | 1.65 | Ambiguous | 0.9 | 0.25 | Likely Benign | 0.95 | Ambiguous | 0.77 | Ambiguous | 0.407 | Likely Benign | -6.96 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.55 | Pathogenic | 0.02 | Affected | 3.39 | 20 | 0.1800 | 0.4584 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||
| c.1091C>G | P364R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 P364R missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; Foldetta’s stability analysis is uncertain. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.390993 | Structured | 0.439474 | Uncertain | 0.942 | 0.590 | 0.250 | -12.652 | Likely Pathogenic | 0.715 | Likely Pathogenic | Likely Benign | 0.95 | Ambiguous | 0.7 | 0.88 | Ambiguous | 0.92 | Ambiguous | 0.73 | Ambiguous | 0.416 | Likely Benign | -6.76 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.57 | Pathogenic | 0.12 | Tolerated | 0.1520 | 0.3977 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1091C>T | P364L 2D  3DClick to see structure in 3D Viewer AISynGAP1 P364L is reported in gnomAD (ID 6‑33437996‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, SIFT, AlphaMissense‑Optimized, and Foldetta; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Three tools—FoldX, Rosetta, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign. Overall, the balance of evidence slightly favors a benign effect, and this conclusion does not contradict any ClinVar classification because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.390993 | Structured | 0.439474 | Uncertain | 0.942 | 0.590 | 0.250 | 6-33437996-C-T | -10.620 | Likely Pathogenic | 0.457 | Ambiguous | Likely Benign | 0.88 | Ambiguous | 0.9 | -0.73 | Ambiguous | 0.08 | Likely Benign | 0.31 | Likely Benign | 0.387 | Likely Benign | -7.78 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.54 | Pathogenic | 0.18 | Tolerated | 3.39 | 20 | 0.2200 | 0.6207 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||
| c.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.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.595A>C | N199H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No predictions are missing or inconclusive. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which contains no pathogenic assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -6.387 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.17 | Likely Benign | 0.1 | 0.15 | Likely Benign | 0.16 | Likely Benign | 0.20 | Likely Benign | 0.064 | Likely Benign | -1.99 | Neutral | 0.952 | Possibly Damaging | 0.496 | Possibly Damaging | 4.17 | Benign | 0.08 | Tolerated | 0.0879 | 0.5635 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.595A>G | N199D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach a consensus classify the variant as benign: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. The only inconclusive results come from ESM1b and Rosetta, which are treated as unavailable. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a benign outcome. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -7.874 | In-Between | 0.338 | Likely Benign | Likely Benign | -0.14 | Likely Benign | 0.1 | -0.67 | Ambiguous | -0.41 | Likely Benign | 0.13 | Likely Benign | 0.028 | Likely Benign | -1.41 | Neutral | 0.276 | Benign | 0.062 | Benign | 4.22 | Benign | 0.35 | Tolerated | 0.1516 | 0.3514 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.595A>T | N199Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N199Y is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 (HumVar), FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from SIFT, PROVEAN, polyPhen‑2 (HumDiv), and ESM1b. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates benign stability. Overall, the majority of conventional tools (8 benign vs. 4 pathogenic) favor a benign effect, and this interpretation does not conflict with the absence of ClinVar annotation. Therefore, the variant is most likely benign based on the current predictive evidence, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -8.575 | Likely Pathogenic | 0.391 | Ambiguous | Likely Benign | -0.06 | Likely Benign | 0.1 | 0.14 | Likely Benign | 0.04 | Likely Benign | 0.20 | Likely Benign | 0.097 | Likely Benign | -3.12 | Deleterious | 0.952 | Possibly Damaging | 0.395 | Benign | 4.15 | Benign | 0.04 | Affected | 0.0389 | 0.5630 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||
| c.596A>C | N199T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify it as benign or likely benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -4.123 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.16 | Likely Benign | 0.2 | -0.10 | Likely Benign | 0.03 | Likely Benign | -0.04 | Likely Benign | 0.025 | Likely Benign | -0.82 | Neutral | 0.002 | Benign | 0.003 | Benign | 4.24 | Benign | 0.10 | Tolerated | 0.0862 | 0.6186 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.596A>G | N199S 2D AIThe SynGAP1 missense variant N199S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All available in‑silico predictors classify the variant as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts pathogenicity. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote) indicates likely benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the variant is most likely benign, and this prediction does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -0.268 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.08 | Likely Benign | 0.4 | -0.08 | Likely Benign | 0.00 | Likely Benign | -0.44 | Likely Benign | 0.040 | Likely Benign | 0.09 | Neutral | 0.160 | Benign | 0.045 | Benign | 4.36 | Benign | 0.57 | Tolerated | 0.2601 | 0.6023 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.596A>T | N199I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields an equal split of benign and pathogenic calls. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -8.299 | Likely Pathogenic | 0.328 | Likely Benign | Likely Benign | 0.27 | Likely Benign | 0.1 | -0.11 | Likely Benign | 0.08 | Likely Benign | 0.20 | Likely Benign | 0.066 | Likely Benign | -3.27 | Deleterious | 0.316 | Benign | 0.045 | Benign | 4.16 | Benign | 0.01 | Affected | 0.0450 | 0.6009 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||
| c.597C>A | N199K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N199K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign. Only ESM1b and AlphaMissense‑Default predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the preponderance of evidence supports a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | Uncertain | 1 | -8.198 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | -0.19 | Likely Benign | 0.1 | 0.03 | Likely Benign | -0.08 | Likely Benign | 0.33 | Likely Benign | 0.024 | Likely Benign | -1.48 | Neutral | 0.276 | Benign | 0.083 | Benign | 4.27 | Benign | 0.13 | Tolerated | 3.47 | 9 | 0.1399 | 0.5218 | 1 | 0 | -0.4 | 14.07 | 207.8 | 21.5 | -0.1 | 1.5 | 0.1 | 0.0 | X | Uncertain | Asn199, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by a positively charged lysine. On the protein surface, both the carboxamide group of Asn199 and the amino group of Lys199 side chains can form hydrogen bonds with the backbone carbonyl groups of residues (e.g., Ala249) at the end of an α helix (res. Ala236-Lys251). However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||||||
| c.597C>G | N199K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the majority of evidence (10 benign vs. 2 pathogenic) supports a benign classification. This consensus does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -8.198 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | -0.19 | Likely Benign | 0.1 | 0.03 | Likely Benign | -0.08 | Likely Benign | 0.33 | Likely Benign | 0.024 | Likely Benign | -1.48 | Neutral | 0.276 | Benign | 0.083 | Benign | 4.27 | Benign | 0.13 | Tolerated | 3.47 | 9 | 0.1399 | 0.5218 | 1 | 0 | -0.4 | 14.07 | 207.8 | 21.5 | -0.1 | 1.5 | 0.1 | 0.0 | X | Uncertain | Asn199, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by a positively charged lysine. On the protein surface, both the carboxamide group of Asn199 and the amino group of Lys199 side chains can form hydrogen bonds with the backbone carbonyl groups of residues (e.g., Ala249) at the end of an α helix (res. Ala236-Lys251). However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||||||||
| c.1195G>A | A399T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399T is listed in ClinVar (ID 1990638.0) as Benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as Uncertain. Overall, the variant is most likely benign, and this conclusion aligns with its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | Benign | 1 | -5.236 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 1.24 | Ambiguous | 0.1 | 0.91 | Ambiguous | 1.08 | Ambiguous | 0.49 | Likely Benign | 0.272 | Likely Benign | -0.40 | Neutral | 0.131 | Benign | 0.039 | Benign | 5.41 | Benign | 0.69 | Tolerated | 3.38 | 26 | 0.1335 | 0.6477 | 1 | 0 | -2.5 | 30.03 | 211.4 | -41.4 | 0.0 | 0.0 | 0.6 | 0.4 | X | Potentially Pathogenic | The methyl group of Ala399, located in an anti-parallel β sheet strand (res. Ala399-Ile411), is swapped for a hydroxyl-containing threonine. In the variant simulations, the hydroxyl group of Thr399 can form H-bonds with the backbone atoms of the residues in the membrane-facing loops (e.g., Gly382) in the C2 domain. Consequently, the ability of the Thr399 side chain to form H-bonds with the membrane-facing loops could adversely affect the dynamics and stability of the SynGAP-membrane association. However, since the effects on the dynamics of the membrane-facing loops can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||||
| c.1195G>C | A399P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A399P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, FATHMM, and polyPhen‑2 HumVar; pathogenic predictions come from FoldX, Rosetta, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a pathogenic effect. Overall, the majority of evidence points toward a deleterious impact. The variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | -8.809 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | 2.29 | Destabilizing | 0.1 | 4.00 | Destabilizing | 3.15 | Destabilizing | 0.74 | Ambiguous | 0.498 | Likely Benign | -1.82 | Neutral | 0.596 | Possibly Damaging | 0.188 | Benign | 5.56 | Benign | 0.10 | Tolerated | 0.1847 | 0.5472 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||
| c.1195G>T | A399S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect, while FoldX, Rosetta, and Foldetta are inconclusive. Grouping by agreement, all available predictors fall into the benign category; none predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, whereas Foldetta’s stability analysis remains uncertain. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | -4.256 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.65 | Ambiguous | 0.1 | 1.13 | Ambiguous | 0.89 | Ambiguous | -0.33 | Likely Benign | 0.161 | Likely Benign | 0.81 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.65 | Benign | 0.86 | Tolerated | 0.2494 | 0.4897 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1196C>A | A399D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, FoldX, SIFT, ESM1b, and AlphaMissense‑Default. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized—return uncertain or inconclusive results. High‑accuracy methods give no definitive verdict: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie and thus unavailable, and Foldetta is uncertain. Overall, the majority of available predictions (five pathogenic vs. four benign) lean toward pathogenicity. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | -10.441 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 2.45 | Destabilizing | 0.2 | 1.17 | Ambiguous | 1.81 | Ambiguous | 0.91 | Ambiguous | 0.525 | Likely Pathogenic | -1.84 | Neutral | 0.421 | Benign | 0.054 | Benign | 5.38 | Benign | 0.05 | Affected | 0.1533 | 0.1760 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||
| c.1196C>G | A399G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399G is not reported in ClinVar and is absent from gnomAD. Across a panel of in silico predictors, all available pathogenicity scores classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. Uncertain results from FoldX, Rosetta, Foldetta, and premPS are treated as unavailable. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore not considered evidence. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | -6.513 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 1.03 | Ambiguous | 0.1 | 1.77 | Ambiguous | 1.40 | Ambiguous | 0.74 | Ambiguous | 0.153 | Likely Benign | -1.59 | Neutral | 0.062 | Benign | 0.024 | Benign | 5.39 | Benign | 0.13 | Tolerated | 0.2174 | 0.4532 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1196C>T | A399V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). No tool predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the evidence overwhelmingly supports a benign classification, and this is consistent with the lack of ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | -4.943 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.49 | Likely Benign | 0.2 | 0.56 | Ambiguous | 0.53 | Ambiguous | 0.22 | Likely Benign | 0.305 | Likely Benign | -1.18 | Neutral | 0.421 | Benign | 0.073 | Benign | 5.37 | Benign | 0.24 | Tolerated | 0.1145 | 0.6807 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.196C>A | P66T 2D AIThe SynGAP1 missense variant P66T 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 the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and the Foldetta protein‑folding stability assessment is unavailable. Overall, the balance of evidence leans toward a benign impact, with one high‑accuracy tool (SGM‑Consensus) supporting this view and no ClinVar entry to contradict it. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.394753 | Structured | 0.474132 | Uncertain | 0.455 | 0.762 | 0.125 | -3.373 | Likely Benign | 0.954 | Likely Pathogenic | Ambiguous | 0.139 | Likely Benign | -1.81 | Neutral | 0.909 | Possibly Damaging | 0.641 | Possibly Damaging | 4.00 | Benign | 0.00 | Affected | 0.1747 | 0.5866 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.196C>G | P66A 2D AIThe SynGAP1 P66A missense variant (ClinVar ID 1303518.0) is listed as “Uncertain” and is not reported in gnomAD. Functional prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. Separately, the high‑accuracy AlphaMissense‑Optimized result is “Uncertain,” the SGM‑Consensus remains “Likely Benign,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the predictions are mixed, but the majority of high‑confidence tools lean toward a benign effect. Thus, the variant is most likely benign based on current computational evidence, and this assessment does not contradict the ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.394753 | Structured | 0.474132 | Uncertain | 0.455 | 0.762 | 0.125 | Uncertain | 1 | -2.845 | Likely Benign | 0.891 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | -1.56 | Neutral | 0.805 | Possibly Damaging | 0.539 | Possibly Damaging | 4.04 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3467 | 0.5138 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.196C>T | P66S 2D AIThe SynGAP1 missense variant P66S is listed in ClinVar (ID 1915017.0) as benign and is present in gnomAD (variant ID 6‑33425804‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, 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 uncertain, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, which is consistent with the ClinVar designation and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.394753 | Structured | 0.474132 | Uncertain | 0.455 | 0.762 | 0.125 | Benign | 1 | 6-33425804-C-T | 2 | 1.24e-6 | -2.760 | Likely Benign | 0.929 | Likely Pathogenic | Ambiguous | 0.081 | Likely Benign | -1.69 | Neutral | 0.909 | Possibly Damaging | 0.641 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3417 | 0.5463 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.197C>A | P66H 2D AIThe SynGAP1 missense variant P66H 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, 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 Uncertain, and the SGM‑Consensus result is benign; Foldetta predictions are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.394753 | Structured | 0.474132 | Uncertain | 0.455 | 0.762 | 0.125 | -4.134 | Likely Benign | 0.941 | Likely Pathogenic | Ambiguous | 0.239 | Likely Benign | -2.26 | Neutral | 0.992 | Probably Damaging | 0.893 | Possibly Damaging | 3.89 | Benign | 0.00 | Affected | 0.1914 | 0.4675 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.197C>G | P66R 2D AIThe SynGAP1 missense variant P66R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are not available. Overall, the majority of evidence points toward a benign impact, and there is no ClinVar entry to contradict this assessment. 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 | 0.394753 | Structured | 0.474132 | Uncertain | 0.455 | 0.762 | 0.125 | -2.708 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.221 | Likely Benign | -2.23 | Neutral | 0.972 | Probably Damaging | 0.804 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.1636 | 0.3928 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.197C>T | P66L 2D AIThe SynGAP1 missense variant P66L 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, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized calling the variant pathogenic, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta results are not available. Overall, the predictions are split evenly between benign and pathogenic, with high‑accuracy tools providing opposing conclusions. Consequently, the variant’s impact remains uncertain and 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 Benign | 0.394753 | Structured | 0.474132 | Uncertain | 0.455 | 0.762 | 0.125 | -2.437 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.194 | Likely Benign | -2.48 | Neutral | 0.909 | Possibly Damaging | 0.713 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.2412 | 0.6687 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2161A>C | I721L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I721L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Two tools (premPS and ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the predictions are split, but the majority of high‑confidence tools lean toward a benign interpretation. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | -7.843 | In-Between | 0.757 | Likely Pathogenic | Likely Benign | 0.35 | Likely Benign | 0.0 | 0.34 | Likely Benign | 0.35 | Likely Benign | 0.65 | Ambiguous | 0.188 | Likely Benign | -1.83 | Neutral | 0.955 | Possibly Damaging | 0.985 | Probably Damaging | 2.37 | Pathogenic | 0.02 | Affected | 0.0627 | 0.3446 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.2161A>G | I721V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the majority of reliable predictors classify the variant as benign, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | -6.730 | Likely Benign | 0.380 | Ambiguous | Likely Benign | 1.22 | Ambiguous | 0.0 | 1.11 | Ambiguous | 1.17 | Ambiguous | 0.48 | Likely Benign | 0.098 | Likely Benign | -0.40 | Neutral | 0.969 | Probably Damaging | 0.960 | Probably Damaging | 2.60 | Benign | 0.45 | Tolerated | 0.0976 | 0.3070 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.2161A>T | I721F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic impact, while premPS remains uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | -12.559 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 4.61 | Destabilizing | 0.1 | 2.74 | Destabilizing | 3.68 | Destabilizing | 0.66 | Ambiguous | 0.295 | Likely Benign | -3.74 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 0.0420 | 0.2931 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.2162T>A | I721N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | -14.905 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.82 | Destabilizing | 0.0 | 3.21 | Destabilizing | 3.02 | Destabilizing | 2.10 | Destabilizing | 0.425 | Likely Benign | -6.30 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.19 | Pathogenic | 0.00 | Affected | 0.0737 | 0.0340 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.2162T>C | I721T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721T is not reported in ClinVar (ClinVar status: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that indicate a benign effect include only REVEL. All other evaluated tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote) yields Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts Pathogenic. No prediction or folding result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | -10.374 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.73 | Destabilizing | 0.0 | 2.56 | Destabilizing | 2.65 | Destabilizing | 2.11 | Destabilizing | 0.417 | Likely Benign | -4.18 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 0.0918 | 0.1019 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.2162T>G | I721S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: the single benign prediction comes from REVEL, while all other evaluated algorithms (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | Uncertain | 1 | -14.032 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.91 | Destabilizing | 0.1 | 3.96 | Destabilizing | 3.94 | Destabilizing | 2.28 | Destabilizing | 0.466 | Likely Benign | -5.26 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.21 | Pathogenic | 0.00 | Affected | 3.50 | 9 | 0.2606 | 0.1110 | -1 | -2 | -5.3 | -26.08 | 203.3 | 49.3 | -0.1 | 0.0 | -1.1 | 0.0 | X | Uncertain | The sec-butyl side chain of Ile721, located on an α-helix (res. Leu714-Arg726), engages in hydrophobic packing with other residues in the hydrophobic inter-helix space, such as Phe420, Tyr417, His693, and Leu717. In the variant simulations, the hydroxyl side chain of Ser721 forms hydrogen bonds with nearby residues, such as Leu717 and His693. Although no major structural changes are observed during the variant simulations, the hydrophilic residue Ser721 could disrupt the hydrophobic packing during folding. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | ||||||||||||||||
| c.2163C>G | I721M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, and PROVEAN, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, premPS, and the SGM‑Consensus score (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No prediction or stability result is missing or inconclusive beyond these stated uncertainties. Overall, the preponderance of evidence points to a pathogenic effect for I721M, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | -9.767 | Likely Pathogenic | 0.872 | Likely Pathogenic | Ambiguous | 0.71 | Ambiguous | 0.0 | 0.45 | Likely Benign | 0.58 | Ambiguous | 1.00 | Destabilizing | 0.225 | Likely Benign | -2.40 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.30 | Pathogenic | 0.00 | Affected | 0.0576 | 0.2726 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.2443C>A | R815S 2D AISynGAP1 R815S is listed in ClinVar as Benign (ID 3645150.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Two tools report uncertainty: ESM1b and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM Consensus as Benign, and Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the majority of predictions lean toward pathogenicity, whereas the consensus and high‑accuracy tools suggest benignity. Thus, the variant is most likely pathogenic based on the prevailing predictions, contradicting its ClinVar benign designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Benign | 1 | -7.324 | In-Between | 0.950 | Likely Pathogenic | Ambiguous | 0.138 | Likely Benign | -1.86 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.67 | Benign | 0.02 | Affected | 0.2937 | 0.4164 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||
| c.2443C>G | R815G 2D AISynGAP1 missense variant R815G is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on benign effect include REVEL and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. Uncertain calls are made by ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Uncertain | 1 | -7.983 | In-Between | 0.854 | Likely Pathogenic | Ambiguous | 0.146 | Likely Benign | -3.22 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.62 | Benign | 0.02 | Affected | 4.32 | 4 | 0.3481 | 0.4015 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.2443C>T | R815C 2D AIThe SynGAP1 missense variant R815C is listed in ClinVar (ID 660618.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33442995‑C‑T). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized result is “Uncertain.” The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 predictions indicates 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 | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Uncertain | 1 | 6-33442995-C-T | 5 | 3.10e-6 | -9.373 | Likely Pathogenic | 0.828 | Likely Pathogenic | Ambiguous | 0.174 | Likely Benign | -3.89 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 4.32 | 4 | 0.3389 | 0.3682 | -4 | -3 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||
| c.2444G>A | R815H 2D AIThe SynGAP1 missense variant R815H (ClinVar ID 833773.0) is classified as benign in ClinVar and is present in gnomAD (6‑33442996‑G‑A). Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar) and SIFT. Two tools report uncertainty: ESM1b and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta stability assessment are unavailable. Overall, the balance of evidence favors a benign effect, consistent with the ClinVar annotation and with no conflict regarding its status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Likely Benign | 2 | 6-33442996-G-A | 24 | 1.49e-5 | -7.474 | In-Between | 0.553 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -1.81 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.02 | Affected | 4.32 | 4 | 0.2944 | 0.2281 | 2 | 0 | 1.3 | -19.05 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.2444G>C | R815P 2D AIThe SynGAP1 missense variant R815P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas 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: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as pathogenic; AlphaMissense‑Optimized remains uncertain, and Foldetta data are unavailable. Overall, the preponderance of evidence indicates that R815P is most likely pathogenic, 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. | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | -7.495 | In-Between | 0.858 | Likely Pathogenic | Ambiguous | 0.153 | Likely Benign | -2.85 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.65 | Benign | 0.02 | Affected | 0.2113 | 0.4897 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2444G>T | R815L 2D AISynGAP1 missense variant R815L is listed in ClinVar (ID 2505666.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools indicates a pathogenic effect, which contrasts with the ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Uncertain | 1 | -8.546 | Likely Pathogenic | 0.865 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | -3.06 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.63 | Benign | 0.03 | Affected | 4.32 | 4 | 0.1817 | 0.5132 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||
| c.1198G>A | V400M 2D  3DClick to see structure in 3D Viewer AISynGAP1 variant V400M is reported in gnomAD (ID 6‑33438103‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. In contrast, only three tools—polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default—predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, SGM‑Consensus is likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No evidence from FoldX or premPS is available. Overall, the preponderance of predictions, including the high‑accuracy methods, supports a benign classification, which is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | 6-33438103-G-A | 3 | 1.86e-6 | -5.438 | Likely Benign | 0.573 | Likely Pathogenic | Likely Benign | -1.12 | Ambiguous | 0.1 | -0.16 | Likely Benign | -0.64 | Ambiguous | 0.55 | Ambiguous | 0.443 | Likely Benign | -1.44 | Neutral | 0.868 | Possibly Damaging | 0.289 | Benign | 5.26 | Benign | 0.01 | Affected | 3.38 | 27 | 0.0851 | 0.4643 | 1 | 2 | -2.3 | 32.06 | ||||||||||||||||||||||||
| c.1198G>C | V400L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400L is listed in ClinVar as Benign (ClinVar ID 1166313.0) and is present in gnomAD (variant ID 6‑33438103‑G‑C). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive result is from FoldX, which is treated as unavailable. High‑accuracy assessments confirm benignity: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Overall, the computational evidence strongly supports a benign classification, consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | Benign | 1 | 6-33438103-G-C | 22 | 1.36e-5 | -1.000 | Likely Benign | 0.137 | Likely Benign | Likely Benign | -0.71 | Ambiguous | 0.2 | 0.39 | Likely Benign | -0.16 | Likely Benign | -0.29 | Likely Benign | 0.325 | Likely Benign | -0.60 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.33 | Benign | 0.64 | Tolerated | 3.38 | 27 | 0.1006 | 0.5242 | 2 | 1 | -0.4 | 14.03 | 251.0 | -30.1 | 0.0 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). Val400 is swapped for another hydrophobic residue, leucine, whose branched hydrocarbon side chain is of a comparable size and thus packs favorably within the C2 domain. In short, the residue swap has no apparent negative effect on the structure based on the variant simulations. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||
| c.1198G>T | V400L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools that agree on a benign effect include REVEL, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, premPS, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive result is from FoldX (Uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | -1.000 | Likely Benign | 0.137 | Likely Benign | Likely Benign | -0.71 | Ambiguous | 0.2 | 0.39 | Likely Benign | -0.16 | Likely Benign | -0.29 | Likely Benign | 0.325 | Likely Benign | -0.60 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.33 | Benign | 0.64 | Tolerated | 3.38 | 27 | 0.1006 | 0.5242 | 2 | 1 | -0.4 | 14.03 | 251.0 | -30.1 | 0.0 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). Val400 is swapped for another hydrophobic residue, leucine, whose branched hydrocarbon side chain is of a comparable size and thus packs favorably within the C2 domain. In short, the residue swap has no apparent negative effect on the structure based on the variant simulations. | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||
| c.1199T>A | V400E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400E is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | Uncertain | 1 | -13.686 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.70 | Destabilizing | 0.2 | 2.46 | Destabilizing | 3.08 | Destabilizing | 2.29 | Destabilizing | 0.810 | Likely Pathogenic | -4.88 | Deleterious | 0.920 | Possibly Damaging | 0.335 | Benign | 5.31 | Benign | 0.00 | Affected | 3.38 | 27 | 0.1044 | 0.1922 | -2 | -2 | -7.7 | 29.98 | 249.1 | -38.8 | -0.1 | 0.1 | 1.0 | 0.0 | X | X | X | Potentially Pathogenic | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). In the variant simulations, the negatively charged carboxylate group of the Glu400 side chain is not suitable for occupying the hydrophobic niche. Consequently, the side chain escapes the center of the C2 domain and interacts with the backbone amide groups of Leu402 in the same β strand and/or Ile269 and Glu270 in a neighboring β strand (res. Arg259-Arg272). This residue swap disrupts the hydrophobic packing and generally has extensive negative effects on the C2 domain structure. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | ||||||||||||||
| c.1199T>C | V400A 2D  3DClick to see structure in 3D Viewer AISynGAP1 V400A is not reported in ClinVar and is absent from gnomAD. Consensus from standard predictors shows a split: benign calls from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls come from FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT and AlphaMissense‑Default. Two high‑accuracy tools give a clear signal: AlphaMissense‑Optimized is uncertain, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta also predicts pathogenic. With most evidence pointing to deleterious effects, the variant is most likely pathogenic, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | -7.564 | In-Between | 0.871 | Likely Pathogenic | Ambiguous | 3.14 | Destabilizing | 0.1 | 3.12 | Destabilizing | 3.13 | Destabilizing | 2.29 | Destabilizing | 0.479 | Likely Benign | -3.12 | Deleterious | 0.435 | Benign | 0.049 | Benign | 5.32 | Benign | 0.01 | Affected | 0.3291 | 0.2767 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||
| c.1199T>G | V400G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V400G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumDiv and FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | -11.508 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 4.84 | Destabilizing | 0.1 | 5.40 | Destabilizing | 5.12 | Destabilizing | 2.40 | Destabilizing | 0.819 | Likely Pathogenic | -5.70 | Deleterious | 0.335 | Benign | 0.920 | Probably Damaging | 5.27 | Benign | 0.00 | Affected | 0.2296 | 0.2522 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.133A>C | N45H 2D AIThe SynGAP1 missense variant N45H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (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 returns 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 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 | -2.620 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -0.62 | Neutral | 0.943 | Possibly Damaging | 0.924 | Probably Damaging | 4.05 | Benign | 0.00 | Affected | 0.2009 | 0.8046 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.133A>G | N45D 2D AIThe SynGAP1 missense variant N45D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; no Foldetta stability result is available. Overall, the majority of evidence—including the consensus and high‑accuracy predictions—supports a benign classification for this 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 | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -3.340 | Likely Benign | 0.278 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.37 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 4.17 | Benign | 0.00 | Affected | 0.2234 | 0.4999 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.133A>T | N45Y 2D AIThe SynGAP1 missense variant N45Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently 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—including the high‑accuracy tools—points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, 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 | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -5.773 | Likely Benign | 0.502 | Ambiguous | Likely Benign | 0.180 | Likely Benign | -1.18 | Neutral | 0.943 | Possibly Damaging | 0.924 | Probably Damaging | 4.04 | Benign | 0.00 | Affected | 0.0741 | 0.7255 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| 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.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.883A>C | T295P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX and AlphaMissense‑Optimized, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome. High‑accuracy assessments further show that AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it as likely pathogenic, and Foldetta reports an uncertain stability change. With the majority of evidence pointing to deleterious effects, the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -9.941 | Likely Pathogenic | 0.688 | Likely Pathogenic | Likely Benign | 0.26 | Likely Benign | 0.2 | 3.30 | Destabilizing | 1.78 | Ambiguous | 0.60 | Ambiguous | 0.531 | Likely Pathogenic | -4.65 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.90 | Pathogenic | 0.02 | Affected | 0.2442 | 0.5327 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.883A>G | T295A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 T295A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into benign (REVEL, FoldX, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM). Four tools are uncertain (Rosetta, Foldetta, premPS, ESM1b). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the majority of conventional predictors lean toward a benign effect, whereas the SGM Consensus indicates a pathogenic signal. Thus, the variant is most likely benign based on the bulk of evidence, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -7.276 | In-Between | 0.336 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.1 | 1.17 | Ambiguous | 0.70 | Ambiguous | 0.56 | Ambiguous | 0.340 | Likely Benign | -3.51 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.96 | Pathogenic | 0.11 | Tolerated | 0.4623 | 0.4190 | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||
| c.883A>T | T295S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; premPS is inconclusive. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority (3 benign vs. 1 pathogenic); and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -4.904 | Likely Benign | 0.335 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.2 | 0.28 | Likely Benign | 0.06 | Likely Benign | 0.54 | Ambiguous | 0.218 | Likely Benign | -2.16 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.02 | Pathogenic | 0.14 | Tolerated | 0.3910 | 0.4473 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.884C>A | T295N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 T295N missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, ESM1b, and Foldetta, while those that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, seven tools predict pathogenicity versus four predicting benign, with no ClinVar evidence to contradict this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -6.588 | Likely Benign | 0.793 | Likely Pathogenic | Ambiguous | 0.24 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.45 | Likely Benign | 0.89 | Ambiguous | 0.438 | Likely Benign | -3.51 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.93 | Pathogenic | 0.03 | Affected | 0.1522 | 0.4457 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.884C>G | T295S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; premPS is inconclusive. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority (3 benign vs. 1 pathogenic); and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -4.904 | Likely Benign | 0.335 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.2 | 0.28 | Likely Benign | 0.06 | Likely Benign | 0.54 | Ambiguous | 0.196 | Likely Benign | -2.16 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.02 | Pathogenic | 0.14 | Tolerated | 0.3910 | 0.4473 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.884C>T | T295I 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant T295I is reported in gnomAD (ID 6‑33437789‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two consensus groups: benign predictions come from FoldX and Foldetta, while pathogenic predictions are supported by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by AlphaMissense‑Optimized, Rosetta, and premPS and are treated as inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic effect, with only a minority of tools indicating benign or uncertain outcomes. This prediction does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | 6-33437789-C-T | 4 | 2.48e-6 | -9.330 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.21 | Likely Benign | 0.2 | 0.55 | Ambiguous | 0.38 | Likely Benign | 0.58 | Ambiguous | 0.607 | Likely Pathogenic | -4.87 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.88 | Pathogenic | 0.04 | Affected | 3.38 | 23 | 0.1025 | 0.5599 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||
| c.2284G>A | D762N 2D AIThe SynGAP1 D762N 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, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, 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 balance of evidence leans toward a benign impact for D762N, 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. | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -3.323 | Likely Benign | 0.640 | Likely Pathogenic | Likely Benign | 0.110 | Likely Benign | -1.51 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.13 | Pathogenic | 0.11 | Tolerated | 0.1698 | 0.8797 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2284G>C | D762H 2D AIThe SynGAP1 D762H missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance 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 | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -4.643 | Likely Benign | 0.909 | Likely Pathogenic | Ambiguous | 0.212 | Likely Benign | -2.73 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.08 | Pathogenic | 0.02 | Affected | 0.2007 | 0.9102 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2284G>T | D762Y 2D AIThe SynGAP1 D762Y variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas a larger group predicts a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic”; Foldetta (a protein‑folding stability approach combining FoldX‑MD and Rosetta) has no available output for this variant. Overall, the majority of evidence points to a pathogenic effect, and this assessment 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 | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -6.959 | Likely Benign | 0.905 | Likely Pathogenic | Ambiguous | 0.219 | Likely Benign | -3.24 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.07 | Pathogenic | 0.01 | Affected | 0.0700 | 0.7929 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2285A>C | D762A 2D AIThe SynGAP1 D762A missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool yields 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 combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward a pathogenic impact. This assessment 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. | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -4.510 | Likely Benign | 0.912 | Likely Pathogenic | Ambiguous | 0.178 | Likely Benign | -2.40 | Neutral | 0.994 | Probably Damaging | 0.900 | Possibly Damaging | 2.12 | Pathogenic | 0.05 | Affected | 0.4632 | 0.8428 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2285A>G | D762G 2D AIThe SynGAP1 missense variant D762G 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, SIFT, and ESM1b, whereas those that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates 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 results are unavailable. Based on the majority of predictions and the SGM‑Consensus outcome, 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 | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -1.062 | Likely Benign | 0.812 | Likely Pathogenic | Ambiguous | 0.170 | Likely Benign | -2.55 | Deleterious | 0.998 | Probably Damaging | 0.949 | Probably Damaging | 2.10 | Pathogenic | 0.08 | Tolerated | 0.4710 | 0.7841 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2285A>T | D762V 2D AIThe SynGAP1 D762V missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b. Tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returned 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 consensus tools predict a pathogenic impact, 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. | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -6.122 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.229 | Likely Benign | -1.98 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.08 | Pathogenic | 0.01 | Affected | 0.1105 | 0.8785 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||||||||||||
| c.2286C>A | D762E 2D AIThe SynGAP1 D762E 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, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta results are unavailable. Overall, the majority of high‑confidence predictions lean toward a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -4.332 | Likely Benign | 0.459 | Ambiguous | Likely Benign | 0.144 | Likely Benign | -1.59 | Neutral | 0.994 | Probably Damaging | 0.891 | Possibly Damaging | 2.18 | Pathogenic | 0.05 | Affected | 0.1911 | 0.8236 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2286C>G | D762E 2D AIThe SynGAP1 D762E 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, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta results are unavailable. Overall, the majority of high‑confidence predictions lean toward a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -4.332 | Likely Benign | 0.459 | Ambiguous | Likely Benign | 0.144 | Likely Benign | -1.59 | Neutral | 0.994 | Probably Damaging | 0.891 | Possibly Damaging | 2.18 | Pathogenic | 0.05 | Affected | 0.1911 | 0.8236 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2296T>A | S766T 2D AIThe SynGAP1 missense variant S766T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. 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. The variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | -4.923 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.25 | Neutral | 0.790 | Possibly Damaging | 0.433 | Benign | 4.15 | Benign | 0.02 | Affected | 0.1461 | 0.6511 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2296T>C | S766P 2D  AIThe SynGAP1 missense variant S766P is reported in gnomAD (ID 6‑33442454‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while SIFT uniquely predicts it as pathogenic. The remaining tools, ESM1b and AlphaMissense‑Default, are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact, 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. | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | 6-33442454-T-C | 1 | 1.28e-6 | -7.343 | In-Between | 0.374 | Ambiguous | Likely Benign | 0.193 | Likely Benign | -0.91 | Neutral | 0.006 | Benign | 0.013 | Benign | 4.07 | Benign | 0.01 | Affected | 3.64 | 6 | 0.2216 | 0.5862 | -1 | 1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.2296T>G | S766A 2D  AIThe SynGAP1 missense variant S766A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. 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 | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | -6.115 | Likely Benign | 0.186 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.98 | Neutral | 0.447 | Benign | 0.198 | Benign | 4.17 | Benign | 0.02 | Affected | 0.5059 | 0.5705 | Strenghten | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2297C>A | S766Y 2D  AIThe SynGAP1 missense variant S766Y is reported in gnomAD (ID 6‑33442455‑C‑A) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote) predicts pathogenic, and no Foldetta stability data are available. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | 6-33442455-C-A | -8.636 | Likely Pathogenic | 0.641 | Likely Pathogenic | Likely Benign | 0.222 | Likely Benign | -2.67 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 3.64 | 6 | 0.0794 | 0.5609 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| c.2297C>G | S766C 2D AIThe SynGAP1 missense variant S766C 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, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. 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 S766C, 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 | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | -7.681 | In-Between | 0.326 | Likely Benign | Likely Benign | 0.192 | Likely Benign | -2.02 | Neutral | 0.997 | Probably Damaging | 0.889 | Possibly Damaging | 4.07 | Benign | 0.00 | Affected | 0.1049 | 0.6110 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2297C>T | S766F 2D  AIThe SynGAP1 missense variant S766F is listed in gnomAD (ID 6‑33442455‑C‑T) but has no ClinVar entry. Functional prediction tools show a split verdict: benign calls come from REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, 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 further reveal AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta results are unavailable. Overall, the majority of evidence points toward 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 | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | 6-33442455-C-T | -8.944 | Likely Pathogenic | 0.709 | Likely Pathogenic | Likely Benign | 0.233 | Likely Benign | -2.87 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 4.08 | Benign | 0.00 | Affected | 3.64 | 6 | 0.0770 | 0.5887 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| c.2317A>C | M773L 2D  AIThe SynGAP1 missense variant M773L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -3.458 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -0.75 | Neutral | 0.038 | Benign | 0.137 | Benign | 4.29 | Benign | 0.81 | Tolerated | 0.1517 | 0.3529 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2317A>G | M773V 2D  AIThe SynGAP1 missense variant M773V has no ClinVar entry and is not reported in gnomAD. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the computational evidence indicates that M773V 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 | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -4.353 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.234 | Likely Benign | -0.70 | Neutral | 0.038 | Benign | 0.284 | Benign | 4.30 | Benign | 0.87 | Tolerated | 0.3145 | 0.3081 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.2317A>T | M773L 2D AIThe SynGAP1 missense variant M773L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess pathogenicity uniformly predict a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the consensus of all available predictions points to a benign impact, and this is consistent with the lack of a ClinVar classification—there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -3.458 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -0.75 | Neutral | 0.038 | Benign | 0.137 | Benign | 4.29 | Benign | 0.81 | Tolerated | 0.1517 | 0.3529 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2318T>A | M773K 2D  AIThe SynGAP1 missense variant M773K 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, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one 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 exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -5.117 | Likely Benign | 0.641 | Likely Pathogenic | Likely Benign | 0.178 | Likely Benign | -1.80 | Neutral | 0.106 | Benign | 0.471 | Possibly Damaging | 4.19 | Benign | 0.02 | Affected | 0.1646 | 0.0851 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2318T>C | M773T 2D  AIThe SynGAP1 missense variant M773T is listed in gnomAD (ID 6‑33442476‑T‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumVar predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus 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 conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | 6-33442476-T-C | 1 | 1.28e-6 | -4.225 | Likely Benign | 0.377 | Ambiguous | Likely Benign | 0.112 | Likely Benign | -1.63 | Neutral | 0.106 | Benign | 0.471 | Possibly Damaging | 4.22 | Benign | 0.06 | Tolerated | 3.64 | 6 | 0.2196 | 0.1586 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||||||
| c.2318T>G | M773R 2D  AIThe SynGAP1 missense variant M773R is listed in gnomAD (ID 6‑33442476‑T‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. No Foldetta (FoldX‑MD/Rosetta stability) result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | 6-33442476-T-G | 1 | 1.28e-6 | -4.340 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 0.183 | Likely Benign | -1.87 | Neutral | 0.220 | Benign | 0.471 | Possibly Damaging | 4.18 | Benign | 0.02 | Affected | 3.64 | 6 | 0.1778 | 0.0800 | -1 | 0 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||||||
| c.2319G>A | M773I 2D  AIThe SynGAP1 missense variant M773I 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. 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 | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -4.799 | Likely Benign | 0.567 | Likely Pathogenic | Likely Benign | 0.099 | Likely Benign | -0.83 | Neutral | 0.038 | Benign | 0.284 | Benign | 4.31 | Benign | 0.22 | Tolerated | 0.1406 | 0.3011 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2319G>C | M773I 2D AIThe SynGAP1 missense variant M773I 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. 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 | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -4.799 | Likely Benign | 0.567 | Likely Pathogenic | Likely Benign | 0.099 | Likely Benign | -0.83 | Neutral | 0.038 | Benign | 0.284 | Benign | 4.31 | Benign | 0.22 | Tolerated | 0.1406 | 0.3011 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2319G>T | M773I 2D AIThe SynGAP1 missense variant M773I 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. 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 | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -4.799 | Likely Benign | 0.567 | Likely Pathogenic | Likely Benign | 0.099 | Likely Benign | -0.83 | Neutral | 0.038 | Benign | 0.284 | Benign | 4.31 | Benign | 0.22 | Tolerated | 0.1406 | 0.3011 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2329C>A | L777I 2D  AIThe SynGAP1 missense variant L777I is listed in gnomAD (ID 6‑33442487‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which reports “Likely Benign.” Pathogenic predictions are made by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | 6-33442487-C-A | -5.346 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.096 | Likely Benign | -0.85 | Neutral | 0.843 | Possibly Damaging | 0.920 | Probably Damaging | 4.05 | Benign | 0.02 | Affected | 3.64 | 6 | 0.1041 | 0.4327 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||
| c.2329C>G | L777V 2D  AIThe SynGAP1 missense variant L777V 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 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 | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | -5.693 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -1.05 | Neutral | 0.843 | Possibly Damaging | 0.920 | Probably Damaging | 4.07 | Benign | 0.05 | Affected | 0.1651 | 0.3977 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2329C>T | L777F 2D  AIThe SynGAP1 missense variant L777F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | -4.499 | Likely Benign | 0.175 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -1.91 | Neutral | 0.968 | Probably Damaging | 0.966 | Probably Damaging | 3.98 | Benign | 0.01 | Affected | 0.0697 | 0.3576 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2330T>A | L777H 2D  AIThe SynGAP1 missense variant L777H has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence—including the consensus of high‑accuracy tools—suggests that the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | -6.719 | Likely Benign | 0.492 | Ambiguous | Likely Benign | 0.230 | Likely Benign | -2.51 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 3.95 | Benign | 0.00 | Affected | 0.1052 | 0.0972 | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2330T>C | L777P 2D  AIThe SynGAP1 missense variant L777P is catalogued in gnomAD (6‑33442488‑T‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also indicates a likely benign outcome. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | 6-33442488-T-C | -5.807 | Likely Benign | 0.361 | Ambiguous | Likely Benign | 0.255 | Likely Benign | -2.13 | Neutral | 0.991 | Probably Damaging | 0.985 | Probably Damaging | 3.94 | Benign | 0.00 | Affected | 3.64 | 6 | 0.3732 | 0.1664 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||
| c.2330T>G | L777R 2D  AIThe SynGAP1 missense variant L777R 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. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | -6.084 | Likely Benign | 0.650 | Likely Pathogenic | Likely Benign | 0.227 | Likely Benign | -2.20 | Neutral | 0.991 | Probably Damaging | 0.985 | Probably Damaging | 3.97 | Benign | 0.00 | Affected | 0.1249 | 0.0846 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.193C>A | H65N 2D  AIThe SynGAP1 missense variant H65N is 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, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are AlphaMissense‑Default and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.411940 | Structured | 0.476188 | Uncertain | 0.458 | 0.758 | 0.125 | -2.788 | Likely Benign | 0.771 | Likely Pathogenic | Likely Benign | 0.038 | Likely Benign | -1.42 | Neutral | 0.273 | Benign | 0.107 | Benign | 4.18 | Benign | 0.00 | Affected | 0.1280 | 0.2200 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.193C>G | H65D 2D  AIThe SynGAP1 H65D missense variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign, and AlphaMissense‑Optimized is classified as Uncertain. 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 | 0.411940 | Structured | 0.476188 | Uncertain | 0.458 | 0.758 | 0.125 | -2.240 | Likely Benign | 0.937 | Likely Pathogenic | Ambiguous | 0.126 | Likely Benign | -1.78 | Neutral | 0.462 | Possibly Damaging | 0.227 | Benign | 4.17 | Benign | 0.00 | Affected | 0.2142 | 0.1828 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.193C>T | H65Y 2D  AIThe SynGAP1 missense variant H65Y has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic designation and the lack of population frequency data. The variant is most likely benign based on predictions, and this does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.411940 | Structured | 0.476188 | Uncertain | 0.458 | 0.758 | 0.125 | -3.644 | Likely Benign | 0.852 | Likely Pathogenic | Ambiguous | 0.037 | Likely Benign | -1.11 | Neutral | 0.273 | Benign | 0.152 | Benign | 4.15 | Benign | 0.00 | Affected | 0.0788 | 0.3628 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.194A>C | H65P 2D  AIThe SynGAP1 missense variant H65P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. 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 H65P, 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 | 0.411940 | Structured | 0.476188 | Uncertain | 0.458 | 0.758 | 0.125 | -1.732 | Likely Benign | 0.479 | Ambiguous | Likely Benign | 0.103 | Likely Benign | -1.47 | Neutral | 0.676 | Possibly Damaging | 0.227 | Benign | 4.16 | Benign | 0.00 | Affected | 0.1915 | 0.3701 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.194A>G | H65R 2D  AIThe SynGAP1 missense variant H65R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33425802‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, 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, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, 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 | 0.411940 | Structured | 0.476188 | Uncertain | 0.458 | 0.758 | 0.125 | Uncertain | 1 | 6-33425802-A-G | 1 | 6.20e-7 | -1.980 | Likely Benign | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.073 | Likely Benign | -1.60 | Neutral | 0.462 | Possibly Damaging | 0.227 | Benign | 4.19 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1483 | 0.1671 | 2 | 0 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||
| c.194A>T | H65L 2D  AIThe SynGAP1 H65L missense variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” AlphaMissense‑Optimized returns an uncertain result, and Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.411940 | Structured | 0.476188 | Uncertain | 0.458 | 0.758 | 0.125 | -1.889 | Likely Benign | 0.836 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -1.65 | Neutral | 0.462 | Possibly Damaging | 0.227 | Benign | 4.22 | Benign | 0.00 | Affected | 0.0718 | 0.4760 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.195C>A | H65Q 2D  AIThe SynGAP1 missense variant H65Q is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33425803‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Benign,” and Foldetta results are unavailable. Based on the overall distribution of 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 | 0.411940 | Structured | 0.476188 | Uncertain | 0.458 | 0.758 | 0.125 | 6-33425803-C-A | 1 | 6.20e-7 | -2.966 | Likely Benign | 0.953 | Likely Pathogenic | Ambiguous | 0.035 | Likely Benign | -1.46 | Neutral | 0.462 | Possibly Damaging | 0.227 | Benign | 4.19 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1059 | 0.2900 | 0 | 3 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||
| c.195C>G | H65Q 2D AIThe SynGAP1 H65Q missense variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, while AlphaMissense‑Optimized is uncertain. 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 status, as no ClinVar classification exists for H65Q. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.411940 | Structured | 0.476188 | Uncertain | 0.458 | 0.758 | 0.125 | -2.966 | Likely Benign | 0.953 | Likely Pathogenic | Ambiguous | 0.035 | Likely Benign | -1.46 | Neutral | 0.462 | Possibly Damaging | 0.227 | Benign | 4.19 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1059 | 0.2900 | 0 | 3 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||
| c.2305C>A | L769I 2D AIThe SynGAP1 missense variant L769I is listed in gnomAD (ID 6‑33442463‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The 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. No Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | 6-33442463-C-A | -3.993 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.15 | Neutral | 0.836 | Possibly Damaging | 0.329 | Benign | 4.09 | Benign | 0.04 | Affected | 3.64 | 6 | 0.0800 | 0.3108 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||
| c.2305C>G | L769V 2D AIThe SynGAP1 missense variant L769V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, but this is the sole discordant call. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | -4.585 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.41 | Neutral | 0.625 | Possibly Damaging | 0.249 | Benign | 4.04 | Benign | 0.25 | Tolerated | 0.1364 | 0.2558 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2305C>T | L769F 2D AIThe SynGAP1 missense variant L769F is listed in ClinVar (ID 3617309.0) 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the high‑accuracy tools) also indicates 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—including the high‑accuracy tools—suggest the variant is most likely benign, which is consistent with its ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | Uncertain | 1 | -5.044 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.89 | Neutral | 0.925 | Possibly Damaging | 0.510 | Possibly Damaging | 3.94 | Benign | 0.02 | Affected | 0.0554 | 0.2881 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||
| c.2306T>A | L769H 2D AIThe SynGAP1 missense variant L769H 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, all of which classify the variant as benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, all of which report the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. 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 | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | -6.038 | Likely Benign | 0.422 | Ambiguous | Likely Benign | 0.235 | Likely Benign | -1.96 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.1016 | 0.0828 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.2306T>C | L769P 2D AIThe SynGAP1 missense variant L769P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for this 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 | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | -6.261 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.200 | Likely Benign | -1.75 | Neutral | 0.925 | Possibly Damaging | 0.427 | Benign | 3.90 | Benign | 0.00 | Affected | 0.3573 | 0.1323 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2306T>G | L769R 2D AIThe SynGAP1 missense variant L769R 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‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | -6.245 | Likely Benign | 0.493 | Ambiguous | Likely Benign | 0.206 | Likely Benign | -1.66 | Neutral | 0.003 | Benign | 0.006 | Benign | 3.91 | Benign | 0.00 | Affected | 0.1286 | 0.0702 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2431C>A | P811T 2D AIThe SynGAP1 missense variant P811T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. 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 is benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect for P811T, 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 | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.329 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.119 | Likely Benign | -1.94 | Neutral | 0.991 | Probably Damaging | 0.864 | Possibly Damaging | 2.77 | Benign | 0.03 | Affected | 0.1679 | 0.6095 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||
| c.2431C>G | P811A 2D AIThe SynGAP1 missense variant P811A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence supports a benign classification for P811A, 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 | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.120 | Likely Benign | 0.287 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -2.11 | Neutral | 0.939 | Possibly Damaging | 0.670 | Possibly Damaging | 2.76 | Benign | 0.57 | Tolerated | 0.3763 | 0.5485 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2431C>T | P811S 2D AIThe SynGAP1 missense variant P811S is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors (AlphaMissense‑Optimized and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, and AlphaMissense‑Default remains uncertain. No Foldetta stability assessment is available, so it does not contribute to the evidence. Overall, the preponderance of evidence points to a benign effect for P811S, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -4.733 | Likely Benign | 0.474 | Ambiguous | Likely Benign | 0.128 | Likely Benign | -1.28 | Neutral | 0.982 | Probably Damaging | 0.824 | Possibly Damaging | 2.79 | Benign | 0.78 | Tolerated | 0.3656 | 0.5960 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||
| c.2432C>A | P811Q 2D  AIThe SynGAP1 missense variant P811Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.145 | Likely Benign | 0.431 | Ambiguous | Likely Benign | 0.138 | Likely Benign | -2.38 | Neutral | 0.982 | Probably Damaging | 0.875 | Possibly Damaging | 2.78 | Benign | 0.01 | Affected | 0.1523 | 0.5338 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||||
| c.2432C>G | P811R 2D AIThe SynGAP1 missense variant P811R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT; AlphaMissense‑Default remains uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic, with one uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as benign, while Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the preponderance of evidence points to a benign impact for P811R, 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. | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.273 | Likely Benign | 0.557 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -2.69 | Deleterious | 0.100 | Benign | 0.066 | Benign | 2.73 | Benign | 0.01 | Affected | 0.1448 | 0.3817 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2432C>T | P811L 2D AIThe SynGAP1 P811L missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. AlphaMissense‑Default is uncertain. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, leans toward benign (2 benign vs. 1 pathogenic, 1 uncertain). 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 preponderance of evidence from high‑accuracy tools and consensus methods indicates that P811L is most likely benign. This assessment does not contradict ClinVar status, as the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -6.184 | Likely Benign | 0.491 | Ambiguous | Likely Benign | 0.150 | Likely Benign | -3.98 | Deleterious | 0.982 | Probably Damaging | 0.824 | Possibly Damaging | 2.71 | Benign | 0.01 | Affected | 0.2327 | 0.6621 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2437C>A | L813M 2D  AIThe SynGAP1 missense variant L813M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus remains likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact 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 | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -4.893 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -0.53 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.58 | Benign | 0.23 | Tolerated | 0.0814 | 0.3922 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||
| c.2437C>G | L813V 2D AIThe SynGAP1 missense variant L813V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments further support a benign outcome: 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 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 | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -4.809 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -0.98 | Neutral | 0.994 | Probably Damaging | 0.856 | Possibly Damaging | 2.62 | Benign | 0.28 | Tolerated | 0.1704 | 0.3744 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2438T>A | L813Q 2D  AIThe SynGAP1 missense variant L813Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the balance of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -5.380 | Likely Benign | 0.660 | Likely Pathogenic | Likely Benign | 0.137 | Likely Benign | -1.30 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.67 | Benign | 0.10 | Tolerated | 0.1122 | 0.1105 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||
| c.2438T>C | L813P 2D AIThe SynGAP1 missense variant L813P is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors (AlphaMissense‑Optimized and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, and AlphaMissense‑Default remains uncertain. No Foldetta stability assessment is available, so it does not influence the overall interpretation. Overall, the preponderance of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -2.572 | Likely Benign | 0.554 | Ambiguous | Likely Benign | 0.122 | Likely Benign | -1.96 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.58 | Benign | 0.21 | Tolerated | 0.3564 | 0.1458 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||
| c.2438T>G | L813R 2D AIThe SynGAP1 missense variant L813R 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, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and Foldetta results are unavailable. Taken together, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -4.697 | Likely Benign | 0.786 | Likely Pathogenic | Ambiguous | 0.160 | Likely Benign | -1.57 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.68 | Benign | 0.11 | Tolerated | 0.1261 | 0.0947 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.2440G>A | A814T 2D AIThe SynGAP1 missense variant A814T is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome, while Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -3.600 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -1.24 | Neutral | 0.103 | Benign | 0.047 | Benign | 2.64 | Benign | 0.09 | Tolerated | 0.1400 | 0.6655 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.2440G>C | A814P 2D AIThe SynGAP1 missense variant A814P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) 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 independent predictors points to a benign effect for A814P, 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 | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -5.247 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.210 | Likely Benign | -1.88 | Neutral | 0.984 | Probably Damaging | 0.855 | Possibly Damaging | 2.64 | Benign | 0.05 | Affected | 0.1845 | 0.4941 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2440G>T | A814S 2D AIThe SynGAP1 missense variant A814S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports likely benign; Foldetta results are not available. Based on the preponderance of evidence, 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 | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -2.542 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -1.22 | Neutral | 0.640 | Possibly Damaging | 0.386 | Benign | 2.63 | Benign | 0.06 | Tolerated | 0.2670 | 0.5366 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2441C>A | A814D 2D AIThe SynGAP1 missense variant A814D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie and thus unavailable, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no reported result. Overall, the balance of evidence from the consensus of standard predictors points to a pathogenic effect. 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. | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -5.641 | Likely Benign | 0.939 | Likely Pathogenic | Ambiguous | 0.158 | Likely Benign | -2.56 | Deleterious | 0.968 | Probably Damaging | 0.810 | Possibly Damaging | 2.59 | Benign | 0.01 | Affected | 0.1740 | 0.2167 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2441C>G | A814G 2D AIThe SynGAP1 missense variant A814G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) score; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) 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 majority of evidence points 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 | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -3.659 | Likely Benign | 0.312 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.83 | Neutral | 0.896 | Possibly Damaging | 0.649 | Possibly Damaging | 2.60 | Benign | 0.05 | Affected | 0.2336 | 0.4504 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2441C>T | A814V 2D AIThe SynGAP1 missense variant A814V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors (AlphaMissense‑Optimized and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, but these are the only tools in disagreement. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available, so these do not influence the overall inference. Overall, the preponderance of evidence points to a benign effect for A814V, 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 | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -4.147 | Likely Benign | 0.374 | Ambiguous | Likely Benign | 0.119 | Likely Benign | -0.14 | Neutral | 0.811 | Possibly Damaging | 0.489 | Possibly Damaging | 2.71 | Benign | 0.83 | Tolerated | 0.1088 | 0.6197 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||||
| c.982T>A | Y328N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.411940 | Structured | 0.392519 | Uncertain | 0.916 | 0.497 | 0.000 | -13.778 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.72 | Destabilizing | 0.1 | 3.88 | Destabilizing | 3.30 | Destabilizing | 2.06 | Destabilizing | 0.548 | Likely Pathogenic | -8.07 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.53 | Pathogenic | 0.01 | Affected | 0.2374 | 0.0703 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.982T>C | Y328H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.411940 | Structured | 0.392519 | Uncertain | 0.916 | 0.497 | 0.000 | -10.885 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 2.08 | Destabilizing | 0.0 | 2.43 | Destabilizing | 2.26 | Destabilizing | 1.35 | Destabilizing | 0.516 | Likely Pathogenic | -4.53 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.54 | Pathogenic | 0.02 | Affected | 0.2572 | 0.0703 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.982T>G | Y328D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328D is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classifies the substitution as pathogenic; no tool predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.411940 | Structured | 0.392519 | Uncertain | 0.916 | 0.497 | 0.000 | -13.701 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.32 | Destabilizing | 0.2 | 4.97 | Destabilizing | 4.65 | Destabilizing | 1.87 | Destabilizing | 0.680 | Likely Pathogenic | -8.93 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.52 | Pathogenic | 0.01 | Affected | 0.4233 | 0.0703 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.983A>C | Y328S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328S is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact on protein stability. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.411940 | Structured | 0.392519 | Uncertain | 0.916 | 0.497 | 0.000 | -12.358 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 3.13 | Destabilizing | 0.1 | 4.55 | Destabilizing | 3.84 | Destabilizing | 1.80 | Destabilizing | 0.586 | Likely Pathogenic | -8.01 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.54 | Pathogenic | 0.01 | Affected | 0.4924 | 0.2449 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.983A>G | Y328C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (integrating FoldX‑MD and Rosetta outputs) also reports a pathogenic outcome. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.411940 | Structured | 0.392519 | Uncertain | 0.916 | 0.497 | 0.000 | -12.385 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 2.52 | Destabilizing | 0.1 | 3.74 | Destabilizing | 3.13 | Destabilizing | 1.40 | Destabilizing | 0.523 | Likely Pathogenic | -8.01 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.55 | Pathogenic | 0.01 | Affected | 0.3154 | 0.2882 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.983A>T | Y328F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.411940 | Structured | 0.392519 | Uncertain | 0.916 | 0.497 | 0.000 | -6.770 | Likely Benign | 0.444 | Ambiguous | Likely Benign | 0.34 | Likely Benign | 0.1 | 0.43 | Likely Benign | 0.39 | Likely Benign | 0.37 | Likely Benign | 0.330 | Likely Benign | -3.21 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 1.67 | Pathogenic | 0.16 | Tolerated | 0.2409 | 0.3643 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||
| c.1093G>A | V365I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365I is reported in gnomAD (variant ID 6‑33437998‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or tolerated. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) reports a benign effect. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, V365I is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | 6-33437998-G-A | 4 | 2.65e-6 | -5.943 | Likely Benign | 0.155 | Likely Benign | Likely Benign | -0.65 | Ambiguous | 0.2 | -0.11 | Likely Benign | -0.38 | Likely Benign | 0.13 | Likely Benign | 0.036 | Likely Benign | -0.47 | Neutral | 0.451 | Benign | 0.137 | Benign | 1.76 | Pathogenic | 0.10 | Tolerated | 3.38 | 21 | 0.0657 | 0.4447 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||||||
| c.1093G>C | V365L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365L is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess sequence conservation and functional impact uniformly classify the substitution as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity; only FoldX and Rosetta report uncertain stability changes, which are treated as unavailable evidence. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, reports a benign effect on protein folding stability. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | -6.141 | Likely Benign | 0.265 | Likely Benign | Likely Benign | -0.72 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.01 | Likely Benign | 0.35 | Likely Benign | 0.065 | Likely Benign | -1.71 | Neutral | 0.005 | Benign | 0.003 | Benign | 2.50 | Benign | 0.25 | Tolerated | 3.38 | 21 | 0.0852 | 0.5309 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||||
| c.1093G>T | V365L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365L is catalogued in gnomAD (ID 6‑33437998‑G‑T) but has no ClinVar entry. Across the available in‑silico predictors, the majority (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly classify the change as benign; only FoldX and Rosetta report uncertain stability effects, which are treated as unavailable evidence. High‑accuracy assessments reinforce this benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from the unanimous benign vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a benign impact. Consequently, the variant is most likely benign based on current computational evidence, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | 6-33437998-G-T | 5 | 3.31e-6 | -6.141 | Likely Benign | 0.265 | Likely Benign | Likely Benign | -0.72 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.01 | Likely Benign | 0.35 | Likely Benign | 0.065 | Likely Benign | -1.71 | Neutral | 0.005 | Benign | 0.003 | Benign | 2.50 | Benign | 0.25 | Tolerated | 3.38 | 21 | 0.0852 | 0.5309 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||||||
| c.1094T>A | V365E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365E is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate 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 assessments corroborate this: 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 pathogenic. With all available evidence pointing to a damaging effect and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | -16.263 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.99 | Destabilizing | 0.3 | 3.81 | Destabilizing | 3.90 | Destabilizing | 2.20 | Destabilizing | 0.613 | Likely Pathogenic | -5.02 | Deleterious | 0.989 | Probably Damaging | 0.688 | Possibly Damaging | 1.66 | Pathogenic | 0.00 | Affected | 0.0849 | 0.2083 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.1094T>C | V365A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by REVEL and polyPhen‑2 HumVar, whereas the remaining tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. High‑accuracy assessments are consistent with a deleterious outcome: 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) reports a pathogenic effect. Taken together, the majority of evidence supports a pathogenic classification for V365A, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | -8.954 | Likely Pathogenic | 0.867 | Likely Pathogenic | Ambiguous | 2.61 | Destabilizing | 0.1 | 2.62 | Destabilizing | 2.62 | Destabilizing | 2.10 | Destabilizing | 0.297 | Likely Benign | -3.18 | Deleterious | 0.622 | Possibly Damaging | 0.235 | Benign | 1.67 | Pathogenic | 0.01 | Affected | 0.2682 | 0.2962 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1094T>G | V365G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign effect. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. All available evidence points to a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | -13.020 | Likely Pathogenic | 0.944 | Likely Pathogenic | Ambiguous | 4.18 | Destabilizing | 0.2 | 4.83 | Destabilizing | 4.51 | Destabilizing | 2.18 | Destabilizing | 0.576 | Likely Pathogenic | -5.88 | Deleterious | 0.688 | Possibly Damaging | 0.989 | Probably Damaging | 1.66 | Pathogenic | 0.00 | Affected | 0.1835 | 0.2717 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1096A>C | T366P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366P is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors leans toward a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign) all classify the substitution as tolerated. In contrast, polyPhen‑2 HumDiv, FATHMM, Rosetta, and the Foldetta stability analysis predict a damaging or pathogenic outcome. FoldX reports an uncertain effect and is therefore not considered evidence. High‑accuracy tools give mixed results: AlphaMissense‑Optimized and the SGM‑Consensus both indicate benign, whereas Foldetta predicts pathogenic. Overall, the majority of predictors (8 benign vs. 4 pathogenic) support a benign classification, and this is consistent with the lack of ClinVar evidence. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | -6.483 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 1.75 | Ambiguous | 0.5 | 3.10 | Destabilizing | 2.43 | Destabilizing | 0.47 | Likely Benign | 0.150 | Likely Benign | -2.49 | Neutral | 0.627 | Possibly Damaging | 0.139 | Benign | 1.70 | Pathogenic | 0.24 | Tolerated | 0.2250 | 0.6251 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1096A>G | T366A 2D AIThe SynGAP1 missense variant T366A is not reported in ClinVar and is absent from gnomAD. Consensus among most in silico predictors indicates a benign effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated. Only FATHMM predicts a pathogenic outcome, while Foldetta, premPS, and Rosetta are inconclusive and are treated as unavailable evidence. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign, and Foldetta provides no definitive stability change. Overall, the computational evidence overwhelmingly favors a benign classification, and this is consistent with the absence of any ClinVar assertion. Therefore, the variant is most likely benign, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | -3.983 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.5 | 0.86 | Ambiguous | 0.54 | Ambiguous | 0.51 | Ambiguous | 0.046 | Likely Benign | -0.94 | Neutral | 0.031 | Benign | 0.016 | Benign | 1.73 | Pathogenic | 0.45 | Tolerated | 0.4141 | 0.4785 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1096A>T | T366S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect. There is no conflict with ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | -3.273 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.92 | Ambiguous | 0.53 | Ambiguous | 0.27 | Likely Benign | 0.058 | Likely Benign | 0.00 | Neutral | 0.005 | Benign | 0.001 | Benign | 1.73 | Pathogenic | 0.78 | Tolerated | 0.3549 | 0.4878 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1097C>A | T366N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change T366N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a benign or likely benign outcome. Only two tools—polyPhen‑2 HumDiv and FATHMM—suggest a pathogenic effect, while premPS remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies the variant as benign. Taken together, the majority of evidence supports a benign impact and is consistent with the absence of any ClinVar pathogenic annotation. Therefore, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | -5.694 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.06 | Likely Benign | 0.0 | 0.36 | Likely Benign | 0.21 | Likely Benign | 0.92 | Ambiguous | 0.038 | Likely Benign | -1.72 | Neutral | 0.454 | Possibly Damaging | 0.038 | Benign | 1.72 | Pathogenic | 0.34 | Tolerated | 0.1595 | 0.4934 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.1097C>G | T366S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect. There is no conflict with ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | -3.273 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.92 | Ambiguous | 0.53 | Ambiguous | 0.27 | Likely Benign | 0.051 | Likely Benign | 0.00 | Neutral | 0.005 | Benign | 0.001 | Benign | 1.73 | Pathogenic | 0.78 | Tolerated | 0.3549 | 0.4878 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1097C>T | T366I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366I is reported in gnomAD (6‑33438002‑C‑T) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. No other tools provide conclusive evidence for pathogenicity. **Based on the aggregate predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none available).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | 6-33438002-C-T | 1 | 6.20e-7 | -4.921 | Likely Benign | 0.279 | Likely Benign | Likely Benign | -0.62 | Ambiguous | 0.1 | -0.31 | Likely Benign | -0.47 | Likely Benign | -0.14 | Likely Benign | 0.058 | Likely Benign | -1.22 | Neutral | 0.002 | Benign | 0.001 | Benign | 1.77 | Pathogenic | 0.26 | Tolerated | 3.38 | 23 | 0.1062 | 0.6215 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||
| c.1186G>A | G396S 2D  AIThe SynGAP1 missense variant G396S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, the SGM‑Consensus is benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No tool predicts pathogenicity. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -3.934 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 1.76 | Ambiguous | 1.6 | 1.12 | Ambiguous | 1.44 | Ambiguous | 0.10 | Likely Benign | 0.223 | Likely Benign | -0.99 | Neutral | 0.004 | Benign | 0.003 | Benign | 3.93 | Benign | 0.56 | Tolerated | 0.2668 | 0.4894 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.1186G>C | G396R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 G396R missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign impact include REVEL, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the variant is more frequently predicted to be pathogenic (five tools) than benign (five tools), and the high‑accuracy consensus leans toward pathogenicity, though Foldetta does not provide a definitive verdict. 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. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -9.310 | Likely Pathogenic | 0.775 | Likely Pathogenic | Likely Benign | 1.68 | Ambiguous | 1.1 | 1.56 | Ambiguous | 1.62 | Ambiguous | 0.66 | Ambiguous | 0.319 | Likely Benign | -2.65 | Deleterious | 0.718 | Possibly Damaging | 0.216 | Benign | 4.42 | Benign | 0.24 | Tolerated | 0.0986 | 0.4007 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1186G>T | G396C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G396C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar; premPS is uncertain. The high‑accuracy consensus methods give a mixed signal: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the majority of individual predictors and the SGM‑Consensus lean toward a benign interpretation, and the two high‑accuracy tools that are available also favor benign over pathogenic. Therefore, 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. | Likely Benign | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -5.459 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 2.15 | Destabilizing | 0.7 | 2.52 | Destabilizing | 2.34 | Destabilizing | 0.59 | Ambiguous | 0.411 | Likely Benign | -3.00 | Deleterious | 0.983 | Probably Damaging | 0.533 | Possibly Damaging | 3.89 | Benign | 0.08 | Tolerated | 0.1181 | 0.4541 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.1187G>A | G396D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G396D 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, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign, whereas only AlphaMissense‑Default predicts a pathogenic outcome. Tools that assess protein stability (FoldX, Rosetta, Foldetta) yield uncertain or inconclusive results. High‑accuracy consensus methods reinforce the benign assessment: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports “Likely Benign”; AlphaMissense‑Optimized also predicts benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -4.148 | Likely Benign | 0.678 | Likely Pathogenic | Likely Benign | 1.92 | Ambiguous | 0.8 | 1.33 | Ambiguous | 1.63 | Ambiguous | 0.17 | Likely Benign | 0.272 | Likely Benign | -1.49 | Neutral | 0.421 | Benign | 0.080 | Benign | 3.91 | Benign | 0.35 | Tolerated | 0.1702 | 0.1122 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.1187G>C | G396A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G396A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign verdict, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Consequently, 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 | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -3.655 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 1.74 | Ambiguous | 0.7 | 1.90 | Ambiguous | 1.82 | Ambiguous | 0.41 | Likely Benign | 0.274 | Likely Benign | -1.28 | Neutral | 0.062 | Benign | 0.024 | Benign | 3.93 | Benign | 0.84 | Tolerated | 0.3846 | 0.5255 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1187G>T | G396V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G396V is catalogued in gnomAD (6‑33438092‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are FoldX, Rosetta, Foldetta, and PROVEAN. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a pathogenic effect. Overall, the majority of predictions lean toward a benign impact, and this consensus does not contradict any ClinVar status (none reported). Thus, based on the available computational evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | 6-33438092-G-T | 6 | 3.72e-6 | -5.663 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 3.49 | Destabilizing | 1.7 | 5.28 | Destabilizing | 4.39 | Destabilizing | 0.34 | Likely Benign | 0.332 | Likely Benign | -2.56 | Deleterious | 0.062 | Benign | 0.014 | Benign | 3.90 | Benign | 0.24 | Tolerated | 3.41 | 15 | 0.1287 | 0.4337 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||
| c.2434C>A | P812T 2D AIThe SynGAP1 missense variant P812T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. 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 likewise indicates Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | -6.956 | Likely Benign | 0.524 | Ambiguous | Likely Benign | 0.105 | Likely Benign | -1.50 | Neutral | 0.994 | Probably Damaging | 0.927 | Probably Damaging | 2.73 | Benign | 0.04 | Affected | 0.1413 | 0.6114 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||
| c.2434C>G | P812A 2D AIThe SynGAP1 missense variant P812A 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‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | -6.113 | Likely Benign | 0.275 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -1.49 | Neutral | 0.989 | Probably Damaging | 0.869 | Possibly Damaging | 2.75 | Benign | 0.08 | Tolerated | 0.3555 | 0.5350 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2434C>T | P812S 2D AIThe SynGAP1 missense variant P812S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442986‑C‑T). Functional 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 and polyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, and no Foldetta stability result is available. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data are missing. 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 | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | Uncertain | 1 | 6-33442986-C-T | 1 | 6.20e-7 | -5.689 | Likely Benign | 0.456 | Ambiguous | Likely Benign | 0.162 | Likely Benign | -0.62 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.89 | Benign | 0.95 | Tolerated | 4.32 | 4 | 0.3417 | 0.5699 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||
| c.2435C>A | P812H 2D AIThe SynGAP1 missense variant P812H is listed in ClinVar with an uncertain significance and is present in the gnomAD database (ID 6‑33442987‑C‑A). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic outcome; ESM1b remains uncertain. High‑accuracy methods give a benign result from AlphaMissense‑Optimized, a pathogenic consensus from the SGM approach (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta data are unavailable. Overall, the balance 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. | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | Uncertain | 2 | 6-33442987-C-A | 3 | 1.86e-6 | -7.470 | In-Between | 0.698 | Likely Pathogenic | Likely Benign | 0.272 | Likely Benign | -2.81 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.68 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1568 | 0.4923 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||
| c.2435C>G | P812R 2D AIThe SynGAP1 P812R missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of standard predictors indicate a pathogenic impact, while the most accurate tools provide no definitive evidence. Thus, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | -6.784 | Likely Benign | 0.799 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | -2.70 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.77 | Benign | 0.01 | Affected | 0.1285 | 0.3525 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2435C>T | P812L 2D AIThe SynGAP1 P812L missense variant is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33442987‑C‑T). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of predictions lean toward pathogenicity, which is consistent with the lack of ClinVar reporting but does not contradict it. Thus, based on the available computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | 6-33442987-C-T | 1 | 6.20e-7 | -7.121 | In-Between | 0.591 | Likely Pathogenic | Likely Benign | 0.172 | Likely Benign | -2.61 | Deleterious | 0.978 | Probably Damaging | 0.824 | Possibly Damaging | 2.76 | Benign | 0.01 | Affected | 4.32 | 4 | 0.2131 | 0.6634 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.2617A>C | S873R 2D AIThe SynGAP1 missense variant S873R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 (2 vs 2), and Foldetta results are unavailable. 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 ClinVar annotation because the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -5.856 | Likely Benign | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.218 | Likely Benign | -2.74 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.67 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.0970 | 0.3667 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.2617A>G | S873G 2D AIThe SynGAP1 missense variant S873G is catalogued in gnomAD (ID 6‑33443169‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict 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 reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | 6-33443169-A-G | 4 | 2.48e-6 | -5.702 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.120 | Likely Benign | -1.88 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.68 | Benign | 0.75 | Tolerated | 3.77 | 5 | 0.2897 | 0.5270 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||
| c.2617A>T | S873C 2D AIThe SynGAP1 missense variant S873C 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, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b) predict a pathogenic impact; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a pathogenic view: AlphaMissense‑Optimized predicts benign, while the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence leans toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -8.293 | Likely Pathogenic | 0.502 | Ambiguous | Likely Benign | 0.224 | Likely Benign | -2.71 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.62 | Benign | 0.04 | Affected | 0.1124 | 0.5887 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2618G>A | S873N 2D AIThe SynGAP1 missense variant S873N 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, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S873N, 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 | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -6.453 | Likely Benign | 0.706 | Likely Pathogenic | Likely Benign | 0.180 | Likely Benign | -1.88 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 2.66 | Benign | 0.12 | Tolerated | 0.1440 | 0.4612 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.2618G>C | S873T 2D AIThe SynGAP1 missense variant S873T 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‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -6.364 | Likely Benign | 0.301 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -1.77 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.68 | Benign | 0.11 | Tolerated | 0.1514 | 0.6288 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2618G>T | S873I 2D AIThe SynGAP1 missense variant S873I has no ClinVar record and is not reported in gnomAD. Functional prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of other in‑silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) indicate a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. 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 residue. High‑accuracy assessment therefore points to a Likely Pathogenic status from SGM‑Consensus, with AlphaMissense‑Optimized inconclusive and Foldetta missing. Overall, the preponderance of evidence suggests the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -9.412 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 0.305 | Likely Benign | -3.44 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.02 | Affected | 0.1012 | 0.5560 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2619C>A | S873R 2D AIThe SynGAP1 missense variant S873R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the balance of evidence (five pathogenic vs. four benign predictions, with a pathogenic high‑accuracy tool) suggests the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -5.856 | Likely Benign | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.192 | Likely Benign | -2.74 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.67 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.0970 | 0.3667 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.2619C>G | S873R 2D AIThe SynGAP1 missense variant S873R is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443171‑C‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 inconclusive (two pathogenic versus two benign votes), and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a pathogenic effect, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | Uncertain | 1 | 6-33443171-C-G | 1 | 6.20e-7 | -5.856 | Likely Benign | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.192 | Likely Benign | -2.74 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.67 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.0970 | 0.3667 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||
| c.3793A>G | R1265G 2D AIThe SynGAP1 missense variant R1265G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all label 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) indicates likely pathogenic, while a Foldetta stability analysis is unavailable. Based on the unanimous pathogenic predictions and the lack of any benign calls, the variant is most likely pathogenic, 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 Pathogenic | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | -12.732 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.523 | Likely Pathogenic | -5.80 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.27 | Pathogenic | 0.00 | Affected | 0.3520 | 0.3759 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3793A>T | R1265W 2D  AIThe SynGAP1 missense variant R1265W is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool in the dataset predicts a benign outcome, so the benign group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates a pathogenic change, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. Foldetta results are not available, so they do not influence the conclusion. Overall, the variant is most likely pathogenic based on the consensus of predictive tools, and this assessment is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | -14.584 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.505 | Likely Pathogenic | -6.54 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.23 | Pathogenic | 0.00 | Affected | 0.1166 | 0.3868 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.3794G>A | R1265K 2D  AIThe SynGAP1 missense variant R1265K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | -5.223 | Likely Benign | 0.951 | Likely Pathogenic | Ambiguous | 0.344 | Likely Benign | -2.49 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.38 | Pathogenic | 0.00 | Affected | 0.4829 | 0.3632 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||||||||||||||
| c.3794G>C | R1265T 2D  AIThe SynGAP1 missense variant R1265T is reported in ClinVar as Pathogenic (ClinVar ID 522047.0) and is not found in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool in the dataset predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Pathogenic verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions supports a pathogenic classification, which is consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | Likely Pathogenic | 1 | -10.129 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.529 | Likely Pathogenic | -4.97 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1947 | 0.4618 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||
| c.3794G>T | R1265M 2D  AIThe SynGAP1 missense variant R1265M is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic status; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that R1265M 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 | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | -13.657 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.495 | Likely Benign | -4.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.25 | Pathogenic | 0.00 | Affected | 0.1442 | 0.4082 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||
| c.3795G>C | R1265S 2D AIThe SynGAP1 missense variant R1265S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. 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 | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | -9.874 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.289 | Likely Benign | -4.96 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0.3525 | 0.3993 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3795G>T | R1265S 2D AIThe SynGAP1 missense variant R1265S is not reported in ClinVar and has no entry in gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the preponderance of pathogenic 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 | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | -9.874 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.289 | Likely Benign | -4.96 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0.3525 | 0.3993 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.490C>G | R164G 2D AIThe SynGAP1 missense variant R164G has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split opinion: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, 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 Pathogenic. High‑accuracy assessments further support a deleterious effect: the SGM‑Consensus remains Likely Pathogenic, AlphaMissense‑Optimized is inconclusive, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic impact. Because there is no ClinVar classification to oppose this, 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 | 0.414856 | Structured | 0.512396 | Binding | 0.317 | 0.666 | 0.250 | -12.416 | Likely Pathogenic | 0.879 | Likely Pathogenic | Ambiguous | 0.190 | Likely Benign | -3.01 | Deleterious | 0.487 | Possibly Damaging | 0.272 | Benign | 3.77 | Benign | 0.00 | Affected | 0.3657 | 0.3631 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.491G>A | R164Q 2D  AISynGAP1 missense variant R164Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33432788‑G‑A). Functional prediction tools show mixed results: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta results are not available. Overall, the balance of evidence slightly favors a benign interpretation, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.414856 | Structured | 0.512396 | Binding | 0.317 | 0.666 | 0.250 | Uncertain | 1 | 6-33432788-G-A | 2 | 1.24e-6 | -11.208 | Likely Pathogenic | 0.600 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | -1.86 | Neutral | 0.957 | Probably Damaging | 0.342 | Benign | 3.82 | Benign | 0.00 | Affected | 3.74 | 4 | 0.3607 | 0.2711 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||||||
| c.491G>C | R164P 2D AIThe SynGAP1 missense variant R164P is reported in gnomAD (ID 6‑33432788‑G‑C) but has no ClinVar entry. Functional prediction tools split in two groups: benign predictions come from REVEL and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized returns an Uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available output for this variant. Overall, the majority of high‑confidence tools predict pathogenicity, and this assessment does not contradict any ClinVar status (none is available). 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 | 0.414856 | Structured | 0.512396 | Binding | 0.317 | 0.666 | 0.250 | 6-33432788-G-C | 1 | 6.20e-7 | -12.792 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 0.339 | Likely Benign | -3.42 | Deleterious | 0.910 | Possibly Damaging | 0.578 | Possibly Damaging | 3.77 | Benign | 0.00 | Affected | 3.74 | 4 | 0.2408 | 0.4730 | -2 | 0 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||
| c.491G>T | R164L 2D AIThe SynGAP1 missense variant R164L is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. Grouping by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Taken together, the majority of evidence, including the SGM Consensus, points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for R164L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.414856 | Structured | 0.512396 | Binding | 0.317 | 0.666 | 0.250 | -10.794 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.274 | Likely Benign | -3.37 | Deleterious | 0.001 | Benign | 0.003 | Benign | 3.80 | Benign | 0.00 | Affected | 0.2137 | 0.5154 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.766A>C | N256H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256H is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta, Foldetta, premPS, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -8.090 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.56 | Ambiguous | 0.3 | 0.26 | Likely Benign | 0.41 | Likely Benign | 0.08 | Likely Benign | 0.698 | Likely Pathogenic | -4.06 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 5.82 | Benign | 0.05 | Affected | 0.1233 | 0.5646 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.766A>G | N256D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N256D is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, Foldetta, premPS, and FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX is uncertain and therefore not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Taken together, the overall consensus leans toward a pathogenic effect, with 10 tools supporting pathogenicity versus 4 supporting benignity. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -12.478 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.69 | Ambiguous | 0.3 | 0.21 | Likely Benign | 0.45 | Likely Benign | 0.44 | Likely Benign | 0.701 | Likely Pathogenic | -4.36 | Deleterious | 0.997 | Probably Damaging | 0.980 | Probably Damaging | 5.81 | Benign | 0.03 | Affected | 0.1890 | 0.3514 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.766A>T | N256Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, and FATHMM, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—label it pathogenic. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the preponderance of evidence from standard predictors and the two high‑accuracy pathogenic calls suggests that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -10.881 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.17 | Likely Benign | 0.2 | -0.80 | Ambiguous | -0.32 | Likely Benign | 0.30 | Likely Benign | 0.868 | Likely Pathogenic | -6.85 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 5.83 | Benign | 0.00 | Affected | 0.0493 | 0.5881 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.767A>C | N256T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). The high‑accuracy AlphaMissense‑Optimized model classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while the Foldetta stability assessment reports a benign effect. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -12.212 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.88 | Ambiguous | 0.1 | -0.18 | Likely Benign | 0.35 | Likely Benign | 0.49 | Likely Benign | 0.819 | Likely Pathogenic | -5.25 | Deleterious | 0.997 | Probably Damaging | 0.980 | Probably Damaging | 5.85 | Benign | 0.01 | Affected | 0.1249 | 0.5848 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.767A>G | N256S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256S is listed in ClinVar as Pathogenic (ClinVar ID 2584352.0) and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic calls come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy subset gives AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of predictions support a pathogenic effect, aligning with the ClinVar classification. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | Likely Pathogenic | 1 | -10.640 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.31 | Likely Benign | 0.2 | 0.36 | Likely Benign | 0.34 | Likely Benign | 0.48 | Likely Benign | 0.707 | Likely Pathogenic | -4.33 | Deleterious | 0.997 | Probably Damaging | 0.970 | Probably Damaging | 5.87 | Benign | 0.02 | Affected | 3.39 | 15 | 0.3024 | 0.5864 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||
| c.767A>T | N256I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, premPS, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give a pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -14.050 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.64 | Ambiguous | 0.4 | 0.45 | Likely Benign | 0.55 | Ambiguous | 0.31 | Likely Benign | 0.849 | Likely Pathogenic | -7.91 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 5.87 | Benign | 0.00 | Affected | 0.0596 | 0.6260 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.768C>A | N256K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and FATHMM. Those that predict pathogenicity comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools favor a pathogenic effect, whereas a minority suggest benign. Thus, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -13.814 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.22 | Likely Benign | 0.3 | -0.10 | Likely Benign | 0.06 | Likely Benign | 0.55 | Ambiguous | 0.569 | Likely Pathogenic | -5.02 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 5.90 | Benign | 0.01 | Affected | 0.1702 | 0.5240 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.768C>G | N256K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and FATHMM. Those that predict pathogenicity comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools support a pathogenic effect, whereas a minority suggest benign. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -13.814 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.22 | Likely Benign | 0.3 | -0.10 | Likely Benign | 0.06 | Likely Benign | 0.55 | Ambiguous | 0.569 | Likely Pathogenic | -5.02 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 5.90 | Benign | 0.01 | Affected | 0.1702 | 0.5240 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.904T>A | S302T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302T is not reported in ClinVar and is absent from gnomAD. All available in silico predictors classify the substitution as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -4.742 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.20 | Likely Benign | 0.1 | 0.10 | Likely Benign | 0.15 | Likely Benign | -0.08 | Likely Benign | 0.043 | Likely Benign | -0.55 | Neutral | 0.037 | Benign | 0.042 | Benign | 4.16 | Benign | 0.15 | Tolerated | 0.1715 | 0.6886 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.904T>C | S302P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302P is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only Rosetta predicts a pathogenic outcome, while FoldX and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also supports a benign classification. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains inconclusive. Overall, the preponderance of evidence points to a benign impact for S302P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -2.485 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 1.19 | Ambiguous | 0.4 | 2.74 | Destabilizing | 1.97 | Ambiguous | 0.14 | Likely Benign | 0.101 | Likely Benign | -0.89 | Neutral | 0.157 | Benign | 0.153 | Benign | 4.11 | Benign | 0.20 | Tolerated | 0.2522 | 0.6243 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.904T>G | S302A 2D AIThe SynGAP1 missense variant S302A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta. No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not currently catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -2.583 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.4 | 0.65 | Ambiguous | 0.43 | Likely Benign | 0.02 | Likely Benign | 0.044 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.16 | Benign | 0.20 | Tolerated | 0.5358 | 0.5407 | Strenghten | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.905C>A | S302Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are SIFT, polyPhen‑2 HumDiv, and ESM1b. Two tools give uncertain results: AlphaMissense‑Default and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta also predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -9.674 | Likely Pathogenic | 0.355 | Ambiguous | Likely Benign | -0.02 | Likely Benign | 0.1 | 0.56 | Ambiguous | 0.27 | Likely Benign | -0.17 | Likely Benign | 0.070 | Likely Benign | -1.03 | Neutral | 0.801 | Possibly Damaging | 0.383 | Benign | 4.07 | Benign | 0.01 | Affected | 0.0882 | 0.5990 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||
| c.905C>G | S302C 2D AIThe SynGAP1 missense variant S302C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, premPS, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain predictions come from Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for S302C, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -7.290 | In-Between | 0.105 | Likely Benign | Likely Benign | 0.32 | Likely Benign | 0.5 | 1.24 | Ambiguous | 0.78 | Ambiguous | -0.04 | Likely Benign | 0.070 | Likely Benign | -0.83 | Neutral | 0.833 | Possibly Damaging | 0.455 | Possibly Damaging | 4.05 | Benign | 0.02 | Affected | 0.1221 | 0.6514 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.905C>T | S302F 2D AIThe SynGAP1 missense variant S302F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and ESM1b; Rosetta’s output is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Taken together, the majority of evidence supports a benign impact for S302F, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -9.483 | Likely Pathogenic | 0.321 | Likely Benign | Likely Benign | -0.04 | Likely Benign | 0.5 | 0.71 | Ambiguous | 0.34 | Likely Benign | -0.21 | Likely Benign | 0.073 | Likely Benign | -0.92 | Neutral | 0.570 | Possibly Damaging | 0.383 | Benign | 4.06 | Benign | 0.01 | Affected | 0.0705 | 0.6092 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.505G>A | D169N 2D AIThe SynGAP1 missense variant D169N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: six methods (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) predict a benign effect, while three (SIFT, ESM1b, AlphaMissense‑Default) predict pathogenicity. High‑accuracy assessments are mixed: AlphaMissense‑Optimized indicates benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. No Foldetta stability data are available. 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. | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | Uncertain | 1 | -10.713 | Likely Pathogenic | 0.761 | Likely Pathogenic | Likely Benign | 0.110 | Likely Benign | -2.04 | Neutral | 0.079 | Benign | 0.052 | Benign | 4.07 | Benign | 0.01 | Affected | 3.74 | 4 | 0.1430 | 0.7391 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||
| c.505G>C | D169H 2D AIThe SynGAP1 D169H variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the majority of computational evidence points toward a pathogenic impact, 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 | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -12.048 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -2.83 | Deleterious | 0.651 | Possibly Damaging | 0.417 | Benign | 4.03 | Benign | 0.00 | Affected | 0.1791 | 0.7624 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.505G>T | D169Y 2D AIThe SynGAP1 missense variant D169Y 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized returns an uncertain result, and no Foldetta (FoldX‑MD/Rosetta) stability data are available. Based on the overall pattern of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -13.524 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 0.282 | Likely Benign | -3.71 | Deleterious | 0.651 | Possibly Damaging | 0.347 | Benign | 4.01 | Benign | 0.00 | Affected | 0.0571 | 0.6896 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.506A>C | D169A 2D AIThe SynGAP1 D169A missense variant is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. Grouping by consensus, the benign set includes REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; the pathogenic set includes PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta predictions are unavailable. Overall, the balance of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -11.065 | Likely Pathogenic | 0.874 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -3.15 | Deleterious | 0.018 | Benign | 0.025 | Benign | 4.10 | Benign | 0.01 | Affected | 0.4012 | 0.6809 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.506A>G | D169G 2D AIThe SynGAP1 missense variant D169G is not 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, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a tie (2 pathogenic vs 2 benign) and is therefore unavailable; Foldetta results are not provided. Overall, the majority of standard predictors lean toward a benign classification, and this is consistent with the lack of ClinVar evidence. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -9.853 | Likely Pathogenic | 0.820 | Likely Pathogenic | Ambiguous | 0.186 | Likely Benign | -2.44 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.04 | Benign | 0.01 | Affected | 0.3907 | 0.6560 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.506A>T | D169V 2D AIThe SynGAP1 D169V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. When predictions are grouped by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this residue. Overall, the balance of evidence, particularly the SGM Consensus and the pathogenic calls from multiple independent predictors, indicates that D169V is most likely pathogenic, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -12.395 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.243 | Likely Benign | -3.77 | Deleterious | 0.380 | Benign | 0.193 | Benign | 4.03 | Benign | 0.00 | Affected | 0.0895 | 0.7166 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.507C>A | D169E 2D AIThe SynGAP1 missense variant D169E is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -4.571 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.23 | Benign | 0.42 | Tolerated | 0.1636 | 0.7316 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.507C>G | D169E 2D AIThe SynGAP1 missense variant D169E is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -4.571 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.23 | Benign | 0.42 | Tolerated | 0.1636 | 0.7316 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.580G>A | E194K 2D  AIThe SynGAP1 missense variant E194K 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational 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 | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -13.294 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.259 | Likely Benign | -2.53 | Deleterious | 0.734 | Possibly Damaging | 0.321 | Benign | 4.04 | Benign | 0.01 | Affected | 0.2231 | 0.5152 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.580G>C | E194Q 2D  AIThe SynGAP1 missense variant E194Q is not 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 and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, while 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, more evidence supports a pathogenic classification (5 pathogenic vs. 3 benign predictions). Thus, 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. | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -8.902 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.140 | Likely Benign | -1.97 | Neutral | 0.849 | Possibly Damaging | 0.478 | Possibly Damaging | 4.00 | Benign | 0.02 | Affected | 0.1043 | 0.4954 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.581A>C | E194A 2D  AIThe SynGAP1 missense variant E194A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized predicts pathogenicity. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic), also indicates pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions—including the high‑accuracy tools—suggest that E194A is likely pathogenic, 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. | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -7.101 | In-Between | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.235 | Likely Benign | -3.75 | Deleterious | 0.009 | Benign | 0.012 | Benign | 3.99 | Benign | 0.01 | Affected | 0.4331 | 0.5079 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.581A>G | E194G 2D  AIThe SynGAP1 missense variant E194G 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts Pathogenic, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic 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 Pathogenic | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -9.136 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.316 | Likely Benign | -4.47 | Deleterious | 0.580 | Possibly Damaging | 0.196 | Benign | 3.96 | Benign | 0.01 | Affected | 0.3633 | 0.4616 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.581A>T | E194V 2D  AIThe SynGAP1 missense variant E194V 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, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, SIFT, 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 pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. No Foldetta stability analysis is available for this variant. Overall, the preponderance of computational 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 | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -10.261 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.284 | Likely Benign | -4.67 | Deleterious | 0.580 | Possibly Damaging | 0.254 | Benign | 3.94 | Benign | 0.00 | Affected | 0.0623 | 0.5469 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.582G>C | E194D 2D  AIThe SynGAP1 missense variant E194D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this assessment, so 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 | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -6.310 | Likely Benign | 0.883 | Likely Pathogenic | Ambiguous | 0.079 | Likely Benign | -2.07 | Neutral | 0.849 | Possibly Damaging | 0.301 | Benign | 4.01 | Benign | 0.04 | Affected | 0.1969 | 0.2779 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.582G>T | E194D 2D AIThe SynGAP1 missense variant E194D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a “Likely Benign” classification, while AlphaMissense‑Optimized is uncertain. Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -6.310 | Likely Benign | 0.883 | Likely Pathogenic | Ambiguous | 0.079 | Likely Benign | -2.07 | Neutral | 0.849 | Possibly Damaging | 0.301 | Benign | 4.01 | Benign | 0.04 | Affected | 0.1969 | 0.2779 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.190A>C | I64L 2D AIThe SynGAP1 missense variant I64L 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 impact for I64L, 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 | 0.422041 | Structured | 0.475481 | Uncertain | 0.478 | 0.747 | 0.125 | -2.498 | Likely Benign | 0.437 | Ambiguous | Likely Benign | 0.087 | Likely Benign | -0.27 | Neutral | 0.010 | Benign | 0.001 | Benign | 4.13 | Benign | 0.00 | Affected | 0.0628 | 0.3030 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.190A>G | I64V 2D AIThe SynGAP1 missense variant I64V is reported as “Likely Benign” in ClinVar and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 majority of computational evidence supports a benign classification, and this is consistent with the ClinVar status (no conflicting pathogenic annotation). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.422041 | Structured | 0.475481 | Uncertain | 0.478 | 0.747 | 0.125 | -2.616 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.086 | Likely Benign | 0.12 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.24 | Benign | 0.00 | Affected | 0.0994 | 0.3302 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.190A>T | I64L 2D AIThe SynGAP1 missense variant I64L 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. 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 | 0.422041 | Structured | 0.475481 | Uncertain | 0.478 | 0.747 | 0.125 | -2.498 | Likely Benign | 0.437 | Ambiguous | Likely Benign | 0.087 | Likely Benign | -0.27 | Neutral | 0.010 | Benign | 0.001 | Benign | 4.13 | Benign | 0.00 | Affected | 0.0628 | 0.3030 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.191T>A | I64K 2D  AIThe SynGAP1 missense variant I64K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT, 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 show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, and this conclusion does not contradict the ClinVar status, which contains no report for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.422041 | Structured | 0.475481 | Uncertain | 0.478 | 0.747 | 0.125 | -3.206 | Likely Benign | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.159 | Likely Benign | -0.47 | Neutral | 0.334 | Benign | 0.029 | Benign | 4.07 | Benign | 0.00 | Affected | 0.0878 | 0.0740 | -2 | -3 | -8.4 | 15.01 | |||||||||||||||||||||||||||||||||||||||
| c.191T>C | I64T 2D AIThe SynGAP1 missense variant I64T is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33425799‑T‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Benign, and the Foldetta protein‑folding stability analysis is unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.422041 | Structured | 0.475481 | Uncertain | 0.478 | 0.747 | 0.125 | 6-33425799-T-C | 1 | 6.20e-7 | -3.183 | Likely Benign | 0.943 | Likely Pathogenic | Ambiguous | 0.075 | Likely Benign | -0.51 | Neutral | 0.092 | Benign | 0.007 | Benign | 4.08 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0978 | 0.0851 | -1 | 0 | -5.2 | -12.05 | ||||||||||||||||||||||||||||||||||
| c.191T>G | I64R 2D  AIThe SynGAP1 missense variant I64R is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which classifies the variant as “Likely Benign.” Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the Foldetta protein‑folding stability assessment is unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar assertion, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.422041 | Structured | 0.475481 | Uncertain | 0.478 | 0.747 | 0.125 | -2.108 | Likely Benign | 0.936 | Likely Pathogenic | Ambiguous | 0.165 | Likely Benign | -0.54 | Neutral | 0.842 | Possibly Damaging | 0.068 | Benign | 4.05 | Benign | 0.00 | Affected | 0.1103 | 0.0940 | -2 | -3 | -9.0 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.192A>G | I64M 2D AIThe SynGAP1 missense variant I64M is listed in gnomAD (ID 6‑33425800‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus 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 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 | 0.422041 | Structured | 0.475481 | Uncertain | 0.478 | 0.747 | 0.125 | 6-33425800-A-G | 2 | 1.24e-6 | -4.327 | Likely Benign | 0.523 | Ambiguous | Likely Benign | 0.047 | Likely Benign | -0.05 | Neutral | 0.637 | Possibly Damaging | 0.047 | Benign | 4.04 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0568 | 0.2310 | 1 | 2 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||||||
| c.397C>A | L133M 2D AIThe SynGAP1 missense variant L133M is not 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, and AlphaMissense‑Default; ESM1b and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta results are unavailable. Overall, the majority of standard predictors (four pathogenic vs. three benign) indicate a pathogenic impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.718429 | Binding | 0.320 | 0.896 | 0.250 | -7.993 | In-Between | 0.841 | Likely Pathogenic | Ambiguous | 0.095 | Likely Benign | -0.77 | Neutral | 0.877 | Possibly Damaging | 0.580 | Possibly Damaging | 3.57 | Benign | 0.03 | Affected | 0.0856 | 0.2229 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.397C>G | L133V 2D AIThe SynGAP1 missense variant L133V is not 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, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are limited: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign votes); Foldetta results are unavailable. Overall, the majority of evidence (five 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. | 0.422041 | Structured | 0.718429 | Binding | 0.320 | 0.896 | 0.250 | -8.429 | Likely Pathogenic | 0.848 | Likely Pathogenic | Ambiguous | 0.082 | Likely Benign | -1.27 | Neutral | 0.247 | Benign | 0.163 | Benign | 3.61 | Benign | 0.03 | Affected | 0.1561 | 0.1883 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.398T>A | L133Q 2D AIThe SynGAP1 missense variant L133Q 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.422041 | Structured | 0.718429 | Binding | 0.320 | 0.896 | 0.250 | -9.054 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.317 | Likely Benign | -2.65 | Deleterious | 0.535 | Possibly Damaging | 0.259 | Benign | 3.53 | Benign | 0.01 | Affected | 0.1316 | 0.0879 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.398T>C | L133P 2D AIThe SynGAP1 missense variant L133P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. ESM1b remains uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic), yields a pathogenic consensus. 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 existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.718429 | Binding | 0.320 | 0.896 | 0.250 | -7.744 | In-Between | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.342 | Likely Benign | -3.16 | Deleterious | 0.700 | Possibly Damaging | 0.483 | Possibly Damaging | 3.52 | Benign | 0.00 | Affected | 0.3270 | 0.1048 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.398T>G | L133R 2D AIThe SynGAP1 missense variant L133R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome (3 pathogenic vs. 1 benign votes). AlphaMissense‑Optimized independently predicts pathogenicity. 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 supports a pathogenic classification for L133R, and this assessment 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 | 0.422041 | Structured | 0.718429 | Binding | 0.320 | 0.896 | 0.250 | -8.857 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.389 | Likely Benign | -2.57 | Deleterious | 0.002 | Benign | 0.005 | Benign | 3.55 | Benign | 0.00 | Affected | 0.1522 | 0.0479 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.568A>C | S190R 2D AIThe SynGAP1 missense variant S190R 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, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority of the four high‑accuracy tools) also predicts 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 indicates that 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 | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -10.137 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.156 | Likely Benign | -2.92 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 4.07 | Benign | 0.04 | Affected | 0.0809 | 0.4059 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.568A>G | S190G 2D AIThe SynGAP1 missense variant S190G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -5.440 | Likely Benign | 0.321 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -1.26 | Neutral | 0.243 | Benign | 0.079 | Benign | 4.11 | Benign | 0.19 | Tolerated | 0.2780 | 0.4765 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.568A>T | S190C 2D AIThe SynGAP1 missense variant S190C 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, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the 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 | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -6.696 | Likely Benign | 0.617 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | -2.04 | Neutral | 0.992 | Probably Damaging | 0.707 | Possibly Damaging | 4.01 | Benign | 0.23 | Tolerated | 0.0937 | 0.6667 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.569G>A | S190N 2D AIThe SynGAP1 missense variant S190N is not 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, SIFT, and FATHMM, while polyPhen‑2 HumDiv and AlphaMissense‑Default predict a pathogenic outcome. The remaining tools, ESM1b and AlphaMissense‑Optimized, are uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is uncertain; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) resolves to benign (two benign votes versus one pathogenic and one uncertain); and Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -7.497 | In-Between | 0.838 | Likely Pathogenic | Ambiguous | 0.160 | Likely Benign | -1.73 | Neutral | 0.759 | Possibly Damaging | 0.202 | Benign | 4.06 | Benign | 0.08 | Tolerated | 0.1119 | 0.5285 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||||
| c.569G>C | S190T 2D AIThe SynGAP1 missense variant S190T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv 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 confirms Likely Benign, and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -6.870 | Likely Benign | 0.408 | Ambiguous | Likely Benign | 0.114 | Likely Benign | -1.31 | Neutral | 0.608 | Possibly Damaging | 0.108 | Benign | 4.08 | Benign | 0.20 | Tolerated | 0.1294 | 0.6920 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.569G>T | S190I 2D AIThe SynGAP1 missense variant S190I 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, 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. AlphaMissense‑Optimized returns an Uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the majority of evidence points to a pathogenic impact, 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 | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -9.868 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 0.316 | Likely Benign | -3.39 | Deleterious | 0.845 | Possibly Damaging | 0.368 | Benign | 4.03 | Benign | 0.03 | Affected | 0.0769 | 0.5963 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.570C>A | S190R 2D AIThe SynGAP1 missense variant S190R 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, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority of the four high‑accuracy tools) also predicts 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 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 | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -10.137 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.146 | Likely Benign | -2.92 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 4.07 | Benign | 0.04 | Affected | 0.0809 | 0.4059 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.570C>G | S190R 2D AIThe SynGAP1 missense variant S190R 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, polyPhen‑2 HumVar, and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy prediction tools indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar annotation exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -10.137 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.146 | Likely Benign | -2.92 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 4.07 | Benign | 0.04 | Affected | 0.0809 | 0.4059 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.574G>A | A192T 2D AIThe SynGAP1 missense variant A192T has no ClinVar record (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic, 1 uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -7.562 | In-Between | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.089 | Likely Benign | -2.46 | Neutral | 0.978 | Probably Damaging | 0.714 | Possibly Damaging | 3.96 | Benign | 0.34 | Tolerated | 0.1148 | 0.5343 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.574G>C | A192P 2D AIThe SynGAP1 missense variant A192P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy prediction tools points to a pathogenic 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 Pathogenic | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -9.795 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.245 | Likely Benign | -3.35 | Deleterious | 0.999 | Probably Damaging | 0.946 | Probably Damaging | 3.90 | Benign | 0.02 | Affected | 0.1658 | 0.3719 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.574G>T | A192S 2D AIThe SynGAP1 missense variant A192S is not 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, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -7.969 | In-Between | 0.757 | Likely Pathogenic | Likely Benign | 0.118 | Likely Benign | -2.01 | Neutral | 0.633 | Possibly Damaging | 0.171 | Benign | 3.98 | Benign | 0.12 | Tolerated | 0.2365 | 0.3764 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||||||
| c.575C>A | A192E 2D AIThe SynGAP1 missense variant A192E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. The protein‑folding stability method Foldetta 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 pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -12.188 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.268 | Likely Benign | -3.52 | Deleterious | 0.997 | Probably Damaging | 0.888 | Possibly Damaging | 3.93 | Benign | 0.01 | Affected | 0.0939 | 0.1628 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.575C>G | A192G 2D AIThe SynGAP1 missense variant A192G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all indicate pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. 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. Overall, the preponderance of evidence from multiple in silico tools points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -9.003 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.133 | Likely Benign | -3.00 | Deleterious | 0.989 | Probably Damaging | 0.621 | Possibly Damaging | 3.91 | Benign | 0.02 | Affected | 0.2081 | 0.2857 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.575C>T | A192V 2D AIThe SynGAP1 missense variant A192V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b remains uncertain. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic majority (2 pathogenic vs. 1 benign, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that A192V is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -7.464 | In-Between | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.172 | Likely Benign | -2.66 | Deleterious | 0.996 | Probably Damaging | 0.877 | Possibly Damaging | 4.01 | Benign | 0.11 | Tolerated | 0.0904 | 0.5066 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||||||
| c.889A>C | K297Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K297Q missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, Rosetta, and Foldetta. In contrast, the majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX is uncertain and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as benign. Overall, the preponderance of evidence points to a pathogenic effect for K297Q. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -8.393 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.66 | Ambiguous | 0.3 | 0.14 | Likely Benign | 0.40 | Likely Benign | 1.06 | Destabilizing | 0.450 | Likely Benign | -3.48 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.65 | Pathogenic | 0.01 | Affected | 0.4768 | 0.1738 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.889A>G | K297E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome; the only inconclusive result is FoldX, which is listed as “Uncertain” and is treated as unavailable. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective predictions, K297E is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -10.143 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.99 | Ambiguous | 0.4 | 2.43 | Destabilizing | 2.21 | Destabilizing | 1.16 | Destabilizing | 0.507 | Likely Pathogenic | -3.54 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.61 | Pathogenic | 0.02 | Affected | 0.4073 | 0.1547 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.890A>C | K297T 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant K297T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are none, whereas those that predict a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy methods specifically show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -10.110 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 1.55 | Ambiguous | 0.1 | 1.19 | Ambiguous | 1.37 | Ambiguous | 0.59 | Ambiguous | 0.551 | Likely Pathogenic | -5.28 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.62 | Pathogenic | 0.01 | Affected | 0.2294 | 0.4024 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.890A>G | K297R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and FATHMM. Predictions that are uncertain or inconclusive are FoldX, Rosetta, premPS, and ESM1b. High‑accuracy methods give a consistent benign signal: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign; and Foldetta, a protein‑folding stability approach combining FoldX‑MD and Rosetta, predicts benign. Based on the aggregate of these predictions, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -7.877 | In-Between | 0.314 | Likely Benign | Likely Benign | -0.86 | Ambiguous | 0.3 | 0.67 | Ambiguous | -0.10 | Likely Benign | 0.66 | Ambiguous | 0.257 | Likely Benign | -2.36 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.66 | Pathogenic | 0.19 | Tolerated | 0.4828 | 0.1506 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.890A>T | K297M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297M is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, and premPS. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized classifies the variant as Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports Likely Pathogenic; whereas Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, reports a Benign effect. Overall, the preponderance of evidence (10 pathogenic vs. 4 benign predictions) points to the variant being most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -11.472 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.09 | Likely Benign | 0.1 | 0.32 | Likely Benign | 0.21 | Likely Benign | 0.49 | Likely Benign | 0.538 | Likely Pathogenic | -5.20 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.61 | Pathogenic | 0.00 | Affected | 0.1438 | 0.4394 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.891G>C | K297N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -11.328 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.08 | Ambiguous | 0.1 | 1.60 | Ambiguous | 1.34 | Ambiguous | 1.15 | Destabilizing | 0.253 | Likely Benign | -4.31 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.61 | Pathogenic | 0.01 | Affected | 0.3797 | 0.2265 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.891G>T | K297N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, K297N is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -11.328 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.08 | Ambiguous | 0.1 | 1.60 | Ambiguous | 1.34 | Ambiguous | 1.15 | Destabilizing | 0.253 | Likely Benign | -4.31 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.61 | Pathogenic | 0.01 | Affected | 0.3797 | 0.2265 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.115T>A | Y39N 2D AIThe SynGAP1 missense variant Y39N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.432876 | Uncertain | 0.343 | 0.787 | 0.375 | -3.098 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.84 | Neutral | 0.824 | Possibly Damaging | 0.828 | Possibly Damaging | 3.99 | Benign | 0.00 | Affected | 0.2375 | 0.0903 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.115T>C | Y39H 2D AIThe SynGAP1 missense variant Y39H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.432876 | Uncertain | 0.343 | 0.787 | 0.375 | -3.166 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.08 | Neutral | 0.824 | Possibly Damaging | 0.775 | Possibly Damaging | 4.02 | Benign | 0.00 | Affected | 0.2569 | 0.0843 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||||||||||||
| c.115T>G | Y39D 2D AIThe SynGAP1 missense variant Y39D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for Y39D, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.432876 | Uncertain | 0.343 | 0.787 | 0.375 | -2.338 | Likely Benign | 0.333 | Likely Benign | Likely Benign | 0.166 | Likely Benign | -1.86 | Neutral | 0.824 | Possibly Damaging | 0.828 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 0.4099 | 0.0903 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.116A>C | Y39S 2D AIThe SynGAP1 missense variant Y39S 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 for Y39S, 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 | 0.425610 | Structured | 0.432876 | Uncertain | 0.343 | 0.787 | 0.375 | -1.634 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -1.57 | Neutral | 0.824 | Possibly Damaging | 0.775 | Possibly Damaging | 4.02 | Benign | 0.00 | Affected | 0.4935 | 0.2649 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.116A>G | Y39C 2D AIThe SynGAP1 missense variant Y39C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Overall, the majority of evidence points to the variant being 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 | 0.425610 | Structured | 0.432876 | Uncertain | 0.343 | 0.787 | 0.375 | -3.109 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.203 | Likely Benign | -2.00 | Neutral | 0.943 | Possibly Damaging | 0.941 | Probably Damaging | 3.96 | Benign | 0.00 | Affected | 0.3007 | 0.2849 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||||||||||||
| c.116A>T | Y39F 2D AIThe SynGAP1 missense variant Y39F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.432876 | Uncertain | 0.343 | 0.787 | 0.375 | -3.410 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.073 | Likely Benign | -0.78 | Neutral | 0.458 | Possibly Damaging | 0.481 | Possibly Damaging | 4.05 | Benign | 0.00 | Affected | 0.2641 | 0.3363 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.184G>A | D62N 2D AIThe SynGAP1 missense variant D62N is reported in gnomAD (variant ID 6‑33423593‑G‑A) but has no ClinVar entry. In silico 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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign status. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of tools indicates that D62N is most likely benign, 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 Benign | 0.425610 | Structured | 0.476010 | Uncertain | 0.575 | 0.720 | 0.125 | 6-33423593-G-A | 1 | 6.20e-7 | -4.607 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -1.08 | Neutral | 0.028 | Benign | 0.032 | Benign | 4.11 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1670 | 0.6154 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||
| c.184G>C | D62H 2D AIThe SynGAP1 missense variant D62H 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 remains 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, D62H 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 | 0.425610 | Structured | 0.476010 | Uncertain | 0.575 | 0.720 | 0.125 | -5.253 | Likely Benign | 0.511 | Ambiguous | Likely Benign | 0.070 | Likely Benign | -1.53 | Neutral | 0.172 | Benign | 0.248 | Benign | 4.05 | Benign | 0.00 | Affected | 0.2059 | 0.6579 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.184G>T | D62Y 2D AIThe SynGAP1 missense variant D62Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. 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 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 majority of computational evidence points to a benign impact, 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 | 0.425610 | Structured | 0.476010 | Uncertain | 0.575 | 0.720 | 0.125 | -6.313 | Likely Benign | 0.569 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -2.17 | Neutral | 0.388 | Benign | 0.328 | Benign | 4.03 | Benign | 0.00 | Affected | 0.0657 | 0.5588 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.185A>C | D62A 2D AIThe SynGAP1 D62A missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.476010 | Uncertain | 0.575 | 0.720 | 0.125 | -3.983 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -1.67 | Neutral | 0.006 | Benign | 0.023 | Benign | 4.09 | Benign | 0.00 | Affected | 0.4152 | 0.5972 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.185A>G | D62G 2D AIThe SynGAP1 D62G missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points 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 | 0.425610 | Structured | 0.476010 | Uncertain | 0.575 | 0.720 | 0.125 | -4.047 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.76 | Neutral | 0.012 | Benign | 0.032 | Benign | 4.07 | Benign | 0.00 | Affected | 0.4016 | 0.6081 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.185A>T | D62V 2D AIThe SynGAP1 missense variant D62V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate a benign outcome, while the sole pathogenic signal comes from SIFT. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy methods reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports Likely Benign, and Foldetta data are missing. Taken together, the preponderance of evidence supports a benign classification for D62V, and this assessment does not conflict with the absence of a ClinVar entry. Therefore, the variant is most likely benign, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.476010 | Uncertain | 0.575 | 0.720 | 0.125 | -4.417 | Likely Benign | 0.489 | Ambiguous | Likely Benign | 0.118 | Likely Benign | -2.04 | Neutral | 0.028 | Benign | 0.088 | Benign | 4.04 | Benign | 0.00 | Affected | 0.1039 | 0.6129 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.186T>A | D62E 2D AIThe SynGAP1 missense variant D62E is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.476010 | Uncertain | 0.575 | 0.720 | 0.125 | -2.653 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -0.19 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.49 | Benign | 0.00 | Affected | 0.1884 | 0.5800 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.186T>G | D62E 2D AIThe SynGAP1 missense variant D62E 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 call 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 | 0.425610 | Structured | 0.476010 | Uncertain | 0.575 | 0.720 | 0.125 | -2.653 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -0.19 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.49 | Benign | 0.00 | Affected | 0.1884 | 0.5800 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3787A>C | I1263L 2D AIThe SynGAP1 missense variant I1263L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, 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 (two benign, two pathogenic). Foldetta results are unavailable. Overall, the majority of evidence points to a benign 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. | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -1.210 | Likely Benign | 0.699 | Likely Pathogenic | Likely Benign | 0.194 | Likely Benign | -1.66 | Neutral | 0.011 | Benign | 0.022 | Benign | 1.94 | Pathogenic | 0.00 | Affected | 0.0717 | 0.2890 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3787A>G | I1263V 2D AIThe SynGAP1 missense variant I1263V is not 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), ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two benign vs. two pathogenic votes), and Foldetta results are unavailable. 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. | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -4.230 | Likely Benign | 0.729 | Likely Pathogenic | Likely Benign | 0.221 | Likely Benign | -0.83 | Neutral | 0.437 | Benign | 0.170 | Benign | 1.99 | Pathogenic | 0.00 | Affected | 0.1136 | 0.3102 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3787A>T | I1263F 2D AIThe SynGAP1 missense variant I1263F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta results are unavailable. Because the majority of evidence points to a deleterious effect and there is 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 | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -5.887 | Likely Benign | 0.952 | Likely Pathogenic | Ambiguous | 0.335 | Likely Benign | -3.32 | Deleterious | 0.968 | Probably Damaging | 0.637 | Possibly Damaging | 1.81 | Pathogenic | 0.00 | Affected | 0.0494 | 0.2375 | 1 | 0 | -1.7 | 34.02 | ||||||||||||||||||||||||||||||||||||||
| c.3788T>A | I1263N 2D AIThe SynGAP1 missense variant I1263N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -9.158 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.379 | Likely Benign | -5.80 | Deleterious | 0.995 | Probably Damaging | 0.913 | Probably Damaging | 1.79 | Pathogenic | 0.00 | Affected | 0.1041 | 0.0340 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3788T>C | I1263T 2D AIThe SynGAP1 missense variant I1263T is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33446780‑T‑C). Functional prediction tools largely agree on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report pathogenicity, while only ESM1b predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a pathogenic effect, which aligns with the ClinVar designation of uncertainty but does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | Uncertain | 1 | 6-33446780-T-C | 2 | 1.24e-6 | -6.564 | Likely Benign | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.529 | Likely Pathogenic | -4.15 | Deleterious | 0.946 | Possibly Damaging | 0.673 | Possibly Damaging | 1.81 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1221 | 0.1051 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||
| c.3788T>G | I1263S 2D AIThe SynGAP1 missense variant I1263S 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 REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled 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 indicates that 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 | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -8.074 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.493 | Likely Benign | -4.97 | Deleterious | 0.984 | Probably Damaging | 0.825 | Possibly Damaging | 1.80 | Pathogenic | 0.00 | Affected | 0.3242 | 0.0910 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3789T>G | I1263M 2D AIThe SynGAP1 missense variant I1263M is not 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, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs 2 benign). High‑accuracy methods are not available: AlphaMissense‑Optimized is benign, but AlphaMissense‑Default is pathogenic; Foldetta results are missing. Overall, the majority of predictions (five pathogenic vs four benign) lean toward a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar classification. 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. | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -2.839 | Likely Benign | 0.701 | Likely Pathogenic | Likely Benign | 0.291 | Likely Benign | -2.49 | Neutral | 0.968 | Probably Damaging | 0.789 | Possibly Damaging | 1.81 | Pathogenic | 0.00 | Affected | 0.0654 | 0.2170 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.496G>A | A166T 2D AIThe SynGAP1 missense variant A166T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the change as benign. No tool in the dataset predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign.” Foldetta results are not available. Overall, the consensus of all available predictions indicates that 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 | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -6.700 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -0.78 | Neutral | 0.399 | Benign | 0.273 | Benign | 4.10 | Benign | 0.31 | Tolerated | 0.1420 | 0.5134 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.496G>C | A166P 2D AIThe SynGAP1 missense variant A166P 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. 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 A166P, 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 | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -9.665 | Likely Pathogenic | 0.273 | Likely Benign | Likely Benign | 0.172 | Likely Benign | -2.04 | Neutral | 0.877 | Possibly Damaging | 0.580 | Possibly Damaging | 3.99 | Benign | 0.02 | Affected | 0.1861 | 0.3668 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.496G>T | A166S 2D AIThe SynGAP1 missense variant A166 S 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 likewise indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -6.008 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -0.78 | Neutral | 0.399 | Benign | 0.212 | Benign | 4.07 | Benign | 0.05 | Affected | 0.2286 | 0.4146 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.497C>A | A166D 2D AIThe SynGAP1 missense variant A166D is not 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. The high‑accuracy consensus method SGM (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, yielding a 2‑to‑2 split. AlphaMissense‑Optimized rates the variant as uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this change. Overall, the majority of tools predict a pathogenic impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -12.171 | Likely Pathogenic | 0.900 | Likely Pathogenic | Ambiguous | 0.144 | Likely Benign | -2.21 | Neutral | 0.877 | Possibly Damaging | 0.580 | Possibly Damaging | 4.02 | Benign | 0.01 | Affected | 0.2031 | 0.2694 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.497C>G | A166G 2D AIThe SynGAP1 missense variant A166G 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 classify the change as benign. Only SIFT and ESM1b predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a majority‑benign vote and is reported as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -8.188 | Likely Pathogenic | 0.215 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -1.16 | Neutral | 0.399 | Benign | 0.212 | Benign | 4.02 | Benign | 0.03 | Affected | 0.1665 | 0.3201 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.497C>T | A166V 2D AIThe SynGAP1 missense variant A166V 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 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 | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -6.689 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.191 | Likely Benign | -1.09 | Neutral | 0.141 | Benign | 0.091 | Benign | 4.07 | Benign | 0.02 | Affected | 0.1027 | 0.4281 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.1189T>A | C397S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign, while Rosetta remains uncertain. When predictions are grouped, the benign category contains all available evidence and the pathogenic category is empty. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. Consequently, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -2.324 | Likely Benign | 0.178 | Likely Benign | Likely Benign | 0.37 | Likely Benign | 0.1 | 0.59 | Ambiguous | 0.48 | Likely Benign | 0.43 | Likely Benign | 0.174 | Likely Benign | -0.01 | Neutral | 0.276 | Benign | 0.066 | Benign | 4.68 | Benign | 0.53 | Tolerated | 0.5221 | 0.2474 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||
| c.1189T>C | C397R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397R is 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, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and AlphaMissense‑Default. The remaining tools (FoldX, premPS, ESM1b) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign (2 benign vs. 1 pathogenic, 1 uncertain), and Foldetta predicts a benign impact on protein folding stability. Overall, the majority 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. | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -7.094 | In-Between | 0.708 | Likely Pathogenic | Likely Benign | 0.55 | Ambiguous | 0.8 | 0.40 | Likely Benign | 0.48 | Likely Benign | 0.96 | Ambiguous | 0.514 | Likely Pathogenic | -1.46 | Neutral | 0.480 | Possibly Damaging | 0.226 | Benign | 4.65 | Benign | 0.11 | Tolerated | 0.1780 | 0.1853 | -4 | -3 | -7.0 | 53.05 | ||||||||||||||||||||||||||||||
| c.1189T>G | C397G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus all indicate a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies it as “Likely Benign.” No tool predicts pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | 1.244 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.68 | Ambiguous | 0.2 | 1.42 | Ambiguous | 1.05 | Ambiguous | 0.04 | Likely Benign | 0.272 | Likely Benign | 1.51 | Neutral | 0.276 | Benign | 0.066 | Benign | 5.93 | Benign | 0.60 | Tolerated | 0.3678 | 0.3729 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.1190G>A | C397Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and the combined Foldetta method. Uncertain results come from AlphaMissense‑Default and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as pathogenic. Overall, the majority of tools and the high‑accuracy consensus lean toward a benign interpretation, and this does not contradict any ClinVar classification (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -7.213 | In-Between | 0.397 | Ambiguous | Likely Benign | 2.01 | Destabilizing | 2.3 | 8.64 | Destabilizing | 5.33 | Destabilizing | 0.12 | Likely Benign | 0.455 | Likely Benign | -1.82 | Neutral | 0.952 | Possibly Damaging | 0.497 | Possibly Damaging | 4.64 | Benign | 0.07 | Tolerated | 0.1299 | 0.5084 | 0 | -2 | -3.8 | 60.04 | ||||||||||||||||||||||||||||||
| c.1190G>C | C397S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). In silico prediction tools that assess pathogenicity largely agree on a benign outcome: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. No tool predicts pathogenicity; Rosetta’s assessment is uncertain and therefore treated as unavailable. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Consequently, the variant is most likely benign based on the collective predictions, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -2.324 | Likely Benign | 0.178 | Likely Benign | Likely Benign | 0.37 | Likely Benign | 0.1 | 0.59 | Ambiguous | 0.48 | Likely Benign | 0.43 | Likely Benign | 0.253 | Likely Benign | -0.01 | Neutral | 0.276 | Benign | 0.066 | Benign | 4.68 | Benign | 0.53 | Tolerated | 0.5221 | 0.2474 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||
| c.1190G>T | C397F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397F is reported in gnomAD (6-33438095-G-T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, Rosetta, and the protein‑folding stability method Foldetta. FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as benign, while Foldetta indicates a pathogenic effect. Because the majority of tools (nine benign vs. four pathogenic) lean toward a benign outcome and the high‑accuracy consensus is split, the variant is most likely benign. This assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | 6-33438095-G-T | 1 | 6.20e-7 | -6.571 | Likely Benign | 0.194 | Likely Benign | Likely Benign | 1.31 | Ambiguous | 1.7 | 3.61 | Destabilizing | 2.46 | Destabilizing | 0.12 | Likely Benign | 0.493 | Likely Benign | -1.95 | Neutral | 0.952 | Possibly Damaging | 0.497 | Possibly Damaging | 4.65 | Benign | 0.07 | Tolerated | 3.41 | 15 | 0.1426 | 0.5231 | -2 | -4 | 0.3 | 44.04 | ||||||||||||||||||||||||
| c.1191C>G | C397W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus, whereas pathogenic calls are made by REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, but Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts pathogenic. Overall, the majority of tools lean toward a benign effect, and this is consistent with the lack of ClinVar evidence. Therefore, the variant is most likely benign, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -6.857 | Likely Benign | 0.614 | Likely Pathogenic | Likely Benign | 2.40 | Destabilizing | 2.3 | 4.46 | Destabilizing | 3.43 | Destabilizing | 0.19 | Likely Benign | 0.545 | Likely Pathogenic | -1.87 | Neutral | 0.987 | Probably Damaging | 0.814 | Possibly Damaging | 4.64 | Benign | 0.02 | Affected | 0.1637 | 0.5092 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.187G>A | E63K 2D AIThe SynGAP1 E63K missense variant (ClinVar ID 2830630.0) is listed as “Uncertain” and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all predict a pathogenic outcome. AlphaMissense‑Optimized is inconclusive, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. Overall, the high‑accuracy consensus leans toward a benign effect, and this assessment does not contradict the ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.474807 | Uncertain | 0.494 | 0.739 | 0.125 | Uncertain | 1 | -4.976 | Likely Benign | 0.894 | Likely Pathogenic | Ambiguous | 0.103 | Likely Benign | -0.70 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1995 | 0.7261 | 1 | 0 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||
| c.187G>C | E63Q 2D AIThe SynGAP1 missense variant E63Q is listed in ClinVar (ID 2132335.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (majority of the four high‑accuracy tools) also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of predictions points to a benign effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.474807 | Uncertain | 0.494 | 0.739 | 0.125 | Uncertain | 1 | -4.038 | Likely Benign | 0.687 | Likely Pathogenic | Likely Benign | 0.078 | Likely Benign | -0.85 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0970 | 0.6787 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.188A>C | E63A 2D AIThe SynGAP1 missense variant E63A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign effect, 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 | 0.429200 | Structured | 0.474807 | Uncertain | 0.494 | 0.739 | 0.125 | -3.426 | Likely Benign | 0.850 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | -1.84 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.3281 | 0.6649 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.188A>G | E63G 2D AIThe SynGAP1 missense variant E63G 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. AlphaMissense‑Optimized yields an uncertain result, and no Foldetta stability assessment is available. Overall, the majority of individual predictors and the SGM‑Consensus lean toward a benign interpretation, with no conflicting evidence from ClinVar. Thus, the variant is most likely benign based on current computational predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.474807 | Uncertain | 0.494 | 0.739 | 0.125 | -3.450 | Likely Benign | 0.898 | Likely Pathogenic | Ambiguous | 0.150 | Likely Benign | -2.24 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 3.87 | Benign | 0.00 | Affected | 0.2705 | 0.5786 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.188A>T | E63V 2D AIThe SynGAP1 E63V missense variant has no ClinVar record and is not present in gnomAD. Prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. AlphaMissense‑Optimized returns an Uncertain result, and no Foldetta stability data are available. Overall, the balance of evidence leans toward a benign effect, with several high‑confidence predictors supporting pathogenicity, leaving the assessment inconclusive. The predictions do not contradict any ClinVar status, as none is assigned. Based on the aggregate predictions, the variant is most likely benign, and this is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.474807 | Uncertain | 0.494 | 0.739 | 0.125 | -3.588 | Likely Benign | 0.921 | Likely Pathogenic | Ambiguous | 0.143 | Likely Benign | -2.15 | Neutral | 0.824 | Possibly Damaging | 0.775 | Possibly Damaging | 3.85 | Benign | 0.00 | Affected | 0.0559 | 0.7584 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.189G>C | E63D 2D AIThe SynGAP1 missense variant E63D 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, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also reports it as likely benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a benign 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 Benign | 0.429200 | Structured | 0.474807 | Uncertain | 0.494 | 0.739 | 0.125 | -3.821 | Likely Benign | 0.594 | Likely Pathogenic | Likely Benign | 0.066 | Likely Benign | -0.83 | Neutral | 0.267 | Benign | 0.585 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 0.1524 | 0.4130 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.189G>T | E63D 2D AIThe SynGAP1 missense variant E63D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the high‑accuracy tools) also indicates benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective evidence points to a benign effect for E63D, and this conclusion does not conflict with ClinVar, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.474807 | Uncertain | 0.494 | 0.739 | 0.125 | -3.821 | Likely Benign | 0.594 | Likely Pathogenic | Likely Benign | 0.066 | Likely Benign | -0.83 | Neutral | 0.267 | Benign | 0.585 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 0.1524 | 0.4130 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3790G>A | G1264S 2D AIThe SynGAP1 missense variant G1264S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: benign predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized classifies the variant as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, 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 | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -0.797 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.147 | Likely Benign | 0.82 | Neutral | 0.062 | Benign | 0.033 | Benign | 2.94 | Benign | 1.00 | Tolerated | 0.2376 | 0.4256 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.3790G>C | G1264R 2D AIThe SynGAP1 missense variant G1264R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those predicting a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) 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 points to the variant being 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 | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -4.482 | Likely Benign | 0.759 | Likely Pathogenic | Likely Benign | 0.094 | Likely Benign | -1.82 | Neutral | 0.934 | Possibly Damaging | 0.541 | Possibly Damaging | 2.73 | Benign | 0.09 | Tolerated | 0.0861 | 0.3860 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3790G>T | G1264C 2D AIThe SynGAP1 missense variant G1264C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence supports a benign classification for G1264C, 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 | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -5.666 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.03 | Neutral | 0.997 | Probably Damaging | 0.870 | Possibly Damaging | 2.74 | Benign | 0.09 | Tolerated | 0.1087 | 0.3691 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||
| c.3791G>A | G1264D 2D AIThe SynGAP1 missense variant G1264D 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), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while only AlphaMissense‑Default predicts it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -4.725 | Likely Benign | 0.648 | Likely Pathogenic | Likely Benign | 0.097 | Likely Benign | -1.29 | Neutral | 0.012 | Benign | 0.011 | Benign | 2.72 | Benign | 0.23 | Tolerated | 0.1658 | 0.1754 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3791G>C | G1264A 2D AIThe SynGAP1 missense variant G1264A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign likelihood. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is consistent with the lack of any ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -3.460 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.32 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.79 | Benign | 0.91 | Tolerated | 0.3504 | 0.4220 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3791G>T | G1264V 2D AIThe SynGAP1 missense variant G1264V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -6.116 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.136 | Likely Benign | -2.33 | Neutral | 0.966 | Probably Damaging | 0.617 | Possibly Damaging | 2.74 | Benign | 0.15 | Tolerated | 0.0972 | 0.3891 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||
| c.3799A>C | M1267L 2D AIThe SynGAP1 missense variant M1267L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evidence (five pathogenic‑predicting tools versus three benign) indicates that 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. | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -1.766 | Likely Benign | 0.399 | Ambiguous | Likely Benign | 0.293 | Likely Benign | -2.52 | Deleterious | 0.813 | Possibly Damaging | 0.456 | Possibly Damaging | 2.36 | Pathogenic | 0.00 | Affected | 0.1392 | 0.3626 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3799A>G | M1267V 2D AIThe SynGAP1 missense variant M1267V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated tools (five pathogenic vs. three benign) indicate a pathogenic effect. This prediction is not contradicted by ClinVar status, as the variant is not yet catalogued there. Thus, based on current computational evidence, the M1267V variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -2.249 | Likely Benign | 0.537 | Ambiguous | Likely Benign | 0.254 | Likely Benign | -3.34 | Deleterious | 0.959 | Probably Damaging | 0.672 | Possibly Damaging | 2.35 | Pathogenic | 0.00 | Affected | 0.3057 | 0.3241 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.3799A>T | M1267L 2D AIThe SynGAP1 missense variant M1267L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence (five pathogenic‑predicting tools versus three benign‑predicting tools) indicates that M1267L 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. | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -1.766 | Likely Benign | 0.399 | Ambiguous | Likely Benign | 0.293 | Likely Benign | -2.52 | Deleterious | 0.813 | Possibly Damaging | 0.456 | Possibly Damaging | 2.36 | Pathogenic | 0.00 | Affected | 0.1392 | 0.3626 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3800T>A | M1267K 2D AIThe SynGAP1 missense variant M1267K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a pathogenic outcome (3/4 pathogenic). AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. Overall, the majority of evidence points to a deleterious effect, classifying the variant as most likely pathogenic. This assessment does not conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -6.415 | Likely Benign | 0.917 | Likely Pathogenic | Ambiguous | 0.366 | Likely Benign | -5.01 | Deleterious | 0.884 | Possibly Damaging | 0.581 | Possibly Damaging | 2.31 | Pathogenic | 0.00 | Affected | 0.1373 | 0.0488 | 0 | -1 | -5.8 | -3.02 | ||||||||||||||||||||||||||||||||||||||
| c.3800T>C | M1267T 2D AIThe SynGAP1 missense variant M1267T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) likewise indicates likely pathogenicity. No Foldetta stability prediction is available for this variant. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -5.315 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.270 | Likely Benign | -5.00 | Deleterious | 0.982 | Probably Damaging | 0.672 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 0.2036 | 0.1934 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||||||||||
| c.3800T>G | M1267R 2D AIThe SynGAP1 missense variant M1267R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Grouping by consensus, two tools predict benign and six predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic impact, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -4.990 | Likely Benign | 0.899 | Likely Pathogenic | Ambiguous | 0.366 | Likely Benign | -5.03 | Deleterious | 0.982 | Probably Damaging | 0.757 | Possibly Damaging | 2.30 | Pathogenic | 0.00 | Affected | 0.1555 | 0.0837 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||||||||||
| c.3801G>A | M1267I 2D AIThe SynGAP1 missense variant M1267I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for M1267I. This conclusion is not contradicted by ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -1.432 | Likely Benign | 0.936 | Likely Pathogenic | Ambiguous | 0.205 | Likely Benign | -3.33 | Deleterious | 0.959 | Probably Damaging | 0.672 | Possibly Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1254 | 0.2741 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3801G>C | M1267I 2D AIThe SynGAP1 missense variant M1267I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) remains Likely Pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for M1267I. 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 | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -1.432 | Likely Benign | 0.936 | Likely Pathogenic | Ambiguous | 0.205 | Likely Benign | -3.33 | Deleterious | 0.959 | Probably Damaging | 0.672 | Possibly Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1254 | 0.2741 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3801G>T | M1267I 2D AIThe SynGAP1 missense variant M1267I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) remains Likely Pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for M1267I. 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 | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -1.432 | Likely Benign | 0.936 | Likely Pathogenic | Ambiguous | 0.205 | Likely Benign | -3.33 | Deleterious | 0.959 | Probably Damaging | 0.672 | Possibly Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1254 | 0.2741 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.391G>A | G131S 2D AIThe SynGAP1 missense variant G131S 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, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -2.953 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -2.75 | Deleterious | 0.115 | Benign | 0.026 | Benign | 4.10 | Benign | 0.02 | Affected | 0.2823 | 0.5338 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.391G>C | G131R 2D AIThe SynGAP1 missense variant G131R 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 REVEL, ESM1b, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive due to a 2‑to‑2 split and therefore does not contribute evidence. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence tools predict a pathogenic effect, and the variant is most likely pathogenic based on current predictions, which does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | Uncertain | 1 | -6.564 | Likely Benign | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.099 | Likely Benign | -3.82 | Deleterious | 0.983 | Probably Damaging | 0.656 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 3.61 | 5 | 0.1070 | 0.4667 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.391G>T | G131C 2D AIThe SynGAP1 missense variant G131C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus again indicates Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of tools predict pathogenicity, and this aligns with the SGM Consensus. Therefore, the variant is most likely pathogenic based on the available predictions, and this conclusion is consistent with the lack of ClinVar reporting rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -8.288 | Likely Pathogenic | 0.727 | Likely Pathogenic | Likely Benign | 0.155 | Likely Benign | -4.42 | Deleterious | 0.998 | Probably Damaging | 0.840 | Possibly Damaging | 3.88 | Benign | 0.00 | Affected | 0.1339 | 0.4356 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.392G>A | G131D 2D AIThe SynGAP1 missense variant G131D 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, polyPhen‑2 HumVar, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Two tools (ESM1b and AlphaMissense‑Optimized) return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence (four pathogenic, three benign, two uncertain) leans toward pathogenicity. This prediction does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -7.477 | In-Between | 0.950 | Likely Pathogenic | Ambiguous | 0.180 | Likely Benign | -3.29 | Deleterious | 0.888 | Possibly Damaging | 0.435 | Benign | 3.92 | Benign | 0.02 | Affected | 0.2093 | 0.2550 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.392G>C | G131A 2D AIThe SynGAP1 missense variant G131A 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, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign. Foldetta results are unavailable. Overall, the majority of evidence (5 benign vs 3 pathogenic) supports a benign classification. 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. | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -4.891 | Likely Benign | 0.512 | Ambiguous | Likely Benign | 0.138 | Likely Benign | -2.96 | Deleterious | 0.620 | Possibly Damaging | 0.157 | Benign | 3.99 | Benign | 0.01 | Affected | 0.3981 | 0.4814 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.392G>T | G131V 2D AIThe SynGAP1 missense variant G131V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a tie and is therefore unavailable, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no result for this variant. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any existing ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -6.248 | Likely Benign | 0.795 | Likely Pathogenic | Ambiguous | 0.199 | Likely Benign | -4.25 | Deleterious | 0.983 | Probably Damaging | 0.559 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.1168 | 0.4175 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.493A>C | S165R 2D AIThe SynGAP1 missense variant S165R is not 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. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, 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 (2 vs 2), and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs four benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -9.527 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.293 | Likely Benign | -1.89 | Neutral | 0.567 | Possibly Damaging | 0.249 | Benign | 4.01 | Benign | 0.00 | Affected | 0.1003 | 0.3969 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.493A>G | S165G 2D AIThe SynGAP1 missense variant S165G 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while 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 further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to the variant being 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 | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -7.691 | In-Between | 0.223 | Likely Benign | Likely Benign | 0.182 | Likely Benign | -1.17 | Neutral | 0.272 | Benign | 0.086 | Benign | 3.99 | Benign | 0.00 | Affected | 0.2622 | 0.4441 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.493A>T | S165C 2D AIThe SynGAP1 missense variant S165C 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and 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 preponderance of evidence points to a benign impact for S165C, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -8.425 | Likely Pathogenic | 0.367 | Ambiguous | Likely Benign | 0.304 | Likely Benign | -1.92 | Neutral | 0.938 | Possibly Damaging | 0.498 | Possibly Damaging | 3.94 | Benign | 0.00 | Affected | 0.1306 | 0.5534 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.494G>A | S165N 2D AIThe SynGAP1 missense variant S165N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for S165N. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -9.041 | Likely Pathogenic | 0.509 | Ambiguous | Likely Benign | 0.074 | Likely Benign | -0.49 | Neutral | 0.532 | Possibly Damaging | 0.229 | Benign | 4.03 | Benign | 0.00 | Affected | 0.1589 | 0.4862 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||||
| c.494G>C | S165T 2D AIThe SynGAP1 missense variant S165T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this conclusion 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 | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -6.952 | Likely Benign | 0.205 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.94 | Neutral | 0.155 | Benign | 0.064 | Benign | 4.02 | Benign | 0.00 | Affected | 0.1754 | 0.5779 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.494G>T | S165I 2D AISynGAP1 missense variant S165I has no ClinVar record and is absent from gnomAD. Individual prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta stability analysis is unavailable. Overall, the majority of single‑tool predictions favor a benign effect, whereas the consensus score suggests pathogenicity. Consequently, the variant is most likely benign according to the bulk of evidence, 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 | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -11.304 | Likely Pathogenic | 0.774 | Likely Pathogenic | Likely Benign | 0.259 | Likely Benign | -2.53 | Deleterious | 0.084 | Benign | 0.031 | Benign | 3.96 | Benign | 0.00 | Affected | 0.0943 | 0.5027 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.495T>A | S165R 2D AIThe SynGAP1 missense variant S165R is not 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. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2). High‑accuracy AlphaMissense‑Optimized predicts pathogenic, while Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) indicate a pathogenic effect. There is no ClinVar annotation to contradict this assessment, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -9.527 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.177 | Likely Benign | -1.89 | Neutral | 0.567 | Possibly Damaging | 0.249 | Benign | 4.01 | Benign | 0.00 | Affected | 0.1003 | 0.3969 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.495T>G | S165R 2D AIThe SynGAP1 missense variant S165R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized as pathogenic, while SGM Consensus and Foldetta are unavailable. Based on the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -9.527 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.177 | Likely Benign | -1.89 | Neutral | 0.567 | Possibly Damaging | 0.249 | Benign | 4.01 | Benign | 0.00 | Affected | 0.1003 | 0.3969 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.499G>A | D167N 2D AIThe SynGAP1 missense variant D167N is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33432796‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the available predictions, the variant is most likely benign; 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. | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | 6-33432796-G-A | 3 | 1.86e-6 | -11.939 | Likely Pathogenic | 0.843 | Likely Pathogenic | Ambiguous | 0.097 | Likely Benign | -2.32 | Neutral | 0.141 | Benign | 0.123 | Benign | 3.96 | Benign | 0.00 | Affected | 3.74 | 4 | 0.1222 | 0.7330 | 1 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.499G>C | D167H 2D AIThe SynGAP1 missense variant D167H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -12.606 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.338 | Likely Benign | -3.29 | Deleterious | 0.898 | Possibly Damaging | 0.557 | Possibly Damaging | 3.93 | Benign | 0.00 | Affected | 0.1478 | 0.7563 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.499G>T | D167Y 2D AIThe SynGAP1 missense variant D167Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and FATHMM, whereas the remaining eight predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized—and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. No Foldetta stability analysis is available for this residue. Overall, the majority of evidence points to a pathogenic impact for D167Y, and this conclusion is not contradicted by any ClinVar annotation, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -14.228 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.414 | Likely Benign | -4.23 | Deleterious | 0.898 | Possibly Damaging | 0.557 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.0493 | 0.6358 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.500A>C | D167A 2D AIThe SynGAP1 D167A missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools split evenly: benign calls come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls come from PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Taken together, the preponderance of evidence, especially the SGM Consensus, points to a pathogenic effect. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -13.473 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 0.291 | Likely Benign | -3.61 | Deleterious | 0.141 | Benign | 0.056 | Benign | 3.97 | Benign | 0.00 | Affected | 0.3429 | 0.6549 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.500A>G | D167G 2D AIThe SynGAP1 missense variant D167G is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the majority of evidence points to a pathogenic impact. The prediction 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 | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -11.806 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 0.338 | Likely Benign | -3.20 | Deleterious | 0.141 | Benign | 0.091 | Benign | 3.93 | Benign | 0.00 | Affected | 0.3580 | 0.6750 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.500A>T | D167V 2D AIThe SynGAP1 D167V variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, 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 | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -14.388 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.396 | Likely Benign | -4.03 | Deleterious | 0.535 | Possibly Damaging | 0.247 | Benign | 3.92 | Benign | 0.00 | Affected | 0.0709 | 0.6905 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.501C>A | D167E 2D AIThe SynGAP1 D167E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it receives two benign votes and two uncertain votes, yielding no clear majority. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, 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. | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -7.636 | In-Between | 0.516 | Ambiguous | Likely Benign | 0.067 | Likely Benign | -1.52 | Neutral | 0.063 | Benign | 0.062 | Benign | 4.07 | Benign | 0.00 | Affected | 0.1392 | 0.7144 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.501C>G | D167E 2D AIThe SynGAP1 D167E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it receives two benign votes and two uncertain votes, yielding no clear majority. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, 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. | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -7.636 | In-Between | 0.516 | Ambiguous | Likely Benign | 0.067 | Likely Benign | -1.52 | Neutral | 0.063 | Benign | 0.062 | Benign | 4.07 | Benign | 0.00 | Affected | 0.1392 | 0.7144 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.571A>C | S191R 2D AIThe SynGAP1 missense variant S191R 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -10.046 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.324 | Likely Benign | -3.82 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 3.78 | Benign | 0.01 | Affected | 0.0973 | 0.4344 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.571A>G | S191G 2D AIThe SynGAP1 missense variant S191G is not 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), FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also leans toward benign (two benign versus two uncertain). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that S191G 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. | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.161 | In-Between | 0.506 | Ambiguous | Likely Benign | 0.173 | Likely Benign | -2.43 | Neutral | 0.131 | Benign | 0.058 | Benign | 3.77 | Benign | 0.03 | Affected | 0.2893 | 0.5335 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.571A>T | S191C 2D AIThe SynGAP1 missense variant S191C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—leans pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of tools and the SGM Consensus predict a pathogenic impact, so 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. | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.009 | In-Between | 0.709 | Likely Pathogenic | Likely Benign | 0.288 | Likely Benign | -3.39 | Deleterious | 0.983 | Probably Damaging | 0.635 | Possibly Damaging | 3.73 | Benign | 0.00 | Affected | 0.1064 | 0.7134 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.572G>A | S191N 2D AIThe SynGAP1 missense variant S191N is not 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, and AlphaMissense‑Default. Two tools report an uncertain outcome: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows that the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign (2 benign vs. 1 pathogenic). AlphaMissense‑Optimized remains uncertain, and Foldetta folding‑stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for S191N, and this conclusion does not contradict any ClinVar annotation, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.887 | In-Between | 0.830 | Likely Pathogenic | Ambiguous | 0.148 | Likely Benign | -2.21 | Neutral | 0.596 | Possibly Damaging | 0.260 | Benign | 3.78 | Benign | 0.03 | Affected | 0.1366 | 0.5898 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||||
| c.572G>C | S191T 2D AIThe SynGAP1 missense variant S191T is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools overwhelmingly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while the majority‑vote SGM‑Consensus also classifies it as likely benign. Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy assessments corroborate the benign consensus: AlphaMissense‑Optimized returns a benign prediction and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports likely benign. Foldetta stability analysis is not available for this variant. Overall, the preponderance of evidence supports a benign classification, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.315 | In-Between | 0.319 | Likely Benign | Likely Benign | 0.150 | Likely Benign | -2.34 | Neutral | 0.231 | Benign | 0.081 | Benign | 3.81 | Benign | 0.03 | Affected | 0.1466 | 0.7405 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.572G>T | S191I 2D AIThe SynGAP1 missense variant S191I is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic predictions arise from PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. When the predictions are grouped by consensus, four tools favor benign and four favor pathogenic. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Taken together, the majority of evidence, including the SGM Consensus, 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 | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -11.271 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 0.283 | Likely Benign | -4.51 | Deleterious | 0.421 | Benign | 0.086 | Benign | 3.76 | Benign | 0.00 | Affected | 0.0954 | 0.6842 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.573T>A | S191R 2D AIThe SynGAP1 missense variant S191R 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -10.046 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.191 | Likely Benign | -3.82 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 3.78 | Benign | 0.01 | Affected | 0.0973 | 0.4344 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.573T>G | S191R 2D AIThe SynGAP1 missense variant S191R 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of computational evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -10.046 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.191 | Likely Benign | -3.82 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 3.78 | Benign | 0.01 | Affected | 0.0973 | 0.4344 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.577G>A | A193T 2D AIThe SynGAP1 missense variant A193T 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, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies 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 balance of evidence favors a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -4.973 | Likely Benign | 0.789 | Likely Pathogenic | Ambiguous | 0.208 | Likely Benign | -1.36 | Neutral | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 4.07 | Benign | 0.21 | Tolerated | 0.1452 | 0.7231 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.577G>C | A193P 2D AIThe SynGAP1 missense variant A193P 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 the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized model classifies the variant as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic), also yields a pathogenic consensus. 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 independent predictors indicates that A193P 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. | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -7.293 | In-Between | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.267 | Likely Benign | -2.70 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 3.99 | Benign | 0.05 | Affected | 0.1855 | 0.5601 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||||||||
| c.577G>T | A193S 2D AIThe SynGAP1 missense variant A193S 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. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -2.408 | Likely Benign | 0.533 | Ambiguous | Likely Benign | 0.180 | Likely Benign | -1.62 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.04 | Benign | 0.04 | Affected | 0.2595 | 0.5852 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.578C>A | A193D 2D AIThe SynGAP1 missense variant A193D 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 the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized model classifies the variant as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic), also yields a pathogenic consensus. 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 A193D is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -7.488 | In-Between | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.217 | Likely Benign | -3.46 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 3.99 | Benign | 0.01 | Affected | 0.1688 | 0.1835 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.578C>G | A193G 2D AIThe SynGAP1 missense variant A193G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, while those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, more tools predict pathogenicity (5) than benignity (3), and no ClinVar evidence contradicts this assessment. Therefore, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -4.822 | Likely Benign | 0.835 | Likely Pathogenic | Ambiguous | 0.136 | Likely Benign | -2.61 | Deleterious | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.00 | Benign | 0.01 | Affected | 0.2283 | 0.4999 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.578C>T | A193V 2D AIThe SynGAP1 A193V missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta stability analysis is 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 | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -3.548 | Likely Benign | 0.744 | Likely Pathogenic | Likely Benign | 0.177 | Likely Benign | 0.52 | Neutral | 0.767 | Possibly Damaging | 0.344 | Benign | 4.30 | Benign | 1.00 | Tolerated | 0.1169 | 0.6775 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.901G>A | A301T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33437806‑G‑A). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is benign. Overall, the majority of evidence points to a benign effect, and this is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | Uncertain | 5 | 6-33437806-G-A | 2 | 1.24e-6 | -3.448 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.2 | -0.33 | Likely Benign | 0.02 | Likely Benign | 0.03 | Likely Benign | 0.150 | Likely Benign | -0.25 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 4.15 | Benign | 0.22 | Tolerated | 4.32 | 14 | 0.1362 | 0.7201 | 1 | 0 | -2.5 | 30.03 | 219.8 | -42.8 | -0.1 | 0.0 | -0.5 | 0.2 | Uncertain | The methyl group of Ala301, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), points outward from the β hairpin loop, and its backbone atoms do not participate in the loop formation in the WT simulations. In the variant simulations, the hydroxyl group of the Thr301 side chain also mostly points outward; however, the guanidinium group of Arg299 is moved away from its central hairpin loop position.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel. | ||||||||||||||
| c.901G>C | A301P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools—polyPhen‑2 HumDiv and polyPhen‑2 HumVar—predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -3.808 | Likely Benign | 0.085 | Likely Benign | Likely Benign | -0.47 | Likely Benign | 0.1 | -0.41 | Likely Benign | -0.44 | Likely Benign | 0.40 | Likely Benign | 0.225 | Likely Benign | -0.83 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.11 | Benign | 0.06 | Tolerated | 0.1907 | 0.5371 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.901G>T | A301S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301S is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess sequence conservation and functional impact uniformly indicate a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy methods corroborate the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. No evidence from these analyses suggests a deleterious effect. Therefore, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -2.488 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.20 | Likely Benign | 0.1 | -0.32 | Likely Benign | -0.06 | Likely Benign | 0.22 | Likely Benign | 0.151 | Likely Benign | -0.28 | Neutral | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 4.21 | Benign | 0.13 | Tolerated | 0.2706 | 0.6022 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.902C>A | A301D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301D is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM all predict benign, whereas polyPhen‑2 (HumDiv and HumVar) and ESM1b predict pathogenic. Tools with uncertain outputs—Rosetta, Foldetta, and AlphaMissense‑Default—do not provide decisive evidence. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized classifies the variant as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign verdict; Foldetta remains inconclusive. Taken together, the preponderance of evidence indicates that A301D is most likely benign, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -10.276 | Likely Pathogenic | 0.488 | Ambiguous | Likely Benign | -0.37 | Likely Benign | 0.2 | -1.15 | Ambiguous | -0.76 | Ambiguous | 0.23 | Likely Benign | 0.224 | Likely Benign | -0.35 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.17 | Benign | 0.07 | Tolerated | 0.1599 | 0.1705 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||
| c.902C>G | A301G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as Benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, classifies the variant as Benign. Overall, the consensus of the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar claim. Therefore, the variant is most likely benign, and this is not contradictory to ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -3.085 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.27 | Likely Benign | 0.1 | 0.34 | Likely Benign | 0.31 | Likely Benign | 0.37 | Likely Benign | 0.128 | Likely Benign | -0.37 | Neutral | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 4.18 | Benign | 0.28 | Tolerated | 0.2425 | 0.5054 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.902C>T | A301V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Thus, the overall evidence supports a benign classification for A301V, and this conclusion is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -2.476 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.25 | Likely Benign | 0.1 | 0.48 | Likely Benign | 0.37 | Likely Benign | 0.06 | Likely Benign | 0.116 | Likely Benign | -0.49 | Neutral | 0.997 | Probably Damaging | 0.983 | Probably Damaging | 4.14 | Benign | 0.26 | Tolerated | 0.1096 | 0.6264 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.1114G>A | G372R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Default. Two tools, FoldX and ESM1b, returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta predicting pathogenic. Overall, the majority of predictions (seven pathogenic vs. five benign) and the consensus of high‑accuracy methods 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. | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -7.344 | In-Between | 0.617 | Likely Pathogenic | Likely Benign | 1.49 | Ambiguous | 0.3 | 2.87 | Destabilizing | 2.18 | Destabilizing | 0.20 | Likely Benign | 0.572 | Likely Pathogenic | -0.61 | Neutral | 0.001 | Benign | 0.001 | Benign | -0.74 | Pathogenic | 0.02 | Affected | 0.1323 | 0.4313 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1114G>C | G372R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Default. Two tools (FoldX and ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. Overall, the majority of predictions (seven pathogenic vs five benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -7.344 | In-Between | 0.617 | Likely Pathogenic | Likely Benign | 1.49 | Ambiguous | 0.3 | 2.87 | Destabilizing | 2.18 | Destabilizing | 0.20 | Likely Benign | 0.572 | Likely Pathogenic | -0.61 | Neutral | 0.001 | Benign | 0.001 | Benign | -0.74 | Pathogenic | 0.02 | Affected | 0.1323 | 0.4313 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1114G>T | G372W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372W has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 HumDiv, SIFT, ESM1b, and FATHMM. The remaining tools (Rosetta, Foldetta, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -8.262 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 2.28 | Destabilizing | 0.5 | 1.14 | Ambiguous | 1.71 | Ambiguous | 0.21 | Likely Benign | 0.649 | Likely Pathogenic | -1.25 | Neutral | 0.657 | Possibly Damaging | 0.075 | Benign | -0.74 | Pathogenic | 0.00 | Affected | 0.1057 | 0.4368 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||
| c.1115G>A | G372E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are REVEL, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while Foldetta predicts pathogenic. The SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split and is treated as unavailable. Overall, the majority of evidence (seven benign vs. five pathogenic) supports a benign classification. This conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -6.682 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 1.58 | Ambiguous | 0.4 | 2.91 | Destabilizing | 2.25 | Destabilizing | 0.34 | Likely Benign | 0.566 | Likely Pathogenic | -0.81 | Neutral | 0.001 | Benign | 0.001 | Benign | -0.74 | Pathogenic | 0.08 | Tolerated | 0.1606 | 0.4103 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.1115G>C | G372A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX and Rosetta individually also return uncertain results. Overall, the majority of evidence points to a benign impact for G372A, and this conclusion does not contradict any ClinVar status, as the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -5.163 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 1.52 | Ambiguous | 0.2 | 1.58 | Ambiguous | 1.55 | Ambiguous | -0.12 | Likely Benign | 0.465 | Likely Benign | -0.32 | Neutral | 0.000 | Benign | 0.000 | Benign | -0.74 | Pathogenic | 0.03 | Affected | 0.3956 | 0.5247 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1115G>T | G372V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372V is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (variant ID 6-33438020-G-T). Functional prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are REVEL, FoldX, Rosetta, FATHMM, and Foldetta. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, while Foldetta (combining FoldX‑MD and Rosetta stability outputs) indicates a pathogenic effect. Overall, the majority of predictions support a benign classification, and there is no conflict with ClinVar status because the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | 6-33438020-G-T | -5.898 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 2.81 | Destabilizing | 0.3 | 2.91 | Destabilizing | 2.86 | Destabilizing | 0.02 | Likely Benign | 0.535 | Likely Pathogenic | -0.92 | Neutral | 0.003 | Benign | 0.000 | Benign | -0.74 | Pathogenic | 0.06 | Tolerated | 3.52 | 18 | 0.1663 | 0.4198 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||
| c.3796C>A | L1266M 2D AIThe SynGAP1 missense variant L1266M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and PROVEAN, whereas a larger set—polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized yields an uncertain result, SGM‑Consensus remains likely pathogenic, and Foldetta data are unavailable. Overall, the majority of evidence points toward a pathogenic effect for L1266M. This conclusion does not conflict with 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 | Coiled-coil | 0.433034 | Structured | 0.802655 | Binding | 0.868 | 0.602 | 0.000 | -8.257 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 0.126 | Likely Benign | -1.67 | Neutral | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 2.12 | Pathogenic | 0.00 | Affected | 0.0627 | 0.3113 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3796C>G | L1266V 2D AIThe SynGAP1 missense variant L1266V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: REVEL predicts a benign outcome, whereas all other evaluated algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.433034 | Structured | 0.802655 | Binding | 0.868 | 0.602 | 0.000 | -10.024 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.125 | Likely Benign | -2.53 | Deleterious | 0.995 | Probably Damaging | 0.890 | Possibly Damaging | 2.16 | Pathogenic | 0.00 | Affected | 0.1301 | 0.3118 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3797T>A | L1266Q 2D AIThe SynGAP1 missense variant L1266Q 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 predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN)—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates likely pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence points to a pathogenic effect for L1266Q, 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 | Coiled-coil | 0.433034 | Structured | 0.802655 | Binding | 0.868 | 0.602 | 0.000 | -16.101 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.374 | Likely Benign | -5.02 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.12 | Pathogenic | 0.00 | Affected | 0.0906 | 0.1249 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||
| c.3797T>C | L1266P 2D AIThe SynGAP1 missense variant L1266P is reported in gnomAD (6‑33447845‑T‑C) but has no ClinVar entry. Prediction tools cluster into two groups: benign predictions are made only by REVEL, whereas all other evaluated algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic effect. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized returns a pathogenic score, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic.” The Foldetta stability analysis is unavailable for this variant. Overall, the consensus of both general and high‑accuracy predictors points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.433034 | Structured | 0.802655 | Binding | 0.868 | 0.602 | 0.000 | 6-33447845-T-C | -16.566 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.424 | Likely Benign | -5.83 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.10 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3150 | 0.2283 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.3797T>G | L1266R 2D AISynGAP1 missense variant L1266R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently 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 further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic, and the SGM‑Consensus confirms a likely pathogenic classification. Foldetta results are unavailable for this variant. Overall, the preponderance of evidence from multiple in silico predictors and high‑accuracy tools points to a pathogenic effect, with no conflict from ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.433034 | Structured | 0.802655 | Binding | 0.868 | 0.602 | 0.000 | -16.676 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.391 | Likely Benign | -5.04 | Deleterious | 0.996 | Probably Damaging | 0.951 | Probably Damaging | 2.13 | Pathogenic | 0.00 | Affected | 0.1063 | 0.0891 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.3805G>A | V1269M 2D AIThe SynGAP1 missense variant V1269M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (majority vote) is 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 points to a pathogenic effect for V1269M, 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 | Coiled-coil | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | -3.743 | Likely Benign | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.300 | Likely Benign | -2.53 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.08 | Pathogenic | 0.00 | Affected | 0.0582 | 0.3676 | 2 | 1 | -2.3 | 32.06 | ||||||||||||||||||||||||||||||||||||||
| c.3805G>C | V1269L 2D AIThe SynGAP1 missense variant V1269L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as 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 tools 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 | Coiled-coil | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | -3.572 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.299 | Likely Benign | -2.53 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.14 | Pathogenic | 0.00 | Affected | 0.0683 | 0.4082 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3805G>T | V1269L 2D AIThe SynGAP1 missense variant V1269L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact. 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 pathogenicity, and the SGM‑Consensus also indicates 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 predictions 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 | Coiled-coil | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | -3.572 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.299 | Likely Benign | -2.53 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.14 | Pathogenic | 0.00 | Affected | 0.0683 | 0.4082 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3806T>A | V1269E 2D AIThe SynGAP1 missense change V1269E is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that flag the variant as benign include only REVEL, whereas the remaining predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classify it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Pathogenic” outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as likely pathogenic; the Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | Uncertain | 1 | -11.418 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.403 | Likely Benign | -5.05 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.09 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.0899 | 0.1557 | -2 | -2 | -7.7 | 29.98 | ||||||||||||||||||||||||||||||||||
| c.3806T>C | V1269A 2D AIThe SynGAP1 missense variant V1269A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas a larger group predicts pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and no Foldetta data. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | -6.115 | Likely Benign | 0.954 | Likely Pathogenic | Ambiguous | 0.291 | Likely Benign | -3.38 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.15 | Pathogenic | 0.00 | Affected | 0.2699 | 0.2312 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||||||||||
| c.3806T>G | V1269G 2D AIThe SynGAP1 missense variant V1269G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include only REVEL, whereas all other evaluated algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus is pathogenic; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | -9.927 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.420 | Likely Benign | -5.91 | Deleterious | 0.995 | Probably Damaging | 0.999 | Probably Damaging | 2.10 | Pathogenic | 0.00 | Affected | 0.2180 | 0.2557 | -1 | -3 | -4.6 | -42.08 | |||||||||||||||||||||||||||||||||||||||
| c.406C>G | R136G 2D AIThe SynGAP1 missense variant R136G is not reported in ClinVar and is absent from gnomAD. Consensus from standard in‑silico predictors shows a split: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic calls arise from PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.433034 | Structured | 0.657394 | Binding | 0.351 | 0.894 | 0.250 | -10.641 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.246 | Likely Benign | -3.46 | Deleterious | 0.487 | Possibly Damaging | 0.211 | Benign | 3.47 | Benign | 0.00 | Affected | 0.3581 | 0.3585 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.406C>T | R136W 2D AIThe SynGAP1 missense variant R136W is listed in ClinVar (ID 1479441.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a deleterious effect, and the SGM‑Consensus also indicates Likely Pathogenic. 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 pathogenic impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.433034 | Structured | 0.657394 | Binding | 0.351 | 0.894 | 0.250 | Uncertain | 2 | -10.453 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.237 | Likely Benign | -4.71 | Deleterious | 0.965 | Probably Damaging | 0.416 | Benign | 3.45 | Benign | 0.00 | Affected | 3.61 | 5 | 0.1189 | 0.3827 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.407G>A | R136Q 2D AIThe SynGAP1 R136Q variant is listed in ClinVar as benign and is present in gnomAD (6‑33432704‑G‑A). 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, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized returns an uncertain result. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive due to a 2‑vs‑2 split, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no reported result for this variant. Based on the available predictions, the variant is most likely benign, which aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.657394 | Binding | 0.351 | 0.894 | 0.250 | Benign | 1 | 6-33432704-G-A | 13 | 9.17e-6 | -11.146 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.190 | Likely Benign | -2.26 | Neutral | 0.957 | Probably Damaging | 0.342 | Benign | 3.52 | Benign | 0.01 | Affected | 3.61 | 5 | 0.3171 | 0.2460 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||||||
| c.407G>C | R136P 2D AIThe SynGAP1 missense variant R136P is listed in ClinVar (ID 579340.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.433034 | Structured | 0.657394 | Binding | 0.351 | 0.894 | 0.250 | Uncertain | 1 | -11.952 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.277 | Likely Benign | -3.72 | Deleterious | 0.910 | Possibly Damaging | 0.578 | Possibly Damaging | 3.47 | Benign | 0.00 | Affected | 3.61 | 5 | 0.2063 | 0.4426 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.407G>T | R136L 2D AIThe SynGAP1 missense variant R136L is catalogued in gnomAD (ID 6‑33432704‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions arise from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. 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 pathogenic impact, and this assessment does not conflict with ClinVar, which currently has no classification for R136L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.433034 | Structured | 0.657394 | Binding | 0.351 | 0.894 | 0.250 | 6-33432704-G-T | 1 | 7.05e-7 | -11.512 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.347 | Likely Benign | -4.19 | Deleterious | 0.190 | Benign | 0.037 | Benign | 3.48 | Benign | 0.01 | Affected | 3.61 | 5 | 0.1718 | 0.4475 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||
| c.40C>A | P14T 2D AIThe SynGAP1 missense variant P14T is reported in gnomAD (ID 6‑33420304‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also reports likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for P14T, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.471596 | Uncertain | 0.399 | 0.909 | 0.375 | 6-33420304-C-A | -3.261 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -0.27 | Neutral | 0.212 | Benign | 0.014 | Benign | 4.20 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1912 | 0.6658 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.40C>G | P14A 2D AIThe SynGAP1 missense variant P14A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign status: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta results are unavailable. Overall, the majority of computational evidence indicates that P14A 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 | 0.433034 | Structured | 0.471596 | Uncertain | 0.399 | 0.909 | 0.375 | -2.919 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -0.01 | Neutral | 0.100 | Benign | 0.007 | Benign | 4.24 | Benign | 0.00 | Affected | 0.3928 | 0.5543 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.40C>T | P14S 2D AIThe SynGAP1 missense variant P14S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points 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 | 0.433034 | Structured | 0.471596 | Uncertain | 0.399 | 0.909 | 0.375 | -2.352 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.02 | Neutral | 0.212 | Benign | 0.014 | Benign | 4.23 | Benign | 0.00 | Affected | 0.3935 | 0.5938 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.41C>A | P14H 2D AIThe SynGAP1 missense variant P14H is listed in gnomAD (ID 6‑33420305‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is unavailable. Overall, the majority of predictions—including the high‑accuracy tools—indicate that P14H 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 | 0.433034 | Structured | 0.471596 | Uncertain | 0.399 | 0.909 | 0.375 | 6-33420305-C-A | -3.747 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -0.27 | Neutral | 0.742 | Possibly Damaging | 0.091 | Benign | 4.15 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1999 | 0.5176 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| c.41C>G | P14R 2D AIThe SynGAP1 missense variant P14R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The high‑accuracy consensus methods give a benign verdict: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” No result is available from Foldetta, so its folding‑stability assessment is not considered. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of any ClinVar classification. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.471596 | Uncertain | 0.399 | 0.909 | 0.375 | -2.794 | Likely Benign | 0.253 | Likely Benign | Likely Benign | 0.183 | Likely Benign | 0.13 | Neutral | 0.486 | Possibly Damaging | 0.032 | Benign | 4.20 | Benign | 0.00 | Affected | 0.1597 | 0.3536 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.41C>T | P14L 2D AIThe SynGAP1 missense variant P14L is catalogued in gnomAD (ID 6‑33420305‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes, while the single pathogenic call comes from 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 reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise favors benign; Foldetta results are unavailable. Overall, the consensus of available predictions points to a benign impact for P14L, and this conclusion is not contradicted by ClinVar status, which currently lacks an entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.471596 | Uncertain | 0.399 | 0.909 | 0.375 | 6-33420305-C-T | -3.277 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.153 | Likely Benign | -0.53 | Neutral | 0.062 | Benign | 0.004 | Benign | 4.19 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2618 | 0.7197 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||
| c.487T>A | F163I 2D  AIThe SynGAP1 missense variant F163I is not 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. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated tools (five pathogenic vs. three 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 is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -10.706 | Likely Pathogenic | 0.912 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | -1.62 | Neutral | 0.981 | Probably Damaging | 0.966 | Probably Damaging | 4.12 | Benign | 0.03 | Affected | 0.2114 | 0.2320 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.487T>C | F163L 2D  AIThe SynGAP1 missense variant F163L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM‑Consensus indicates a likely benign outcome; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this assessment does not contradict the ClinVar status, which currently has no classification for F163L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -6.380 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.193 | Likely Benign | -1.22 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.21 | Benign | 0.37 | Tolerated | 0.2191 | 0.3491 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.487T>G | F163V 2D  AIThe SynGAP1 missense variant F163V is not 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 polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict a pathogenic impact. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and therefore unavailable; Foldetta data are not provided. Overall, the majority of available predictions (five pathogenic vs. three benign) indicate that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -12.580 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 0.236 | Likely Benign | -2.06 | Neutral | 0.981 | Probably Damaging | 0.954 | Probably Damaging | 4.13 | Benign | 0.02 | Affected | 0.2214 | 0.2547 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||||||
| c.488T>A | F163Y 2D  AIThe SynGAP1 missense variant F163Y is not 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, 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) and is therefore treated as unavailable. High‑accuracy methods show AlphaMissense‑Optimized as benign; Foldetta results are not provided, so its stability prediction is unavailable. Overall, the majority of available predictions (5 pathogenic vs. 4 benign) indicate that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -10.087 | Likely Pathogenic | 0.722 | Likely Pathogenic | Likely Benign | 0.125 | Likely Benign | -1.09 | Neutral | 0.981 | Probably Damaging | 0.931 | Probably Damaging | 4.03 | Benign | 0.04 | Affected | 0.1529 | 0.2152 | 7 | 3 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||||||||||||
| c.488T>C | F163S 2D  AIThe SynGAP1 missense variant F163S has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—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 a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus reports it as Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence indicates that F163S is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -13.338 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.273 | Likely Benign | -2.64 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 4.05 | Benign | 0.00 | Affected | 0.5240 | 0.0358 | Weaken | -3 | -2 | -3.6 | -60.10 | ||||||||||||||||||||||||||||||||||||||
| c.488T>G | F163C 2D  AIThe SynGAP1 missense variant F163C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus indicates a likely pathogenic status. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of predictions, including the high‑accuracy tools, point to a pathogenic 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 Pathogenic | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -12.221 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.282 | Likely Benign | -2.99 | Deleterious | 0.999 | Probably Damaging | 0.990 | Probably Damaging | 4.01 | Benign | 0.00 | Affected | 0.2860 | 0.1232 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||||||
| c.489C>A | F163L 2D AIThe SynGAP1 missense variant F163L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM‑Consensus indicates a likely benign outcome; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this assessment does not contradict the ClinVar status, which currently has no classification for F163L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -6.380 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | -1.22 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.21 | Benign | 0.37 | Tolerated | 0.2191 | 0.3491 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.489C>G | F163L 2D AIThe SynGAP1 missense variant F163L 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, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, six tools favor a benign outcome versus four favoring pathogenicity, and the high‑accuracy predictions are conflicting. Thus, the variant is most likely benign based on the current consensus, 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 | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -6.380 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | -1.22 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.21 | Benign | 0.37 | Tolerated | 0.2191 | 0.3491 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.502C>A | H168N 2D AIThe SynGAP1 missense variant H168N is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. No tools predict pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -4.764 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -0.14 | Neutral | 0.016 | Benign | 0.015 | Benign | 4.29 | Benign | 0.60 | Tolerated | 0.1516 | 0.2589 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.502C>G | H168D 2D AIThe SynGAP1 missense variant H168D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign consensus, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This prediction is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -8.519 | Likely Pathogenic | 0.481 | Ambiguous | Likely Benign | 0.131 | Likely Benign | -1.24 | Neutral | 0.016 | Benign | 0.021 | Benign | 4.24 | Benign | 0.08 | Tolerated | 0.2365 | 0.2017 | 1 | -1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||||||||
| c.502C>T | H168Y 2D AIThe SynGAP1 missense variant H168Y is listed in ClinVar (ID 956914.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are SIFT and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | Benign | 1 | -8.914 | Likely Pathogenic | 0.264 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.53 | Neutral | 0.192 | Benign | 0.062 | Benign | 4.18 | Benign | 0.01 | Affected | 4.32 | 3 | 0.0695 | 0.4657 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||
| c.503A>C | H168P 2D AIThe SynGAP1 missense variant H168P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome, while ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Taken together, the preponderance of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -7.686 | In-Between | 0.124 | Likely Benign | Likely Benign | 0.279 | Likely Benign | -1.66 | Neutral | 0.072 | Benign | 0.043 | Benign | 4.19 | Benign | 0.02 | Affected | 0.2004 | 0.3960 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.503A>G | H168R 2D AIThe SynGAP1 missense variant H168R is reported in gnomAD (ID 6‑33432800‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized all classify the change as benign, whereas SIFT predicts it to be pathogenic. Two tools (ESM1b and AlphaMissense‑Default) return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it contains two benign and two uncertain calls, and Foldetta data are not available. Overall, the preponderance of evidence points to a benign impact. This conclusion does not contradict ClinVar, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | 6-33432800-A-G | 1 | 6.20e-7 | -7.334 | In-Between | 0.395 | Ambiguous | Likely Benign | 0.153 | Likely Benign | -1.08 | Neutral | 0.016 | Benign | 0.011 | Benign | 4.26 | Benign | 0.02 | Affected | 4.32 | 3 | 0.1752 | 0.2499 | 0 | 2 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||
| c.503A>T | H168L 2D AIThe SynGAP1 H168L missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this 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 | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -7.936 | In-Between | 0.178 | Likely Benign | Likely Benign | 0.250 | Likely Benign | -2.36 | Neutral | 0.037 | Benign | 0.021 | Benign | 4.21 | Benign | 0.01 | Affected | 0.0752 | 0.5602 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.504T>A | H168Q 2D AIThe SynGAP1 missense variant H168Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar or gnomAD entries—there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -5.177 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.85 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.31 | Benign | 0.02 | Affected | 0.1307 | 0.3873 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.504T>G | H168Q 2D AIThe SynGAP1 missense variant H168Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar or gnomAD entries—there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -5.177 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.85 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.31 | Benign | 0.02 | Affected | 0.1307 | 0.3873 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.991T>A | S331T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while FoldX and premPS are inconclusive (Uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Taken together, the majority of evidence indicates that S331T is most likely benign, and this conclusion does not contradict the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.346458 | Uncertain | 0.658 | 0.475 | 0.250 | -2.474 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.60 | Ambiguous | 0.2 | -0.10 | Likely Benign | 0.25 | Likely Benign | -0.72 | Ambiguous | 0.095 | Likely Benign | 1.13 | Neutral | 0.003 | Benign | 0.002 | Benign | 1.86 | Pathogenic | 0.98 | Tolerated | 0.1505 | 0.4552 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.991T>C | S331P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are Rosetta, polyPhen‑2 HumDiv, and FATHMM. Two tools give inconclusive results: AlphaMissense‑Default and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.433034 | Structured | 0.346458 | Uncertain | 0.658 | 0.475 | 0.250 | -5.104 | Likely Benign | 0.409 | Ambiguous | Likely Benign | 0.33 | Likely Benign | 0.2 | 2.35 | Destabilizing | 1.34 | Ambiguous | 0.44 | Likely Benign | 0.186 | Likely Benign | -1.81 | Neutral | 0.784 | Possibly Damaging | 0.390 | Benign | 1.83 | Pathogenic | 0.26 | Tolerated | 0.2306 | 0.4086 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.991T>G | S331A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign majority vote (3 benign vs. 1 pathogenic). High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote) is benign; and Foldetta, combining FoldX‑MD and Rosetta outputs, is benign. No prediction or folding‑stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.346458 | Uncertain | 0.658 | 0.475 | 0.250 | -2.199 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.1 | -0.08 | Likely Benign | 0.07 | Likely Benign | -0.15 | Likely Benign | 0.071 | Likely Benign | -0.44 | Neutral | 0.139 | Benign | 0.060 | Benign | 1.89 | Pathogenic | 0.67 | Tolerated | 0.5314 | 0.3008 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.992C>T | S331L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only FATHMM predicts pathogenicity, while FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the consensus of the majority of tools supports a benign classification, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.346458 | Uncertain | 0.658 | 0.475 | 0.250 | -6.570 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.54 | Ambiguous | 0.0 | 1.06 | Ambiguous | 0.80 | Ambiguous | 0.07 | Likely Benign | 0.090 | Likely Benign | -1.72 | Neutral | 0.270 | Benign | 0.136 | Benign | 1.87 | Pathogenic | 0.58 | Tolerated | 0.0953 | 0.4124 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||
| c.1192C>A | P398T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P398T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, and SIFT. The remaining tools (Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy methods give a benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta is uncertain. Overall, the majority of high‑confidence predictions lean toward a benign impact, although several other predictors indicate pathogenicity. There is no 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. | C2 | 0.436924 | Structured | 0.401041 | Uncertain | 0.891 | 0.525 | 0.250 | -6.670 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 2.11 | Destabilizing | 0.4 | 1.57 | Ambiguous | 1.84 | Ambiguous | 0.78 | Ambiguous | 0.608 | Likely Pathogenic | -5.70 | Deleterious | 0.816 | Possibly Damaging | 0.307 | Benign | 5.51 | Benign | 0.01 | Affected | 0.1671 | 0.6607 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
| c.1192C>G | P398A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P398A is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438097‑C‑G). Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only PROVEAN predicts a pathogenic outcome. Tools with inconclusive results—FoldX, Rosetta, Foldetta, and premPS—are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign effect for P398A, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.436924 | Structured | 0.401041 | Uncertain | 0.891 | 0.525 | 0.250 | 6-33438097-C-G | 2 | 1.24e-6 | -5.321 | Likely Benign | 0.184 | Likely Benign | Likely Benign | 1.80 | Ambiguous | 0.2 | 1.15 | Ambiguous | 1.48 | Ambiguous | 0.92 | Ambiguous | 0.290 | Likely Benign | -5.17 | Deleterious | 0.008 | Benign | 0.005 | Benign | 5.55 | Benign | 0.12 | Tolerated | 3.40 | 16 | 0.3644 | 0.5487 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||
| c.1192C>T | P398S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P398S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 (HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv), and SIFT. 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 benign, and Foldetta as uncertain. Overall, the majority of definitive predictions lean toward a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.436924 | Structured | 0.401041 | Uncertain | 0.891 | 0.525 | 0.250 | -6.757 | Likely Benign | 0.490 | Ambiguous | Likely Benign | 1.86 | Ambiguous | 0.3 | 1.78 | Ambiguous | 1.82 | Ambiguous | 0.85 | Ambiguous | 0.544 | Likely Pathogenic | -5.58 | Deleterious | 0.478 | Possibly Damaging | 0.130 | Benign | 5.68 | Benign | 0.03 | Affected | 0.3619 | 0.5737 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.1193C>A | P398Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P398Q 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 only FATHMM, while the majority of tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default) predict a pathogenic impact. Two tools report uncertainty: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.436924 | Structured | 0.401041 | Uncertain | 0.891 | 0.525 | 0.250 | -7.402 | In-Between | 0.792 | Likely Pathogenic | Ambiguous | 2.13 | Destabilizing | 0.1 | 2.01 | Destabilizing | 2.07 | Destabilizing | 1.01 | Destabilizing | 0.719 | Likely Pathogenic | -5.57 | Deleterious | 0.996 | Probably Damaging | 0.724 | Possibly Damaging | 5.48 | Benign | 0.00 | Affected | 0.1522 | 0.5176 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||
| c.1193C>G | P398R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P398R variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include only FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—indicate a pathogenic effect, while Rosetta, premPS, and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.436924 | Structured | 0.401041 | Uncertain | 0.891 | 0.525 | 0.250 | -9.575 | Likely Pathogenic | 0.889 | Likely Pathogenic | Ambiguous | 3.01 | Destabilizing | 0.5 | 1.35 | Ambiguous | 2.18 | Destabilizing | 0.98 | Ambiguous | 0.755 | Likely Pathogenic | -6.55 | Deleterious | 0.988 | Probably Damaging | 0.724 | Possibly Damaging | 5.49 | Benign | 0.00 | Affected | 0.1479 | 0.3472 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1193C>T | P398L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P398L (ClinVar ID 2415189.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33438098‑C‑T). Functional prediction tools that agree on a benign effect include Foldetta, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, and SIFT. Predictions that are uncertain or inconclusive are FoldX, Rosetta, premPS, 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 inconclusive. Based on the available predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.436924 | Structured | 0.401041 | Uncertain | 0.891 | 0.525 | 0.250 | Uncertain | 1 | 6-33438098-C-T | 8 | 4.96e-6 | -7.518 | In-Between | 0.547 | Ambiguous | Likely Benign | 1.48 | Ambiguous | 0.2 | -0.54 | Ambiguous | 0.47 | Likely Benign | 0.62 | Ambiguous | 0.599 | Likely Pathogenic | -7.10 | Deleterious | 0.961 | Probably Damaging | 0.256 | Benign | 5.72 | Benign | 0.01 | Affected | 3.40 | 16 | 0.2248 | 0.7157 | -3 | -3 | 5.4 | 16.04 | 245.8 | -68.6 | -0.1 | 0.0 | -0.3 | 0.2 | X | Potentially Pathogenic | Pro398 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. Although the residue swap does not influence the nearby secondary structure elements, proline is often found at the ends of β sheets due to its disfavored status during folding.Additionally, the Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone. Ω loops are known to play significant roles in protein functions that require flexibility, and thus hydrophobic residues like leucine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Leu398 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. Since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||
| c.2269G>A | G757S 2D AIThe SynGAP1 missense variant G757S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess pathogenicity uniformly predict a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool in the dataset predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the collective predictions strongly suggest that the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | -1.492 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 0.47 | Neutral | 0.007 | Benign | 0.008 | Benign | 2.73 | Benign | 0.29 | Tolerated | 0.2595 | 0.3877 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2269G>C | G757R 2D AIThe SynGAP1 missense variant G757R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports likely benign; Foldetta results are unavailable. Based on the collective 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 | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | -2.254 | Likely Benign | 0.534 | Ambiguous | Likely Benign | 0.158 | Likely Benign | -0.04 | Neutral | 0.801 | Possibly Damaging | 0.494 | Possibly Damaging | 2.79 | Benign | 0.05 | Affected | 0.0903 | 0.3481 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2269G>T | G757C 2D AIThe SynGAP1 missense variant G757C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | -6.652 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.179 | Likely Benign | -1.74 | Neutral | 0.997 | Probably Damaging | 0.870 | Possibly Damaging | 2.65 | Benign | 0.04 | Affected | 0.1302 | 0.3630 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.2270G>A | G757D 2D AIThe SynGAP1 missense variant G757D is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Only polyPhen‑2 HumDiv flags it as pathogenic, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, 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. Taken together, the preponderance of evidence supports a benign interpretation, and this assessment does not contradict any ClinVar annotation (none is present). Therefore, the variant is most likely benign, with no conflict with ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | -4.613 | Likely Benign | 0.387 | Ambiguous | Likely Benign | 0.150 | Likely Benign | -0.90 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.71 | Benign | 0.11 | Tolerated | 0.1826 | 0.1611 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2270G>C | G757A 2D AIThe SynGAP1 missense change G757A is catalogued in ClinVar (ID 3635272.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction algorithms uniformly classify the variant as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool in the dataset predicts pathogenicity. High‑accuracy consensus methods corroborate this view: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect, and AlphaMissense‑Optimized also predicts benign. The Foldetta stability assessment is unavailable for this variant. Taken together, the evidence overwhelmingly supports a benign interpretation, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | Uncertain | 1 | -2.626 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.45 | Neutral | 0.267 | Benign | 0.127 | Benign | 2.73 | Benign | 0.35 | Tolerated | 0.3690 | 0.3842 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2270G>T | G757V 2D AIThe SynGAP1 missense variant G757V 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‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | -4.840 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.087 | Likely Benign | -1.47 | Neutral | 0.801 | Possibly Damaging | 0.494 | Possibly Damaging | 2.68 | Benign | 0.07 | Tolerated | 0.1089 | 0.3512 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2308C>A | Q770K 2D  AIThe SynGAP1 missense variant Q770K 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, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -4.768 | Likely Benign | 0.367 | Ambiguous | Likely Benign | 0.106 | Likely Benign | -0.72 | Neutral | 0.002 | Benign | 0.003 | Benign | 4.20 | Benign | 0.14 | Tolerated | 0.1984 | 0.4737 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2308C>G | Q770E 2D  AIThe SynGAP1 missense variant Q770E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also 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 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 | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -4.782 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -0.82 | Neutral | 0.002 | Benign | 0.003 | Benign | 4.19 | Benign | 0.04 | Affected | 0.1465 | 0.2833 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2309A>C | Q770P 2D  AIThe SynGAP1 missense variant Q770P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for Q770P, 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 | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -3.948 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -1.00 | Neutral | 0.748 | Possibly Damaging | 0.170 | Benign | 4.10 | Benign | 0.02 | Affected | 0.2435 | 0.5717 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2309A>G | Q770R 2D  AIThe SynGAP1 missense variant Q770R is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default 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 further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable. Overall, the collective evidence strongly suggests that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -3.873 | Likely Benign | 0.344 | Ambiguous | Likely Benign | 0.175 | Likely Benign | -1.38 | Neutral | 0.194 | Benign | 0.071 | Benign | 4.14 | Benign | 0.07 | Tolerated | 0.1610 | 0.2580 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2309A>T | Q770L 2D  AIThe SynGAP1 missense variant Q770L is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is 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 Q770L, 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 | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -5.524 | Likely Benign | 0.521 | Ambiguous | Likely Benign | 0.197 | Likely Benign | -2.17 | Neutral | 0.095 | Benign | 0.030 | Benign | 4.14 | Benign | 0.01 | Affected | 0.0776 | 0.6230 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2310G>C | Q770H 2D  AIThe SynGAP1 missense variant Q770H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for Q770H. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -4.241 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.27 | Neutral | 0.962 | Probably Damaging | 0.515 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 0.1579 | 0.4344 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2310G>T | Q770H 2D AIThe SynGAP1 missense variant Q770H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -4.241 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.27 | Neutral | 0.962 | Probably Damaging | 0.515 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 0.1579 | 0.4344 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2311T>A | S771T 2D AIThe SynGAP1 missense variant S771T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also 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 the majority of tools and the high‑accuracy predictions point to a benign impact. This conclusion is consistent with the lack of ClinVar evidence and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -4.765 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -1.38 | Neutral | 0.649 | Possibly Damaging | 0.433 | Benign | 4.07 | Benign | 0.23 | Tolerated | 0.1497 | 0.6310 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2311T>C | S771P 2D AIThe SynGAP1 missense variant S771P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -5.045 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.180 | Likely Benign | -1.32 | Neutral | 0.901 | Possibly Damaging | 0.692 | Possibly Damaging | 4.03 | Benign | 0.19 | Tolerated | 0.2194 | 0.5515 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2311T>G | S771A 2D AIThe SynGAP1 missense variant S771A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -4.337 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -1.09 | Neutral | 0.025 | Benign | 0.014 | Benign | 4.09 | Benign | 0.62 | Tolerated | 0.5201 | 0.4745 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2312C>A | S771Y 2D AIThe SynGAP1 missense variant S771Y 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools, ESM1b and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it contains two benign and two uncertain calls, and Foldetta data are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -7.041 | In-Between | 0.397 | Ambiguous | Likely Benign | 0.176 | Likely Benign | -2.13 | Neutral | 0.990 | Probably Damaging | 0.892 | Possibly Damaging | 4.02 | Benign | 0.05 | Affected | 0.0707 | 0.5155 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2312C>G | S771C 2D AIThe SynGAP1 missense variant S771C 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, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta 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 | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -8.014 | Likely Pathogenic | 0.167 | Likely Benign | Likely Benign | 0.177 | Likely Benign | -1.99 | Neutral | 0.990 | Probably Damaging | 0.917 | Probably Damaging | 4.01 | Benign | 0.07 | Tolerated | 0.1022 | 0.5899 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2312C>T | S771F 2D AIThe SynGAP1 missense variant S771F 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, polyPhen‑2 HumVar, and SIFT. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is uncertain, and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not conflict with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -7.988 | In-Between | 0.525 | Ambiguous | Likely Benign | 0.189 | Likely Benign | -2.29 | Neutral | 0.990 | Probably Damaging | 0.892 | Possibly Damaging | 4.02 | Benign | 0.04 | Affected | 0.0624 | 0.5428 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.43G>A | A15T 2D AIThe SynGAP1 missense variant A15T is listed in ClinVar (ID 1925632.0) with an “Uncertain” clinical significance and is present in gnomAD (6‑33420307‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as “Likely Benign”; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.466055 | Uncertain | 0.330 | 0.912 | 0.375 | Uncertain | 1 | 6-33420307-G-A | 4 | 2.60e-6 | -3.720 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -0.08 | Neutral | 0.602 | Possibly Damaging | 0.017 | Benign | 4.16 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2053 | 0.7423 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||
| c.43G>C | A15P 2D AIThe SynGAP1 missense variant A15P is listed in ClinVar (ID 3688743.0) with an *Uncertain* clinical significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as *Likely Benign*. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.466055 | Uncertain | 0.330 | 0.912 | 0.375 | Uncertain | 1 | -3.436 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -0.23 | Neutral | 0.880 | Possibly Damaging | 0.123 | Benign | 4.09 | Benign | 0.00 | Affected | 0.2573 | 0.6988 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||
| c.43G>T | A15S 2D AIThe SynGAP1 missense variant A15S is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33420307‑G‑T). 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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign status. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for A15S, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.466055 | Uncertain | 0.330 | 0.912 | 0.375 | 6-33420307-G-T | -2.925 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.074 | Likely Benign | 0.11 | Neutral | 0.122 | Benign | 0.010 | Benign | 4.17 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3115 | 0.5830 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.44C>A | A15E 2D AIThe SynGAP1 missense variant A15E is reported in gnomAD (ID 6‑33420308‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.466055 | Uncertain | 0.330 | 0.912 | 0.375 | 6-33420308-C-A | -3.423 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.169 | Likely Benign | 0.46 | Neutral | 0.406 | Benign | 0.040 | Benign | 4.13 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1563 | 0.1908 | -1 | 0 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.44C>G | A15G 2D AIThe SynGAP1 missense variant A15G is reported in gnomAD (ID 6‑33420308‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also reports likely benign; Foldetta results are not available. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.466055 | Uncertain | 0.330 | 0.912 | 0.375 | 6-33420308-C-G | 3 | 1.95e-6 | -3.261 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -0.04 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.12 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2753 | 0.5196 | 0 | 1 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.44C>T | A15V 2D AIThe SynGAP1 missense variant A15V is listed in ClinVar (ID 1801174.0) with an “Uncertain” status and is present in gnomAD (6‑33420308‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while polyPhen‑2 HumDiv and SIFT predict 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 show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this does not contradict the ClinVar designation, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.466055 | Uncertain | 0.330 | 0.912 | 0.375 | Uncertain | 1 | 6-33420308-C-T | 1 | 6.49e-7 | -3.560 | Likely Benign | 0.161 | Likely Benign | Likely Benign | 0.105 | Likely Benign | 0.20 | Neutral | 0.602 | Possibly Damaging | 0.015 | Benign | 4.19 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1809 | 0.7669 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||
| c.46A>C | M16L 2D AIThe SynGAP1 missense variant M16L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.440853 | Structured | 0.459925 | Uncertain | 0.346 | 0.908 | 0.375 | -1.277 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.33 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.37 | Benign | 0.00 | Affected | 0.1805 | 0.4629 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.46A>G | M16V 2D AIThe SynGAP1 missense variant M16V is reported in gnomAD (ID 6‑33420310‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant 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 status. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for M16V, and this conclusion does not contradict any ClinVar classification, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.440853 | Structured | 0.459925 | Uncertain | 0.346 | 0.908 | 0.375 | 6-33420310-A-G | 16 | 1.05e-5 | -1.595 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.073 | Likely Benign | -0.07 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.30 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3561 | 0.3937 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||
| c.46A>T | M16L 2D AIThe SynGAP1 missense variant M16L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points 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 | 0.440853 | Structured | 0.459925 | Uncertain | 0.346 | 0.908 | 0.375 | -1.277 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.33 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.37 | Benign | 0.00 | Affected | 0.1805 | 0.4629 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.47T>A | M16K 2D AIThe SynGAP1 missense variant M16K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, 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 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 majority of computational predictions and the high‑accuracy consensus suggest that M16K is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.440853 | Structured | 0.459925 | Uncertain | 0.346 | 0.908 | 0.375 | -2.567 | Likely Benign | 0.635 | Likely Pathogenic | Likely Benign | 0.185 | Likely Benign | -0.37 | Neutral | 0.003 | Benign | 0.001 | Benign | 4.23 | Benign | 0.00 | Affected | 0.1984 | 0.1112 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.47T>C | M16T 2D AIThe SynGAP1 missense variant M16T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign and the SGM‑Consensus classifies it as likely benign. No Foldetta stability analysis is available for this residue, so folding‑stability evidence is lacking. Overall, the majority of computational evidence indicates that M16T 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 | 0.440853 | Structured | 0.459925 | Uncertain | 0.346 | 0.908 | 0.375 | -2.060 | Likely Benign | 0.515 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -0.46 | Neutral | 0.006 | Benign | 0.001 | Benign | 4.23 | Benign | 0.00 | Affected | 0.2385 | 0.2545 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.47T>G | M16R 2D AIThe SynGAP1 missense variant M16R 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, the SGM‑Consensus also indicates likely benign, and no Foldetta stability data are available. Taken together, the preponderance of evidence supports a benign classification for M16R, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.440853 | Structured | 0.459925 | Uncertain | 0.346 | 0.908 | 0.375 | -1.475 | Likely Benign | 0.485 | Ambiguous | Likely Benign | 0.191 | Likely Benign | -0.25 | Neutral | 0.014 | Benign | 0.003 | Benign | 4.21 | Benign | 0.00 | Affected | 0.1992 | 0.1093 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.48G>A | M16I 2D AIThe SynGAP1 missense variant M16I is listed in ClinVar with an “Uncertain” status (ClinVar ID 1424213.0) and is present in gnomAD (6‑33420312‑G‑A). 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, 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, and this is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.440853 | Structured | 0.459925 | Uncertain | 0.346 | 0.908 | 0.375 | Uncertain | 1 | 6-33420312-G-A | 1 | 6.49e-7 | -2.198 | Likely Benign | 0.722 | Likely Pathogenic | Likely Benign | 0.057 | Likely Benign | -0.15 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.28 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1606 | 0.3877 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||
| c.48G>C | M16I 2D AIThe SynGAP1 missense variant M16I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, 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 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 majority of computational predictions and the high‑accuracy consensus suggest that M16I is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.440853 | Structured | 0.459925 | Uncertain | 0.346 | 0.908 | 0.375 | -2.198 | Likely Benign | 0.722 | Likely Pathogenic | Likely Benign | 0.057 | Likely Benign | -0.15 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.28 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1606 | 0.3877 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.48G>T | M16I 2D AIThe SynGAP1 missense variant M16I is not reported in ClinVar (ClinVar ID = None) but is present in gnomAD (ID = 6‑33420312‑G‑T). 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 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 majority of computational evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.440853 | Structured | 0.459925 | Uncertain | 0.346 | 0.908 | 0.375 | 6-33420312-G-T | -2.198 | Likely Benign | 0.722 | Likely Pathogenic | Likely Benign | 0.057 | Likely Benign | -0.15 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.28 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1606 | 0.3877 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||
| c.1111A>C | S371R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change S371R is catalogued in gnomAD (ID 6‑33438016‑A‑C) but has no ClinVar entry. Functional prediction programs largely agree on a benign effect: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus score (Likely Benign) all report a non‑pathogenic outcome. Only AlphaMissense‑Default predicts a pathogenic effect, while FoldX and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) is benign. Taken together, the majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | 6-33438016-A-C | -6.415 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.51 | Ambiguous | 1.2 | -0.25 | Likely Benign | 0.13 | Likely Benign | 0.57 | Ambiguous | 0.295 | Likely Benign | -1.17 | Neutral | 0.396 | Benign | 0.099 | Benign | 5.35 | Benign | 0.26 | Tolerated | 3.52 | 18 | 0.1362 | 0.4131 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||
| c.1111A>G | S371G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371G is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined—REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized—classifies the substitution as benign. No pathogenic predictions are present. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -2.073 | Likely Benign | 0.053 | Likely Benign | Likely Benign | 0.47 | Likely Benign | 0.3 | 0.49 | Likely Benign | 0.48 | Likely Benign | 0.35 | Likely Benign | 0.164 | Likely Benign | -1.32 | Neutral | 0.213 | Benign | 0.067 | Benign | 4.63 | Benign | 0.17 | Tolerated | 0.3192 | 0.5295 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.1111A>T | S371C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall consensus of the majority of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -6.330 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.19 | Likely Benign | 0.2 | -0.34 | Likely Benign | -0.08 | Likely Benign | 0.23 | Likely Benign | 0.450 | Likely Benign | -1.41 | Neutral | 0.875 | Possibly Damaging | 0.359 | Benign | 4.61 | Benign | 0.02 | Affected | 0.1786 | 0.6580 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.1112G>A | S371N 2D AIThe SynGAP1 missense variant S371N is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta remains uncertain. High‑accuracy assessments are consistent: AlphaMissense‑Optimized classifies the variant as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -5.950 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.8 | -0.59 | Ambiguous | -0.19 | Likely Benign | 0.25 | Likely Benign | 0.208 | Likely Benign | -0.31 | Neutral | 0.666 | Possibly Damaging | 0.067 | Benign | 4.64 | Benign | 0.27 | Tolerated | 0.2068 | 0.5100 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||
| c.1112G>C | S371T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371T is not reported in ClinVar and is absent from gnomAD. All available in silico predictors classify the substitution as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -4.512 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.38 | Likely Benign | 0.1 | -0.27 | Likely Benign | 0.06 | Likely Benign | 0.05 | Likely Benign | 0.173 | Likely Benign | -0.65 | Neutral | 0.213 | Benign | 0.067 | Benign | 4.64 | Benign | 0.22 | Tolerated | 0.2245 | 0.6462 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1112G>T | S371I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX and Rosetta, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a benign effect. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -6.888 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.4 | -0.50 | Ambiguous | 0.00 | Likely Benign | -0.11 | Likely Benign | 0.433 | Likely Benign | -1.06 | Neutral | 0.028 | Benign | 0.016 | Benign | 4.62 | Benign | 0.07 | Tolerated | 0.1423 | 0.5924 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.1113T>A | S371R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the substitution as benign, while AlphaMissense‑Optimized also predicts benign. Only AlphaMissense‑Default indicates a pathogenic outcome; FoldX and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the majority of evidence supports a benign impact, and this is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -6.415 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.51 | Ambiguous | 1.2 | -0.25 | Likely Benign | 0.13 | Likely Benign | 0.57 | Ambiguous | 0.344 | Likely Benign | -1.17 | Neutral | 0.396 | Benign | 0.099 | Benign | 5.35 | Benign | 0.26 | Tolerated | 3.52 | 18 | 0.1362 | 0.4131 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||
| c.1113T>G | S371R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371R is reported in gnomAD (variant ID 6‑33438018‑T‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM‑Consensus is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No prediction or stability result is missing or inconclusive. Overall, the evidence strongly favors a benign classification, and this is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | 6-33438018-T-G | 1 | 1.18e-6 | -6.415 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.51 | Ambiguous | 1.2 | -0.25 | Likely Benign | 0.13 | Likely Benign | 0.57 | Ambiguous | 0.340 | Likely Benign | -1.17 | Neutral | 0.396 | Benign | 0.099 | Benign | 5.35 | Benign | 0.26 | Tolerated | 3.52 | 18 | 0.1362 | 0.4131 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||
| c.2323C>G | R775G 2D AIThe SynGAP1 missense variant R775G 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. 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 R775G, 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 | 0.444081 | Structured | 0.895337 | Binding | 0.320 | 0.896 | 0.250 | -4.186 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.118 | Likely Benign | -1.23 | Neutral | 0.933 | Possibly Damaging | 0.871 | Possibly Damaging | 4.12 | Benign | 0.07 | Tolerated | 0.3194 | 0.3761 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2324G>A | R775Q 2D AIThe SynGAP1 missense variant R775Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33442482‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from the same set of high‑confidence predictors) is “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, 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 | 0.444081 | Structured | 0.895337 | Binding | 0.320 | 0.896 | 0.250 | Conflicting | 3 | 6-33442482-G-A | 11 | 1.41e-5 | -4.476 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.63 | Neutral | 0.969 | Probably Damaging | 0.863 | Possibly Damaging | 4.17 | Benign | 0.16 | Tolerated | 3.64 | 6 | 0.2844 | 0.2863 | 1 | 1 | 1.0 | -28.06 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.2324G>C | R775P 2D AIThe SynGAP1 missense variant R775P is listed in ClinVar (ID 2959355) as Benign and is not reported in gnomAD. Functional 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). Two tools (polyPhen‑2 HumDiv and HumVar) predict a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus also indicating a likely benign status, and Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, which is consistent with the ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.444081 | Structured | 0.895337 | Binding | 0.320 | 0.896 | 0.250 | Benign | 2 | -5.072 | Likely Benign | 0.452 | Ambiguous | Likely Benign | 0.168 | Likely Benign | -0.79 | Neutral | 0.971 | Probably Damaging | 0.944 | Probably Damaging | 4.13 | Benign | 0.07 | Tolerated | 3.64 | 6 | 0.1891 | 0.4834 | -2 | 0 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.2324G>T | R775L 2D AIThe SynGAP1 missense variant R775L (ClinVar ID 4327035) is present in gnomAD (ID 6‑33442482‑G‑T). Prediction tools that agree on benign include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those predicting pathogenic are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 results are unavailable. Overall, the consensus of computational evidence points to a benign effect, consistent with the ClinVar annotation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.444081 | Structured | 0.895337 | Binding | 0.320 | 0.896 | 0.250 | 1 | 6-33442482-G-T | -5.951 | Likely Benign | 0.598 | Likely Pathogenic | Likely Benign | 0.124 | Likely Benign | -1.86 | Neutral | 0.933 | Possibly Damaging | 0.871 | Possibly Damaging | 4.13 | Benign | 0.06 | Tolerated | 3.64 | 6 | 0.1665 | 0.5089 | -2 | -3 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.31G>A | G11R 2D AIThe SynGAP1 missense variant G11R is catalogued in gnomAD (ID 6‑33420295‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.444081 | Structured | 0.501027 | Binding | 0.348 | 0.915 | 0.375 | 6-33420295-G-A | -3.418 | Likely Benign | 0.428 | Ambiguous | Likely Benign | 0.102 | Likely Benign | -0.47 | Neutral | 0.498 | Possibly Damaging | 0.026 | Benign | 3.92 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1022 | 0.4596 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.31G>C | G11R 2D AIThe SynGAP1 missense variant G11R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective predictions, 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 | 0.444081 | Structured | 0.501027 | Binding | 0.348 | 0.915 | 0.375 | -3.418 | Likely Benign | 0.428 | Ambiguous | Likely Benign | 0.109 | Likely Benign | -0.47 | Neutral | 0.498 | Possibly Damaging | 0.026 | Benign | 3.92 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1022 | 0.4596 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.31G>T | G11W 2D AIThe SynGAP1 missense variant G11W is catalogued in gnomAD (ID 6‑33420295‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.444081 | Structured | 0.501027 | Binding | 0.348 | 0.915 | 0.375 | 6-33420295-G-T | -5.819 | Likely Benign | 0.403 | Ambiguous | Likely Benign | 0.096 | Likely Benign | -0.67 | Neutral | 0.959 | Probably Damaging | 0.318 | Benign | 3.87 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0747 | 0.4731 | -2 | -7 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||
| c.32G>A | G11E 2D AIThe SynGAP1 missense variant G11E is reported in gnomAD (variant ID 6-33420296‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus itself is likely benign. Foldetta results are not available, so they do not influence the assessment. Overall, the preponderance of evidence points to a benign variant, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.444081 | Structured | 0.501027 | Binding | 0.348 | 0.915 | 0.375 | 6-33420296-G-A | 5 | 3.24e-6 | -4.206 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.109 | Likely Benign | 0.09 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.95 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1444 | 0.4628 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.32G>C | G11A 2D AIThe SynGAP1 missense variant G11A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points 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 | 0.444081 | Structured | 0.501027 | Binding | 0.348 | 0.915 | 0.375 | -3.611 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.28 | Neutral | 0.105 | Benign | 0.007 | Benign | 4.00 | Benign | 0.00 | Affected | 0.4045 | 0.5440 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.32G>T | G11V 2D AIThe SynGAP1 missense variant G11V is reported in gnomAD (variant ID 6‑33420296‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates that G11V is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.444081 | Structured | 0.501027 | Binding | 0.348 | 0.915 | 0.375 | 6-33420296-G-T | -4.079 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -0.38 | Neutral | 0.668 | Possibly Damaging | 0.049 | Benign | 3.93 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1292 | 0.4522 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||
| c.592C>A | L198I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198I is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain or inconclusive results come from AlphaMissense‑Default, FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -10.411 | Likely Pathogenic | 0.563 | Ambiguous | Likely Benign | 0.59 | Ambiguous | 0.1 | 0.70 | Ambiguous | 0.65 | Ambiguous | 0.10 | Likely Benign | 0.234 | Likely Benign | -1.72 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 3.43 | Benign | 0.00 | Affected | 0.0921 | 0.3307 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||
| c.592C>G | L198V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L198V variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (3 pathogenic vs. 1 benign) indicates pathogenicity; Foldetta remains uncertain. Overall, the majority of evaluated tools predict a pathogenic impact, and this is not contradicted by any ClinVar annotation (none exists). Thus, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -9.343 | Likely Pathogenic | 0.747 | Likely Pathogenic | Likely Benign | 1.10 | Ambiguous | 0.2 | 1.24 | Ambiguous | 1.17 | Ambiguous | 0.34 | Likely Benign | 0.265 | Likely Benign | -2.54 | Deleterious | 0.990 | Probably Damaging | 0.675 | Possibly Damaging | 3.44 | Benign | 0.00 | Affected | 0.1520 | 0.3017 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.592C>T | L198F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198F has no ClinVar entry and is absent from gnomAD. Functional prediction tools split into two consensus groups: benign predictions come from REVEL, Rosetta, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments are mixed: AlphaMissense‑Optimized and Foldetta report uncertain results, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect. No evidence from ClinVar contradicts these findings. Overall, the preponderance of pathogenic predictions and the SGM‑Consensus designation suggest that the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -10.602 | Likely Pathogenic | 0.930 | Likely Pathogenic | Ambiguous | 1.03 | Ambiguous | 0.2 | 0.27 | Likely Benign | 0.65 | Ambiguous | 0.00 | Likely Benign | 0.282 | Likely Benign | -3.33 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 3.39 | Benign | 0.00 | Affected | 0.0586 | 0.3112 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||
| c.593T>A | L198H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for L198H. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -15.650 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.09 | Ambiguous | 0.2 | 1.04 | Ambiguous | 1.07 | Ambiguous | 0.74 | Ambiguous | 0.419 | Likely Benign | -5.91 | Deleterious | 0.999 | Probably Damaging | 0.936 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 0.1057 | 0.0519 | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||
| c.593T>C | L198P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198P has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a deleterious effect. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -12.250 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.55 | Ambiguous | 0.3 | 0.40 | Likely Benign | 0.98 | Ambiguous | 0.65 | Ambiguous | 0.491 | Likely Benign | -5.87 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 0.3882 | 0.1582 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||
| c.593T>G | L198R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from multiple in‑silico predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -15.992 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.74 | Ambiguous | 0.2 | 1.56 | Ambiguous | 1.15 | Ambiguous | 0.69 | Ambiguous | 0.410 | Likely Benign | -4.98 | Deleterious | 0.982 | Probably Damaging | 0.648 | Possibly Damaging | 3.34 | Benign | 0.00 | Affected | 0.1180 | 0.0719 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||
| c.886T>A | S296T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S296T missense variant is not reported in ClinVar and is absent from gnomAD. Consensus from most in silico predictors shows a split: six tools (REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT) and AlphaMissense‑Optimized predict a benign effect, whereas four tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default) predict pathogenicity. ESM1b remains uncertain. High‑accuracy assessments give a more definitive picture: AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -7.020 | In-Between | 0.645 | Likely Pathogenic | Likely Benign | 0.09 | Likely Benign | 0.4 | 0.38 | Likely Benign | 0.24 | Likely Benign | 0.19 | Likely Benign | 0.201 | Likely Benign | -2.10 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.13 | Pathogenic | 0.13 | Tolerated | 0.1437 | 0.6340 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.886T>C | S296P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, and SIFT, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. When predictions are grouped by agreement, four tools predict benign and seven predict pathogenic, with premPS remaining uncertain. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. Thus, the majority of evidence leans toward pathogenicity, and this conclusion is consistent with the lack of ClinVar annotation and gnomAD absence, which do not contradict the prediction. Overall, the variant is most likely pathogenic based on the current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -8.302 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.04 | Likely Benign | 0.4 | 0.18 | Likely Benign | 0.11 | Likely Benign | 0.72 | Ambiguous | 0.439 | Likely Benign | -3.74 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.92 | Pathogenic | 0.12 | Tolerated | 0.2273 | 0.6320 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.886T>G | S296A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296A (ClinVar ID 469166.0) is listed as ClinVar status Uncertain and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign or neutral. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict pathogenic. Grouping by consensus, the benign‑predicting tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a benign effect. No evidence from the available tools suggests a deleterious impact. Therefore, the variant is most likely benign, and this conclusion is consistent with its ClinVar status of Uncertain rather than pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | Uncertain | 1 | -6.847 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.3 | -0.26 | Likely Benign | 0.12 | Likely Benign | 0.35 | Likely Benign | 0.209 | Likely Benign | -1.79 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.97 | Pathogenic | 0.65 | Tolerated | 3.40 | 16 | 0.4958 | 0.5522 | 1 | 1 | 2.6 | -16.00 | 182.5 | 26.6 | -0.2 | 0.1 | -0.5 | 0.0 | X | Potentially Pathogenic | The hydroxyl group of the Ser296 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), stably hydrogen bonds with the carboxylate group of Asp330 in a neighboring β strand (res. Ala322-Asp332). The backbone carbonyl group of Ser296 also hydrogen bonds with the guanidinium group of Arg279 in another nearby β strand (res. Arg279-Cys285). In the variant simulations, the methyl group of the Ala296 side chain cannot hydrogen bond with Asp330, causing the carboxylate group positioning to fluctuate more than in the WT simulations.Although the residue swap does not seem to affect the anti-parallel β sheet assembly during the simulations, it is possible that the Ser296-Asp330 hydrogen bond plays a crucial role in maintaining the C2 domain fold. Notably, because Ser296 is located near the membrane interface, the potential effect of the residue swap on the SynGAP-membrane association cannot be addressed by solvent-only simulations. | ||||||||||||||||
| c.887C>A | S296Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and premPS, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. The variant is most likely pathogenic based on predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -12.148 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.46 | Ambiguous | 0.2 | 0.48 | Likely Benign | 0.97 | Ambiguous | 0.15 | Likely Benign | 0.486 | Likely Benign | -4.34 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.93 | Pathogenic | 0.05 | Affected | 0.0800 | 0.5610 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.887C>G | S296C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as benign. No predictions or stability results are missing or inconclusive. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -7.842 | In-Between | 0.286 | Likely Benign | Likely Benign | 0.46 | Likely Benign | 0.1 | -0.11 | Likely Benign | 0.18 | Likely Benign | 0.09 | Likely Benign | 0.361 | Likely Benign | -1.46 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.91 | Pathogenic | 0.05 | Affected | 0.1052 | 0.6052 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.887C>T | S296F 2D AIThe SynGAP1 missense variant S296F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, and premPS. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive and therefore unavailable as evidence. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -11.721 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.29 | Ambiguous | 1.6 | 0.24 | Likely Benign | 0.77 | Ambiguous | 0.29 | Likely Benign | 0.494 | Likely Benign | -4.34 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.94 | Pathogenic | 0.04 | Affected | 0.0720 | 0.5905 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.1015A>C | K339Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evaluated tools (8 pathogenic vs. 4 benign) indicate a pathogenic effect. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -10.952 | Likely Pathogenic | 0.863 | Likely Pathogenic | Ambiguous | 0.06 | Likely Benign | 0.0 | -0.50 | Ambiguous | -0.22 | Likely Benign | -0.02 | Likely Benign | 0.458 | Likely Benign | -3.06 | Deleterious | 0.982 | Probably Damaging | 0.824 | Possibly Damaging | 1.90 | Pathogenic | 0.04 | Affected | 0.4041 | 0.1012 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1015A>G | K339E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and premPS. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -14.284 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.13 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.05 | Likely Benign | 0.40 | Likely Benign | 0.482 | Likely Benign | -3.00 | Deleterious | 0.939 | Possibly Damaging | 0.670 | Possibly Damaging | 1.92 | Pathogenic | 0.03 | Affected | 0.3421 | 0.0882 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1016A>C | K339T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339T missense variant is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools are split: benign calls come from FoldX, Rosetta, Foldetta, premPS, and SIFT, whereas pathogenic calls are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further highlight this discordance: the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect, whereas Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. AlphaMissense‑Optimized returned an uncertain result and is treated as unavailable. Overall, the majority of robust predictors lean toward pathogenicity, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -10.061 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.32 | Likely Benign | 0.0 | 0.10 | Likely Benign | 0.21 | Likely Benign | -0.04 | Likely Benign | 0.512 | Likely Pathogenic | -4.73 | Deleterious | 0.991 | Probably Damaging | 0.795 | Possibly Damaging | 1.94 | Pathogenic | 0.10 | Tolerated | 0.1900 | 0.3020 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1016A>G | K339R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K339R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. No predictions or stability results are missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -5.773 | Likely Benign | 0.120 | Likely Benign | Likely Benign | -0.15 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.16 | Likely Benign | 0.08 | Likely Benign | 0.134 | Likely Benign | -2.05 | Neutral | 0.046 | Benign | 0.040 | Benign | 1.94 | Pathogenic | 0.48 | Tolerated | 0.4197 | 0.0976 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.1016A>T | K339M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339M missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX and premPS, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results are Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for K339M. This conclusion is not contradicted by ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -13.387 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.23 | Likely Benign | 0.0 | 0.88 | Ambiguous | 0.56 | Ambiguous | -0.37 | Likely Benign | 0.575 | Likely Pathogenic | -4.95 | Deleterious | 0.999 | Probably Damaging | 0.964 | Probably Damaging | 1.92 | Pathogenic | 0.01 | Affected | 0.0967 | 0.3541 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1017G>C | K339N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and premPS. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of evidence points to a pathogenic impact for K339N, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -11.117 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.20 | Likely Benign | 0.0 | 0.35 | Likely Benign | 0.28 | Likely Benign | 0.00 | Likely Benign | 0.410 | Likely Benign | -3.88 | Deleterious | 0.991 | Probably Damaging | 0.864 | Possibly Damaging | 1.91 | Pathogenic | 0.02 | Affected | 0.3224 | 0.1158 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1017G>T | K339N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K339N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and premPS. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta stability outputs) predicts a benign effect. Overall, the majority of evidence points toward a pathogenic impact for K339N, and this conclusion does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -11.117 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.20 | Likely Benign | 0.0 | 0.35 | Likely Benign | 0.28 | Likely Benign | 0.00 | Likely Benign | 0.410 | Likely Benign | -3.88 | Deleterious | 0.991 | Probably Damaging | 0.864 | Possibly Damaging | 1.91 | Pathogenic | 0.02 | Affected | 0.3224 | 0.1158 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.400A>C | S134R 2D AIThe SynGAP1 missense variant S134R 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | -9.053 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.292 | Likely Benign | -2.54 | Deleterious | 0.380 | Benign | 0.147 | Benign | 3.84 | Benign | 0.00 | Affected | 0.0719 | 0.3528 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.400A>G | S134G 2D AIThe SynGAP1 missense variant S134G 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 high‑accuracy consensus (SGM‑Consensus) is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yielding a “Likely Benign” classification. AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple independent predictors and the high‑accuracy consensus indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | -6.722 | Likely Benign | 0.457 | Ambiguous | Likely Benign | 0.120 | Likely Benign | -2.19 | Neutral | 0.034 | Benign | 0.035 | Benign | 3.84 | Benign | 0.00 | Affected | 0.2268 | 0.4008 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.400A>T | S134C 2D AIThe SynGAP1 missense variant S134C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen2_HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, 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, while the SGM‑Consensus remains pathogenic; Foldetta results are unavailable. Overall, the majority of tools and the consensus prediction lean toward pathogenicity, which is not contradicted by ClinVar (no entry) but is opposed by the AlphaMissense‑Optimized benign call. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | -9.184 | Likely Pathogenic | 0.774 | Likely Pathogenic | Likely Benign | 0.247 | Likely Benign | -3.12 | Deleterious | 0.876 | Possibly Damaging | 0.417 | Benign | 3.79 | Benign | 0.00 | Affected | 0.0767 | 0.5151 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.401G>A | S134N 2D AIThe SynGAP1 missense variant S134N is listed in ClinVar with an “Uncertain” status (ClinVar ID 2819575.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Those that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The remaining tools—AlphaMissense‑Optimized and the SGM‑Consensus—are inconclusive; the consensus score is “Likely Benign” based on a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the balance of evidence points to a benign impact, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | Uncertain | 1 | -5.534 | Likely Benign | 0.813 | Likely Pathogenic | Ambiguous | 0.075 | Likely Benign | -1.62 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.90 | Benign | 0.00 | Affected | 3.61 | 5 | 0.0964 | 0.4381 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||
| c.401G>C | S134T 2D AIThe SynGAP1 missense variant S134T is listed in gnomAD (ID 6‑33432698‑G‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors 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 points to a benign impact; this conclusion is not contradicted by ClinVar, which contains no classification for S134T. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | 6-33432698-G-C | 1 | 6.32e-7 | -5.187 | Likely Benign | 0.563 | Ambiguous | Likely Benign | 0.069 | Likely Benign | -1.76 | Neutral | 0.034 | Benign | 0.047 | Benign | 3.85 | Benign | 0.00 | Affected | 3.61 | 5 | 0.1083 | 0.5326 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.401G>T | S134I 2D AIThe SynGAP1 missense variant S134I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | -8.860 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.230 | Likely Benign | -3.27 | Deleterious | 0.041 | Benign | 0.031 | Benign | 3.81 | Benign | 0.00 | Affected | 0.0683 | 0.5191 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.402C>A | S134R 2D AIThe SynGAP1 missense variant S134R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict pathogenicity are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized also predicts Pathogenic, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | -9.053 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.146 | Likely Benign | -2.54 | Deleterious | 0.380 | Benign | 0.147 | Benign | 3.84 | Benign | 0.00 | Affected | 0.0719 | 0.3528 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.402C>G | S134R 2D AIThe SynGAP1 missense variant S134R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict pathogenicity are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized also predicts Pathogenic, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | -9.053 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.146 | Likely Benign | -2.54 | Deleterious | 0.380 | Benign | 0.147 | Benign | 3.84 | Benign | 0.00 | Affected | 0.0719 | 0.3528 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.748G>A | V250I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V250I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in silico predictors classify the change as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The high‑accuracy tools likewise predict a benign effect: AlphaMissense‑Optimized is benign, the SGM Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -6.696 | Likely Benign | 0.085 | Likely Benign | Likely Benign | -0.44 | Likely Benign | 0.1 | -0.01 | Likely Benign | -0.23 | Likely Benign | 0.35 | Likely Benign | 0.362 | Likely Benign | -0.79 | Neutral | 0.384 | Benign | 0.070 | Benign | 6.09 | Benign | 0.13 | Tolerated | 0.0571 | 0.3644 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||
| c.748G>C | V250L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250L variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict pathogenicity are REVEL, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—Foldetta and premPS—are noted as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is ambiguous (two pathogenic vs. two benign votes), and Foldetta remains uncertain. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -11.649 | Likely Pathogenic | 0.587 | Likely Pathogenic | Likely Benign | -0.23 | Likely Benign | 0.1 | 2.47 | Destabilizing | 1.12 | Ambiguous | 0.66 | Ambiguous | 0.690 | Likely Pathogenic | -2.47 | Neutral | 0.767 | Possibly Damaging | 0.344 | Benign | 5.81 | Benign | 0.04 | Affected | 0.0698 | 0.4229 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.748G>T | V250L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250L variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict pathogenicity are REVEL, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—Foldetta and premPS—are noted as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is ambiguous (two pathogenic vs. two benign votes), and Foldetta remains uncertain. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -11.649 | Likely Pathogenic | 0.587 | Likely Pathogenic | Likely Benign | -0.23 | Likely Benign | 0.1 | 2.47 | Destabilizing | 1.12 | Ambiguous | 0.66 | Ambiguous | 0.690 | Likely Pathogenic | -2.47 | Neutral | 0.767 | Possibly Damaging | 0.344 | Benign | 5.81 | Benign | 0.04 | Affected | 0.0698 | 0.4229 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.749T>A | V250E 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V250E is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, whereas the remaining 12 tools (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the change as pathogenic. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. No prediction or stability result is inconclusive. Consequently, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -15.723 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 1.85 | Ambiguous | 0.1 | 3.34 | Destabilizing | 2.60 | Destabilizing | 2.01 | Destabilizing | 0.906 | Likely Pathogenic | -5.13 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.74 | Benign | 0.00 | Affected | 0.0787 | 0.1564 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.749T>C | V250A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250A missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a pathogenic effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all indicate pathogenicity, whereas ESM1b and FATHMM predict a benign outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) and AlphaMissense‑Optimized return uncertain results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is balanced and therefore unavailable, and Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for V250A, and this assessment does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -6.385 | Likely Benign | 0.852 | Likely Pathogenic | Ambiguous | 0.82 | Ambiguous | 0.1 | 1.22 | Ambiguous | 1.02 | Ambiguous | 1.48 | Destabilizing | 0.818 | Likely Pathogenic | -3.11 | Deleterious | 0.930 | Possibly Damaging | 0.584 | Possibly Damaging | 5.82 | Benign | 0.02 | Affected | 0.2491 | 0.2151 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||
| c.749T>G | V250G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default, while only FATHMM predicts a benign outcome. Uncertain results are reported by FoldX and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, AlphaMissense‑Optimized remains uncertain, and Foldetta is pathogenic. Taken together, the overwhelming majority of evidence indicates a pathogenic effect. This conclusion is consistent with the absence of a ClinVar classification; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -11.255 | Likely Pathogenic | 0.917 | Likely Pathogenic | Ambiguous | 1.65 | Ambiguous | 0.3 | 3.18 | Destabilizing | 2.42 | Destabilizing | 2.08 | Destabilizing | 0.900 | Likely Pathogenic | -5.90 | Deleterious | 0.879 | Possibly Damaging | 0.997 | Probably Damaging | 5.75 | Benign | 0.00 | Affected | 0.1884 | 0.1996 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.751A>C | K251Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar, while premPS and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, the majority of evidence supports a benign classification for K251Q, and this conclusion does not contradict the absence of a ClinVar entry. Based on the aggregate predictions, K251Q is most likely benign, and this is consistent with its absence from ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -5.869 | Likely Benign | 0.362 | Ambiguous | Likely Benign | 0.36 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.39 | Likely Benign | -0.62 | Ambiguous | 0.465 | Likely Benign | 0.55 | Neutral | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.86 | Benign | 0.63 | Tolerated | 0.4466 | 0.1085 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.751A>G | K251E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K251E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, SIFT, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain results. High‑accuracy methods are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, with a small but notable benign signal. Therefore, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -12.812 | Likely Pathogenic | 0.906 | Likely Pathogenic | Ambiguous | 0.88 | Ambiguous | 0.2 | 0.99 | Ambiguous | 0.94 | Ambiguous | 0.40 | Likely Benign | 0.571 | Likely Pathogenic | -0.54 | Neutral | 0.970 | Probably Damaging | 0.584 | Possibly Damaging | 5.80 | Benign | 0.46 | Tolerated | 0.3929 | 0.0860 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||
| c.752A>C | K251T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include premPS, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports a pathogenic prediction, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the balance of evidence favors a pathogenic effect for K251T, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -10.552 | Likely Pathogenic | 0.841 | Likely Pathogenic | Ambiguous | 1.21 | Ambiguous | 0.4 | 0.50 | Ambiguous | 0.86 | Ambiguous | 0.46 | Likely Benign | 0.742 | Likely Pathogenic | -2.72 | Deleterious | 0.970 | Probably Damaging | 0.749 | Possibly Damaging | 5.76 | Benign | 0.28 | Tolerated | 0.2353 | 0.2852 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.752A>G | K251R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Rosetta and Foldetta give uncertain results. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -4.355 | Likely Benign | 0.123 | Likely Benign | Likely Benign | -0.37 | Likely Benign | 0.0 | -0.64 | Ambiguous | -0.51 | Ambiguous | 0.14 | Likely Benign | 0.531 | Likely Pathogenic | -0.61 | Neutral | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 5.92 | Benign | 0.34 | Tolerated | 0.4756 | 0.1049 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.752A>T | K251M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K251M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, premPS, PROVEAN, and FATHMM. Those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a benign effect. Overall, the evidence is evenly split between benign and pathogenic predictions, with the most reliable high‑accuracy tools leaning toward a benign outcome. Thus, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -10.678 | Likely Pathogenic | 0.796 | Likely Pathogenic | Ambiguous | 0.14 | Likely Benign | 0.1 | 0.10 | Likely Benign | 0.12 | Likely Benign | 0.05 | Likely Benign | 0.751 | Likely Pathogenic | -2.36 | Neutral | 0.999 | Probably Damaging | 0.970 | Probably Damaging | 5.73 | Benign | 0.05 | Affected | 0.1271 | 0.3475 | 0 | -1 | 5.8 | 3.02 | ||||||||||||||||||||||||||||||
| c.753G>C | K251N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM (nine tools). Only AlphaMissense‑Default predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the preponderance of evidence indicates that K251N is most likely benign, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -7.978 | In-Between | 0.930 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.25 | Likely Benign | 0.32 | Likely Benign | 0.298 | Likely Benign | -1.29 | Neutral | 0.384 | Benign | 0.070 | Benign | 5.73 | Benign | 0.39 | Tolerated | 0.3848 | 0.1196 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
| c.753G>T | K251N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM (nine tools). Only AlphaMissense‑Default predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the preponderance of evidence indicates that K251N is most likely benign, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -7.978 | In-Between | 0.930 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.25 | Likely Benign | 0.32 | Likely Benign | 0.298 | Likely Benign | -1.29 | Neutral | 0.384 | Benign | 0.070 | Benign | 5.73 | Benign | 0.39 | Tolerated | 0.3848 | 0.1196 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
| c.2314T>A | F772I 2D AIThe SynGAP1 missense variant F772I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The predictions do 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 | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -2.925 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -0.38 | Neutral | 0.845 | Possibly Damaging | 0.899 | Possibly Damaging | 4.24 | Benign | 0.41 | Tolerated | 0.1544 | 0.2051 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2314T>C | F772L 2D AIThe SynGAP1 missense variant F772L is listed in gnomAD (6‑33442472‑T‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus 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. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | 6-33442472-T-C | 1 | 1.28e-6 | -1.751 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.161 | Likely Benign | -0.47 | Neutral | 0.508 | Possibly Damaging | 0.786 | Possibly Damaging | 4.31 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1661 | 0.3033 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||
| c.2314T>G | F772V 2D AIThe SynGAP1 missense variant F772V 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‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are not available for this variant. Overall, the majority of computational evidence points to a benign impact, 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 | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -2.886 | Likely Benign | 0.191 | Likely Benign | Likely Benign | 0.161 | Likely Benign | -0.43 | Neutral | 0.845 | Possibly Damaging | 0.899 | Possibly Damaging | 4.27 | Benign | 0.37 | Tolerated | 0.1687 | 0.2419 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||||||||||||
| c.2315T>A | F772Y 2D AIThe SynGAP1 missense variant F772Y 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‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, 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 | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -2.657 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -0.54 | Neutral | 0.705 | Possibly Damaging | 0.786 | Possibly Damaging | 4.17 | Benign | 0.35 | Tolerated | 0.1058 | 0.1892 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2315T>C | F772S 2D AIThe SynGAP1 missense variant F772S is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) suggest pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus likewise indicates Likely Benign; Foldetta data are not available. Overall, the preponderance of evidence points to a benign effect for F772S, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -2.722 | Likely Benign | 0.442 | Ambiguous | Likely Benign | 0.138 | Likely Benign | -0.26 | Neutral | 0.845 | Possibly Damaging | 0.899 | Possibly Damaging | 4.21 | Benign | 0.56 | Tolerated | 0.4134 | 0.0558 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2315T>G | F772C 2D AIThe SynGAP1 missense variant F772C 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‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The predictions do not contradict any ClinVar status, as no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -4.498 | Likely Benign | 0.248 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -1.46 | Neutral | 0.979 | Probably Damaging | 0.985 | Probably Damaging | 4.14 | Benign | 0.10 | Tolerated | 0.2450 | 0.1419 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||||||
| c.2316C>A | F772L 2D AIThe SynGAP1 missense variant F772L is catalogued in gnomAD (ID 6‑33442474‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the preponderance of evidence indicates that F772L 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 | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | 6-33442474-C-A | -1.751 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -0.47 | Neutral | 0.508 | Possibly Damaging | 0.786 | Possibly Damaging | 4.31 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1661 | 0.3033 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.2316C>G | F772L 2D AIThe SynGAP1 missense variant F772L has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; no Foldetta stability data are available, so it is treated as unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -1.751 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -0.47 | Neutral | 0.508 | Possibly Damaging | 0.786 | Possibly Damaging | 4.31 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1661 | 0.3033 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||
| c.2320G>A | A774T 2D AIThe SynGAP1 missense variant A774T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -3.238 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.46 | Neutral | 0.037 | Benign | 0.063 | Benign | 4.20 | Benign | 0.39 | Tolerated | 0.1436 | 0.7578 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2320G>C | A774P 2D AIThe SynGAP1 missense variant A774P 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‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. 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 also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the preponderance of 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 | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -3.869 | Likely Benign | 0.192 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -0.94 | Neutral | 0.801 | Possibly Damaging | 0.481 | Possibly Damaging | 4.15 | Benign | 0.18 | Tolerated | 0.1902 | 0.5749 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2320G>T | A774S 2D AIThe SynGAP1 missense variant A774S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -2.780 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.09 | Neutral | 0.071 | Benign | 0.115 | Benign | 4.27 | Benign | 0.43 | Tolerated | 0.2711 | 0.6399 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2321C>A | A774D 2D AIThe SynGAP1 missense variant A774D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv 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; 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 | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -4.455 | Likely Benign | 0.603 | Likely Pathogenic | Likely Benign | 0.123 | Likely Benign | -0.46 | Neutral | 0.570 | Possibly Damaging | 0.386 | Benign | 4.21 | Benign | 0.06 | Tolerated | 0.1645 | 0.1793 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2321C>G | A774G 2D AIThe SynGAP1 missense variant A774G is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -3.129 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.68 | Neutral | 0.135 | Benign | 0.152 | Benign | 4.16 | Benign | 0.22 | Tolerated | 0.2392 | 0.5436 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2321C>T | A774V 2D AIThe SynGAP1 missense variant A774V is catalogued in gnomAD (ID 6‑33442479‑C‑T) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently scores the variant as benign. No pathogenic predictions are reported. Grouping by agreement, the benign‑predicting tools comprise the entire set, while the pathogenic group is empty. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” 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 variant is most likely benign, and this assessment does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | 6-33442479-C-T | 1 | 1.28e-6 | -3.075 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.73 | Neutral | 0.000 | Benign | 0.003 | Benign | 4.20 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1070 | 0.6659 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.394T>A | F132I 2D AISynGAP1 missense variant F132I is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic, two benign) and Foldetta results are unavailable. Because the majority of consensus tools predict benign and no ClinVar evidence contradicts this, the variant is most likely benign, although the pathogenic signal from AlphaMissense‑Optimized and the inconclusive SGM Consensus leave some uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | -6.245 | Likely Benign | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.211 | Likely Benign | -3.23 | Deleterious | 0.084 | Benign | 0.020 | Benign | 3.36 | Benign | 0.00 | Affected | 0.2306 | 0.1698 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.394T>C | F132L 2D AIThe SynGAP1 missense variant F132L is not reported in ClinVar (status: none) but is present in gnomAD (ID 6‑33432691‑T‑C). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta (combining FoldX‑MD and Rosetta) has no available output. Overall, the majority of consensus tools lean toward a benign interpretation, and the single high‑accuracy pathogenic prediction is counterbalanced by inconclusive consensus and missing folding‑stability data. Thus, 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. | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | 6-33432691-T-C | -5.401 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.165 | Likely Benign | -2.99 | Deleterious | 0.000 | Benign | 0.002 | Benign | 3.46 | Benign | 0.00 | Affected | 3.61 | 5 | 0.2564 | 0.2669 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||
| c.394T>G | F132V 2D AIThe SynGAP1 missense variant F132V 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence predictions indicate a pathogenic effect, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | -7.637 | In-Between | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.328 | Likely Benign | -3.86 | Deleterious | 0.084 | Benign | 0.034 | Benign | 3.38 | Benign | 0.00 | Affected | 0.2349 | 0.1725 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||||||
| c.395T>A | F132Y 2D AIThe SynGAP1 missense variant F132Y is not 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, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of available predictions (five benign vs three pathogenic) suggest a benign impact. This consensus does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | -8.220 | Likely Pathogenic | 0.839 | Likely Pathogenic | Ambiguous | 0.165 | Likely Benign | -1.98 | Neutral | 0.272 | Benign | 0.126 | Benign | 3.39 | Benign | 0.00 | Affected | 0.1635 | 0.1526 | 7 | 3 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||||||||||||
| c.395T>C | F132S 2D AIThe SynGAP1 missense variant F132S is not 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, ESM1b, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the balance of evidence (five pathogenic vs four benign predictions) indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | -4.177 | Likely Benign | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.329 | Likely Benign | -4.54 | Deleterious | 0.567 | Possibly Damaging | 0.249 | Benign | 3.31 | Benign | 0.00 | Affected | 0.4869 | 0.0000 | -3 | -2 | -3.6 | -60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.395T>G | F132C 2D AIThe SynGAP1 missense variant F132C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Pathogenic” based on a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (derived from the four high‑accuracy predictors) also indicates likely pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | -10.013 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.331 | Likely Benign | -4.55 | Deleterious | 0.938 | Possibly Damaging | 0.498 | Possibly Damaging | 3.29 | Benign | 0.00 | Affected | 0.2677 | 0.0925 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||||||
| c.396C>A | F132L 2D AIThe SynGAP1 missense variant F132L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). Foldetta, a protein‑folding‑stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools (AlphaMissense‑Optimized and AlphaMissense‑Default) both predict pathogenicity, while the consensus and stability analyses are inconclusive or missing. Overall, the majority of individual predictors and the high‑accuracy tools lean toward a pathogenic effect, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | -5.401 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.137 | Likely Benign | -2.99 | Deleterious | 0.000 | Benign | 0.002 | Benign | 3.46 | Benign | 0.00 | Affected | 3.61 | 5 | 0.2564 | 0.2669 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||||
| c.396C>G | F132L 2D AIThe SynGAP1 missense variant F132L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools (AlphaMissense‑Optimized and AlphaMissense‑Default) both predict pathogenicity, whereas the consensus and stability analyses are inconclusive or missing. Overall, the majority of individual predictors and the two high‑accuracy tools suggest a pathogenic effect, 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. | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | -5.401 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.137 | Likely Benign | -2.99 | Deleterious | 0.000 | Benign | 0.002 | Benign | 3.46 | Benign | 0.00 | Affected | 3.61 | 5 | 0.2564 | 0.2669 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||||
| c.730G>A | E244K 2D AISynGAP1 missense variant E244K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from FoldX, Rosetta, Foldetta, SIFT, and FATHMM, whereas pathogenic predictions are reported by REVEL, PROVEAN, both polyPhen‑2 HumDiv and HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). The high‑accuracy methods give a clearer picture: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. With the majority of consensus tools leaning toward pathogenic and the two high‑accuracy pathogenic predictions outweighing the benign Foldetta result, the variant is most likely pathogenic. This assessment does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -13.975 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 1.0 | 0.45 | Likely Benign | 0.43 | Likely Benign | 0.80 | Ambiguous | 0.841 | Likely Pathogenic | -3.37 | Deleterious | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 5.82 | Benign | 0.07 | Tolerated | 0.1887 | 0.6177 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.730G>C | E244Q 2D AIThe SynGAP1 E244Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, six tools predict pathogenicity versus five predicting benignity, with no ClinVar evidence to contradict these findings. Thus, the variant is most likely pathogenic based on the current predictive landscape. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -10.245 | Likely Pathogenic | 0.928 | Likely Pathogenic | Ambiguous | 0.23 | Likely Benign | 0.9 | -0.77 | Ambiguous | -0.27 | Likely Benign | 0.40 | Likely Benign | 0.695 | Likely Pathogenic | -2.49 | Neutral | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 5.78 | Benign | 0.05 | Affected | 0.1016 | 0.5610 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.731A>C | E244A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244A missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, and FATHMM, while pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign stability. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -11.227 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.39 | Likely Benign | 0.1 | -0.45 | Likely Benign | -0.03 | Likely Benign | 0.82 | Ambiguous | 0.865 | Likely Pathogenic | -4.99 | Deleterious | 0.970 | Probably Damaging | 0.584 | Possibly Damaging | 5.74 | Benign | 0.01 | Affected | 0.2672 | 0.4926 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.731A>G | E244G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of computational evidence points to the variant being most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -10.452 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 1.28 | Ambiguous | 0.0 | 0.74 | Ambiguous | 1.01 | Ambiguous | 1.01 | Destabilizing | 0.900 | Likely Pathogenic | -5.67 | Deleterious | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 5.73 | Benign | 0.01 | Affected | 0.2266 | 0.5252 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.731A>T | E244V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244V missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -12.118 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.04 | Ambiguous | 0.1 | 1.02 | Ambiguous | 1.03 | Ambiguous | 0.56 | Ambiguous | 0.925 | Likely Pathogenic | -5.90 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.68 | Benign | 0.00 | Affected | 0.0636 | 0.6073 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.732G>C | E244D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic classification for E244D, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -7.839 | In-Between | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.46 | Likely Benign | 0.1 | 1.61 | Ambiguous | 1.04 | Ambiguous | 0.93 | Ambiguous | 0.730 | Likely Pathogenic | -2.53 | Deleterious | 0.976 | Probably Damaging | 0.675 | Possibly Damaging | 5.78 | Benign | 0.03 | Affected | 0.1740 | 0.3783 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.732G>T | E244D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results come from Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence points to a likely pathogenic effect for E244D, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -7.839 | In-Between | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.46 | Likely Benign | 0.1 | 1.61 | Ambiguous | 1.04 | Ambiguous | 0.93 | Ambiguous | 0.730 | Likely Pathogenic | -2.53 | Deleterious | 0.976 | Probably Damaging | 0.675 | Possibly Damaging | 5.78 | Benign | 0.03 | Affected | 0.1740 | 0.3783 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.907G>A | G303R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G303R is catalogued in gnomAD (6-33437812-G-A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome; the remaining tools (FoldX, Foldetta, premPS, ESM1b) are inconclusive. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, while Foldetta remains uncertain. Taken together, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | 6-33437812-G-A | 1 | 6.20e-7 | -7.493 | In-Between | 0.724 | Likely Pathogenic | Likely Benign | 1.44 | Ambiguous | 0.4 | 0.23 | Likely Benign | 0.84 | Ambiguous | 0.73 | Ambiguous | 0.048 | Likely Benign | -1.38 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.99 | Benign | 0.06 | Tolerated | 3.55 | 18 | 0.0839 | 0.4490 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||
| c.907G>C | G303R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. The remaining tools—FoldX, Foldetta, premPS, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, while Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -7.493 | In-Between | 0.724 | Likely Pathogenic | Likely Benign | 1.44 | Ambiguous | 0.4 | 0.23 | Likely Benign | 0.84 | Ambiguous | 0.73 | Ambiguous | 0.048 | Likely Benign | -1.38 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.99 | Benign | 0.06 | Tolerated | 3.55 | 18 | 0.0839 | 0.4490 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||
| c.907G>T | G303W 2D 3DClick to see structure in 3D Viewer AIClinVar reports no entry for this SynGAP1 G303W variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta’s stability prediction is also unavailable. Overall, the evidence is evenly split between benign and pathogenic predictions, providing no clear bias toward either outcome. This balanced prediction does not contradict ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -9.041 | Likely Pathogenic | 0.579 | Likely Pathogenic | Likely Benign | 1.69 | Ambiguous | 0.3 | 1.11 | Ambiguous | 1.40 | Ambiguous | 0.28 | Likely Benign | 0.157 | Likely Benign | -1.63 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 3.93 | Benign | 0.00 | Affected | 0.0663 | 0.4553 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||
| c.908G>A | G303E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303E is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437813‑G‑A). Across the available in‑silico predictors, benign calls are made by REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by SIFT and ESM1b; the remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Default) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta remains uncertain. Taken together, the majority of evidence points to a benign effect; this conclusion is not contradicted by any ClinVar annotation, as no pathogenic classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | 6-33437813-G-A | 3 | 1.86e-6 | -9.339 | Likely Pathogenic | 0.549 | Ambiguous | Likely Benign | 1.87 | Ambiguous | 0.5 | 0.37 | Likely Benign | 1.12 | Ambiguous | 0.89 | Ambiguous | 0.063 | Likely Benign | -1.56 | Neutral | 0.001 | Benign | 0.005 | Benign | 4.04 | Benign | 0.05 | Affected | 3.55 | 18 | 0.1155 | 0.4172 | -2 | 0 | -3.1 | 72.06 | |||||||||||||||||||||||||
| c.908G>C | G303A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta’s stability analysis is uncertain. Overall, the variant is most likely benign based on the consensus of predictive tools, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -1.965 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 1.66 | Ambiguous | 0.2 | -0.51 | Ambiguous | 0.58 | Ambiguous | 0.10 | Likely Benign | 0.034 | Likely Benign | -0.90 | Neutral | 0.112 | Benign | 0.058 | Benign | 4.07 | Benign | 0.35 | Tolerated | 0.3724 | 0.5325 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.908G>T | G303V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign) all indicate a tolerated change. Pathogenic signals arise only from SIFT and FoldX, while Rosetta and Foldetta are inconclusive. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields Likely Benign, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -3.046 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 3.06 | Destabilizing | 0.6 | -0.72 | Ambiguous | 1.17 | Ambiguous | 0.14 | Likely Benign | 0.071 | Likely Benign | -1.57 | Neutral | 0.011 | Benign | 0.017 | Benign | 3.96 | Benign | 0.01 | Affected | 0.1002 | 0.4577 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.475A>C | I159L 2D AIThe SynGAP1 missense variant I159L 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. 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 I159L, 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 | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -7.936 | In-Between | 0.195 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -0.39 | Neutral | 0.904 | Possibly Damaging | 0.847 | Possibly Damaging | 4.04 | Benign | 0.00 | Affected | 0.0776 | 0.2652 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.475A>G | I159V 2D AIThe SynGAP1 I159V 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus (2 benign vs. 1 pathogenic, with one uncertain). Foldetta results are unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -9.714 | Likely Pathogenic | 0.384 | Ambiguous | Likely Benign | 0.113 | Likely Benign | -0.25 | Neutral | 0.803 | Possibly Damaging | 0.847 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 0.1111 | 0.2736 | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.475A>T | I159F 2D AIThe SynGAP1 missense variant I159F is not 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, polyPhen‑2 HumVar, SIFT, and ESM1b. AlphaMissense‑Default is uncertain. 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, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence, particularly from the high‑accuracy tools, points to a benign impact. This conclusion is not contradicted by any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -9.530 | Likely Pathogenic | 0.447 | Ambiguous | Likely Benign | 0.200 | Likely Benign | -1.41 | Neutral | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.87 | Benign | 0.00 | Affected | 0.0490 | 0.2446 | 1 | 0 | -1.7 | 34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.476T>A | I159N 2D AIThe SynGAP1 missense variant I159N 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 impact. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑vs‑2 split. Foldetta, which would assess protein‑folding stability, has no available output for this variant. Overall, the majority of tools (five out of eight) predict pathogenicity, while three predict benign and one is uncertain. 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. | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -14.684 | Likely Pathogenic | 0.891 | Likely Pathogenic | Ambiguous | 0.218 | Likely Benign | -1.93 | Neutral | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 3.82 | Benign | 0.00 | Affected | 0.0919 | 0.0342 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.476T>C | I159T 2D AIThe SynGAP1 missense variant I159T is not 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 predict a pathogenic effect comprise polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy AlphaMissense‑Optimized predicts pathogenic, while AlphaMissense‑Default also predicts pathogenic. Given that six of the seven individual tools predict pathogenicity versus three predicting benign, the variant is most likely pathogenic. This prediction does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -12.422 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.218 | Likely Benign | -1.69 | Neutral | 0.981 | Probably Damaging | 0.966 | Probably Damaging | 3.86 | Benign | 0.00 | Affected | 0.1069 | 0.0685 | 0 | -1 | -5.2 | -12.05 | ||||||||||||||||||||||||||||||||||||||||
| c.476T>G | I159S 2D AIThe SynGAP1 missense variant I159S is not 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 are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward pathogenicity. 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. | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -13.684 | Likely Pathogenic | 0.905 | Likely Pathogenic | Ambiguous | 0.241 | Likely Benign | -1.70 | Neutral | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.85 | Benign | 0.00 | Affected | 0.2854 | 0.0712 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.477C>G | I159M 2D AIThe SynGAP1 missense variant I159M 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -9.838 | Likely Pathogenic | 0.142 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.48 | Neutral | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 3.89 | Benign | 0.00 | Affected | 0.0678 | 0.2500 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.478C>A | L160M 2D AIThe SynGAP1 missense variant L160M is not 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, 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 because it yields a 2‑to‑2 split. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus is unavailable; and Foldetta, which combines FoldX‑MD and Rosetta stability calculations, has no reported output for this variant. Overall, the balance of evidence leans toward a pathogenic interpretation, but the single high‑accuracy benign prediction and the lack of a ClinVar assertion mean the variant’s clinical significance remains uncertain. This assessment does not contradict any existing ClinVar status, as none is available. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.454136 | Structured | 0.526760 | Binding | 0.275 | 0.728 | 0.125 | -11.120 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 0.097 | Likely Benign | -0.94 | Neutral | 0.877 | Possibly Damaging | 0.580 | Possibly Damaging | 3.85 | Benign | 0.00 | Affected | 0.0837 | 0.3613 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.478C>G | L160V 2D AIThe SynGAP1 missense variant L160V is not 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. three pathogenic) indicate that the variant is most likely benign. This conclusion is consistent with the lack of ClinVar evidence and gnomAD presence, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.454136 | Structured | 0.526760 | Binding | 0.275 | 0.728 | 0.125 | -12.506 | Likely Pathogenic | 0.729 | Likely Pathogenic | Likely Benign | 0.055 | Likely Benign | -1.44 | Neutral | 0.247 | Benign | 0.113 | Benign | 3.90 | Benign | 0.00 | Affected | 0.1553 | 0.3319 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.479T>A | L160Q 2D AIThe SynGAP1 missense variant L160Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.454136 | Structured | 0.526760 | Binding | 0.275 | 0.728 | 0.125 | -16.626 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.227 | Likely Benign | -2.83 | Deleterious | 0.700 | Possibly Damaging | 0.483 | Possibly Damaging | 3.87 | Benign | 0.00 | Affected | 0.1248 | 0.1060 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.479T>C | L160P 2D AIThe SynGAP1 missense variant L160P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a majority pathogenic vote (3 pathogenic vs. 1 benign) and is labeled “Likely Pathogenic.” AlphaMissense‑Optimized independently predicts pathogenicity. 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 variant 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 | 0.454136 | Structured | 0.526760 | Binding | 0.275 | 0.728 | 0.125 | -15.939 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.283 | Likely Benign | -3.06 | Deleterious | 0.001 | Benign | 0.000 | Benign | 3.86 | Benign | 0.00 | Affected | 0.3589 | 0.1484 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.479T>G | L160R 2D AIThe SynGAP1 missense variant L160R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. The protein‑folding stability method Foldetta did not provide a result, so its status is unavailable. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.454136 | Structured | 0.526760 | Binding | 0.275 | 0.728 | 0.125 | -14.539 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | -2.83 | Deleterious | 0.700 | Possibly Damaging | 0.483 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.1482 | 0.0702 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.733A>C | N245H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245H is not reported in ClinVar and is absent from gnomAD. Among in‑silico predictors, benign calls come from FoldX, Rosetta, and FATHMM, whereas pathogenic calls are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. The overall pattern of predictions leans toward pathogenicity, with a majority of tools indicating a deleterious effect. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -11.536 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.23 | Likely Benign | 0.1 | -0.20 | Likely Benign | 0.02 | Likely Benign | 0.55 | Ambiguous | 0.825 | Likely Pathogenic | -4.15 | Deleterious | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.84 | Benign | 0.01 | Affected | 0.1437 | 0.7271 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.733A>G | N245D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, SIFT, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools, premPS and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions (six pathogenic vs five benign) and the consensus of high‑accuracy methods lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -7.847 | In-Between | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.27 | Likely Benign | 0.0 | 0.09 | Likely Benign | 0.18 | Likely Benign | 0.79 | Ambiguous | 0.712 | Likely Pathogenic | -3.62 | Deleterious | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 5.84 | Benign | 0.13 | Tolerated | 0.1953 | 0.4599 | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.733A>T | N245Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N245Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, and FATHMM, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a pathogenic majority (3/4). AlphaMissense‑Optimized independently predicts pathogenicity, while Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. premPS remains uncertain. Overall, the majority of evidence points toward a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Thus, the variant is most likely pathogenic, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -12.476 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | -0.36 | Likely Benign | 0.1 | 0.11 | Likely Benign | -0.13 | Likely Benign | 0.59 | Ambiguous | 0.855 | Likely Pathogenic | -6.68 | Deleterious | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.86 | Benign | 0.00 | Affected | 0.0706 | 0.6771 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.734A>C | N245T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include FATHMM, Rosetta, and Foldetta, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support this dichotomy: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic, while Foldetta predicts a benign effect. No predictions are missing or inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for the variant, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -11.955 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.52 | Ambiguous | 0.1 | 0.04 | Likely Benign | 0.28 | Likely Benign | 0.76 | Ambiguous | 0.794 | Likely Pathogenic | -4.79 | Deleterious | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.87 | Benign | 0.01 | Affected | 0.1397 | 0.7734 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.734A>G | N245S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence (8 benign vs. 5 pathogenic) supports a benign classification. This conclusion does not contradict ClinVar, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -6.792 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.46 | Likely Benign | 0.1 | -0.16 | Likely Benign | 0.15 | Likely Benign | 0.42 | Likely Benign | 0.524 | Likely Pathogenic | -3.75 | Deleterious | 0.787 | Possibly Damaging | 0.404 | Benign | 5.90 | Benign | 0.07 | Tolerated | 0.3557 | 0.7229 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||
| c.734A>T | N245I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245I is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include Rosetta, Foldetta, and FATHMM, while those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -14.527 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | -0.56 | Ambiguous | 0.1 | 0.04 | Likely Benign | -0.26 | Likely Benign | 0.60 | Ambiguous | 0.831 | Likely Pathogenic | -7.46 | Deleterious | 0.995 | Probably Damaging | 0.832 | Possibly Damaging | 5.88 | Benign | 0.00 | Affected | 0.0672 | 0.6999 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.735T>A | N245K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM, aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and yields a majority pathogenic verdict. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, classifies the variant as benign. Overall, the majority of individual predictors and the SGM consensus favor a pathogenic effect, while Foldetta and a subset of benign tools suggest stability preservation. Given the predominance of pathogenic predictions and the absence of ClinVar annotation, the variant is most likely pathogenic and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -12.110 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | -0.32 | Likely Benign | 0.1 | 0.01 | Likely Benign | -0.16 | Likely Benign | 0.83 | Ambiguous | 0.474 | Likely Benign | -4.86 | Deleterious | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.88 | Benign | 0.01 | Affected | 0.2271 | 0.5645 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.735T>G | N245K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a Benign effect. Overall, the preponderance of evidence—including the high‑accuracy tools—points to a pathogenic impact for N245K, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -12.110 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | -0.32 | Likely Benign | 0.1 | 0.01 | Likely Benign | -0.16 | Likely Benign | 0.83 | Ambiguous | 0.474 | Likely Benign | -4.86 | Deleterious | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.88 | Benign | 0.01 | Affected | 0.2271 | 0.5645 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.199C>A | L67I 2D AIThe SynGAP1 missense variant L67I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the variant, 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 | 0.458154 | Structured | 0.473668 | Uncertain | 0.428 | 0.761 | 0.125 | -4.387 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -0.29 | Neutral | 0.458 | Possibly Damaging | 0.364 | Benign | 4.10 | Benign | 0.00 | Affected | 0.0680 | 0.2919 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.199C>G | L67V 2D AIThe SynGAP1 missense variant L67V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the L67V substitution, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.458154 | Structured | 0.473668 | Uncertain | 0.428 | 0.761 | 0.125 | -3.617 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -0.31 | Neutral | 0.458 | Possibly Damaging | 0.364 | Benign | 4.15 | Benign | 0.00 | Affected | 0.1138 | 0.2817 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.200T>A | L67Q 2D AIThe SynGAP1 missense variant L67Q 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 not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.458154 | Structured | 0.473668 | Uncertain | 0.428 | 0.761 | 0.125 | -3.948 | Likely Benign | 0.687 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | -0.66 | Neutral | 0.943 | Possibly Damaging | 0.766 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 0.0861 | 0.0719 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.200T>C | L67P 2D AIThe SynGAP1 missense variant L67P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact. The variant’s predicted benign status does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.458154 | Structured | 0.473668 | Uncertain | 0.428 | 0.761 | 0.125 | -2.852 | Likely Benign | 0.945 | Likely Pathogenic | Ambiguous | 0.150 | Likely Benign | -0.80 | Neutral | 0.943 | Possibly Damaging | 0.766 | Possibly Damaging | 4.07 | Benign | 0.00 | Affected | 0.3052 | 0.1382 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.200T>G | L67R 2D AIThe SynGAP1 missense variant L67R 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, 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 Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Thus, the variant is most likely benign based on current predictive tools. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.458154 | Structured | 0.473668 | Uncertain | 0.428 | 0.761 | 0.125 | -3.430 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.115 | Likely Benign | -0.84 | Neutral | 0.943 | Possibly Damaging | 0.766 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 0.1159 | 0.0719 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2266C>A | Q756K 2D AIThe SynGAP1 missense variant Q756K 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. 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 Q756K, 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 | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -6.059 | Likely Benign | 0.340 | Likely Benign | Likely Benign | 0.199 | Likely Benign | -1.47 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 1.60 | Pathogenic | 0.21 | Tolerated | 0.1816 | 0.4797 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2266C>G | Q756E 2D AIThe SynGAP1 missense variant Q756E 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, 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 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 Q756E, 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 | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -4.149 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.174 | Likely Benign | -1.19 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 1.58 | Pathogenic | 0.23 | Tolerated | 0.1465 | 0.2853 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2267A>C | Q756P 2D AIThe SynGAP1 missense variant Q756P has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion 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 Benign | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -4.226 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.315 | Likely Benign | -0.93 | Neutral | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 1.54 | Pathogenic | 0.23 | Tolerated | 0.2590 | 0.5186 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2267A>G | Q756R 2D AIThe SynGAP1 missense variant Q756R 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for Q756R, 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 | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -5.044 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.245 | Likely Benign | -1.77 | Neutral | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 1.58 | Pathogenic | 0.14 | Tolerated | 0.1500 | 0.2440 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2267A>T | Q756L 2D AIThe SynGAP1 missense variant Q756L 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is labeled “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for Q756L, 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 | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -3.697 | Likely Benign | 0.339 | Likely Benign | Likely Benign | 0.274 | Likely Benign | -1.95 | Neutral | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 1.56 | Pathogenic | 0.08 | Tolerated | 0.0797 | 0.5700 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2268G>C | Q756H 2D AIThe SynGAP1 missense variant Q756H 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, 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 | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -4.625 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.197 | Likely Benign | -2.17 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 1.54 | Pathogenic | 0.05 | Affected | 0.1545 | 0.4404 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2268G>T | Q756H 2D AIThe SynGAP1 missense variant Q756H 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, 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 | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -4.625 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.197 | Likely Benign | -2.17 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 1.54 | Pathogenic | 0.05 | Affected | 0.1545 | 0.4404 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3802C>A | L1268M 2D AIThe SynGAP1 missense variant L1268M is reported in gnomAD (ID 6‑33447850‑C‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. 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; a Foldetta stability analysis is not available. Overall, the preponderance of evidence from multiple in silico predictors and consensus methods 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 | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | 6-33447850-C-A | -4.689 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.07 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.67 | Benign | 0.08 | Tolerated | 3.77 | 5 | 0.0627 | 0.2297 | 2 | 4 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.3802C>G | L1268V 2D AIThe SynGAP1 missense variant L1268V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports likely benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for the variant, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | -4.137 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.24 | Neutral | 0.649 | Possibly Damaging | 0.157 | Benign | 2.73 | Benign | 0.25 | Tolerated | 0.1331 | 0.2289 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3803T>A | L1268Q 2D AIThe SynGAP1 missense variant L1268Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two PolyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates benign. Foldetta results are not available, so they do not influence the assessment. Overall, the preponderance of evidence points to a benign impact for this 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 | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | -5.707 | Likely Benign | 0.143 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.50 | Neutral | 0.990 | Probably Damaging | 0.637 | Possibly Damaging | 2.68 | Benign | 0.08 | Tolerated | 0.0988 | 0.0558 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||
| c.3803T>C | L1268P 2D AIThe SynGAP1 missense variant L1268P is not 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. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑accuracy predictors (5 vs. 4) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | -9.062 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.091 | Likely Benign | -1.03 | Neutral | 0.970 | Probably Damaging | 0.637 | Possibly Damaging | 2.65 | Benign | 0.24 | Tolerated | 0.3261 | 0.1053 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3803T>G | L1268R 2D AIThe SynGAP1 missense change L1268R is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign) all support a neutral impact. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome, while ESM1b remains uncertain. High‑accuracy tools reinforce the benign assessment: AlphaMissense‑Optimized returns a benign prediction and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. Foldetta results are not available, so they do not influence the interpretation. Overall, the preponderance of evidence points to a benign effect for L1268R, 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 | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | -7.010 | In-Between | 0.293 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.79 | Neutral | 0.970 | Probably Damaging | 0.637 | Possibly Damaging | 2.68 | Benign | 0.08 | Tolerated | 0.1135 | 0.0558 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.556T>A | L186M 2D AIThe SynGAP1 missense variant L186M is not 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 are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 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 (5 pathogenic vs. 3 benign) suggest a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -11.783 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 0.146 | Likely Benign | -1.58 | Neutral | 0.952 | Possibly Damaging | 0.694 | Possibly Damaging | 3.50 | Benign | 0.00 | Affected | 0.0671 | 0.3396 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.556T>G | L186V 2D AIThe SynGAP1 missense variant L186V is not 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. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments are mixed: AlphaMissense‑Optimized predicts pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields no clear majority and is therefore unavailable; Foldetta results are also unavailable. Overall, the majority of available predictions (five pathogenic vs. four benign) indicate a pathogenic effect. There is no ClinVar entry to contradict this assessment, so 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. | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -9.385 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.090 | Likely Benign | -2.27 | Neutral | 0.734 | Possibly Damaging | 0.185 | Benign | 3.60 | Benign | 0.00 | Affected | 0.1419 | 0.3665 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.557T>C | L186S 2D  AIThe SynGAP1 missense variant L186S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a deleterious effect, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels the variant as 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 the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -13.906 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.250 | Likely Benign | -4.73 | Deleterious | 0.952 | Possibly Damaging | 0.601 | Possibly Damaging | 3.51 | Benign | 0.00 | Affected | 0.3214 | 0.0808 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.557T>G | L186W 2D  AIThe SynGAP1 missense variant L186W has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—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 a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -16.177 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.274 | Likely Benign | -4.78 | Deleterious | 0.996 | Probably Damaging | 0.819 | Possibly Damaging | 3.46 | Benign | 0.00 | Affected | 0.0539 | 0.3138 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||||||
| c.558G>C | L186F 2D AIThe SynGAP1 missense variant L186F is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM. In contrast, tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) also indicates likely pathogenic. 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 pathogenic effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | Uncertain | 1 | -11.861 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.132 | Likely Benign | -3.03 | Deleterious | 0.009 | Benign | 0.012 | Benign | 3.50 | Benign | 0.00 | Affected | 0.0524 | 0.3177 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||
| c.558G>T | L186F 2D AIThe SynGAP1 missense variant L186F has no ClinVar entry (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic.” 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 indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -11.861 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.132 | Likely Benign | -3.03 | Deleterious | 0.009 | Benign | 0.012 | Benign | 3.50 | Benign | 0.00 | Affected | 0.0524 | 0.3177 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.1108G>A | G370S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G370S is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6‑33438013‑G‑A). Consensus predictions from standard in silico tools cluster into two groups: benign (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (FoldX, FATHMM). Two tools report uncertainty: Rosetta and Foldetta. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Benign; Foldetta remains uncertain. Overall, the preponderance of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | Uncertain | 1 | 6-33438013-G-A | 15 | 9.31e-6 | -3.533 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 2.83 | Destabilizing | 2.0 | 1.05 | Ambiguous | 1.94 | Ambiguous | -0.02 | Likely Benign | 0.282 | Likely Benign | 0.47 | Neutral | 0.000 | Benign | 0.000 | Benign | 1.33 | Pathogenic | 0.77 | Tolerated | 3.42 | 19 | 0.2664 | 0.5086 | 1 | 0 | -0.4 | 30.03 | 196.6 | -49.6 | 0.9 | 2.2 | -0.1 | 0.4 | Uncertain | Gly370 is located in the Gly-rich Ω loop (res. Pro364- Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because, the Ω loop is assumed to be directly interacting with the membrane, it is only seen to move arbitrarily throughout the WT solvent simulations. The Ω loop is potentially playing a crucial loop in the SynGAP-membrane complex association, stability and dynamics, regardless, this aspect cannot be addressed through the solvent simulations only. The Ω-loops are known to have a major role in protein functions that requires flexibility and thus, they are rich in glycines, prolines and to a lesser extent, hydrophilic residues to ensure maximum flexibility. Thus, Ser370 in the variant is potentially tolerated in the Ω loop. However, since the effect on the Gly-rich Ω loop dynamics can only be well-studied through the SynGAP-membrane complex, no definite conclusions can be withdrawn. | ||||||||||||||
| c.1108G>C | G370R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are SGM‑Consensus, FoldX, ESM1b, FATHMM, AlphaMissense‑Default, and Foldetta; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Overall, the balance of evidence leans toward pathogenicity, with two of the three high‑accuracy tools supporting this view. The variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -8.375 | Likely Pathogenic | 0.731 | Likely Pathogenic | Likely Benign | 3.62 | Destabilizing | 3.7 | 1.72 | Ambiguous | 2.67 | Destabilizing | 0.22 | Likely Benign | 0.373 | Likely Benign | -0.80 | Neutral | 0.016 | Benign | 0.002 | Benign | 1.32 | Pathogenic | 0.55 | Tolerated | 0.0978 | 0.4313 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1108G>T | G370C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370C has no ClinVar entry and is not reported in gnomAD. Functional prediction tools fall into two groups: benign predictions come from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from REVEL, FoldX, Rosetta, Foldetta, and FATHMM. ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. No prediction or stability result is missing. Overall, the majority of tools predict a benign effect, and the high‑accuracy consensus also leans benign, while only one high‑accuracy method (Foldetta) suggests pathogenicity. Thus, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -7.071 | In-Between | 0.119 | Likely Benign | Likely Benign | 3.01 | Destabilizing | 2.1 | 2.03 | Destabilizing | 2.52 | Destabilizing | 0.29 | Likely Benign | 0.511 | Likely Pathogenic | -1.00 | Neutral | 0.353 | Benign | 0.010 | Benign | 1.32 | Pathogenic | 0.06 | Tolerated | 0.1245 | 0.4412 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||
| c.1109G>A | G370D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, FATHMM, and AlphaMissense‑Default. The high‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts benign, Foldetta (a folding‑stability method that integrates FoldX‑MD and Rosetta outputs) predicts pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it yields an equal split of benign and pathogenic calls. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -5.332 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 3.64 | Destabilizing | 3.8 | 0.83 | Ambiguous | 2.24 | Destabilizing | 0.30 | Likely Benign | 0.372 | Likely Benign | -0.44 | Neutral | 0.007 | Benign | 0.001 | Benign | 1.32 | Pathogenic | 0.64 | Tolerated | 0.1632 | 0.1494 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||
| c.1109G>C | G370A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from FoldX, Foldetta, and FATHMM, while Rosetta remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicating a likely benign outcome, and Foldetta suggesting a pathogenic impact via combined FoldX‑MD and Rosetta stability analysis. Overall, the majority of evidence points to a benign effect, with only a minority of tools predicting pathogenicity. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -3.334 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 2.44 | Destabilizing | 1.3 | 1.62 | Ambiguous | 2.03 | Destabilizing | -0.14 | Likely Benign | 0.304 | Likely Benign | 0.54 | Neutral | 0.000 | Benign | 0.000 | Benign | 1.33 | Pathogenic | 0.79 | Tolerated | 0.3883 | 0.5247 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1109G>T | G370V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster into two groups: benign (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Benign) and pathogenic (FoldX, Rosetta, Foldetta, and FATHMM). High‑accuracy assessments further refine this picture: AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic outcome. Overall, the majority of evidence points toward a benign impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -5.328 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 4.98 | Destabilizing | 3.8 | 5.61 | Destabilizing | 5.30 | Destabilizing | -0.43 | Likely Benign | 0.427 | Likely Benign | 0.03 | Neutral | 0.000 | Benign | 0.000 | Benign | 1.32 | Pathogenic | 0.29 | Tolerated | 0.1306 | 0.4198 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.2776T>A | S926T 2D AIThe SynGAP1 missense variant S926T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus (SGM Consensus) is inconclusive, with two pathogenic and two benign votes. AlphaMissense‑Optimized, a high‑accuracy model, predicts benign, while Foldetta stability analysis is unavailable. Overall, the majority of standard tools favor a pathogenic effect, whereas the single high‑accuracy model suggests benign. Thus, 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. | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -2.917 | Likely Benign | 0.651 | Likely Pathogenic | Likely Benign | 0.226 | Likely Benign | -2.34 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.55 | Pathogenic | 0.00 | Affected | 0.1174 | 0.5663 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2776T>C | S926P 2D AIThe SynGAP1 missense variant S926P 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 ESM1b, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic), yielding a Likely Pathogenic classification. AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for S926P. 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 | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -3.873 | Likely Benign | 0.916 | Likely Pathogenic | Ambiguous | 0.424 | Likely Benign | -3.79 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | 0.1738 | 0.5058 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2776T>G | S926A 2D AIThe SynGAP1 missense variant S926A is not 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, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of reliable predictions indicate 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. | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -3.042 | Likely Benign | 0.463 | Ambiguous | Likely Benign | 0.186 | Likely Benign | -2.13 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.59 | Pathogenic | 0.00 | Affected | 0.4657 | 0.4488 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||||
| c.2777C>A | S926Y 2D AIThe SynGAP1 missense variant S926Y 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 and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports it as 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 points to a pathogenic effect for S926Y, 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 | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -6.602 | Likely Benign | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.444 | Likely Benign | -4.53 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | 0.0602 | 0.4932 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2777C>G | S926C 2D AIThe SynGAP1 missense variant S926C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the majority of predictions lean toward pathogenicity, with the high‑accuracy AlphaMissense‑Optimized result providing a conflicting benign signal. Thus, the variant is most likely pathogenic based on the collective evidence, 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 | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -6.546 | Likely Benign | 0.680 | Likely Pathogenic | Likely Benign | 0.414 | Likely Benign | -3.81 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | 0.0815 | 0.5487 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2777C>T | S926F 2D AIThe SynGAP1 missense variant S926F 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 ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that S926F is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -6.157 | Likely Benign | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.458 | Likely Benign | -4.57 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | 0.0585 | 0.5220 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.424A>C | K142Q 2D AIThe SynGAP1 missense variant K142Q 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, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. No Foldetta stability analysis is available for this variant. Overall, the preponderance of computational 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 | 0.461924 | Structured | 0.558796 | Binding | 0.374 | 0.859 | 0.500 | -11.295 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.191 | Likely Benign | -2.50 | Deleterious | 0.700 | Possibly Damaging | 0.383 | Benign | 3.50 | Benign | 0.00 | Affected | 0.4232 | 0.1132 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.424A>G | K142E 2D AIThe SynGAP1 missense variant K142E is not reported in ClinVar (no ClinVar entry) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts Pathogenic, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions point to 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 | 0.461924 | Structured | 0.558796 | Binding | 0.374 | 0.859 | 0.500 | -14.450 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.249 | Likely Benign | -2.59 | Deleterious | 0.247 | Benign | 0.125 | Benign | 3.49 | Benign | 0.00 | Affected | 0.3644 | 0.0952 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.425A>C | K142T 2D AIThe SynGAP1 missense variant K142T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as Likely Pathogenic; Foldetta results are unavailable. 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 | 0.461924 | Structured | 0.558796 | Binding | 0.374 | 0.859 | 0.500 | -12.013 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.251 | Likely Benign | -3.77 | Deleterious | 0.247 | Benign | 0.166 | Benign | 3.47 | Benign | 0.00 | Affected | 0.2034 | 0.2708 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.425A>G | K142R 2D AIThe SynGAP1 missense variant K142R is not 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.461924 | Structured | 0.558796 | Binding | 0.374 | 0.859 | 0.500 | -9.327 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -1.87 | Neutral | 0.399 | Benign | 0.212 | Benign | 3.65 | Benign | 0.00 | Affected | 0.4459 | 0.0858 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||||
| c.425A>T | K142I 2D  AIThe SynGAP1 missense variant K142I 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts Pathogenic, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational 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 | 0.461924 | Structured | 0.558796 | Binding | 0.374 | 0.859 | 0.500 | -14.597 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.296 | Likely Benign | -4.81 | Deleterious | 0.700 | Possibly Damaging | 0.403 | Benign | 3.44 | Benign | 0.00 | Affected | 0.1005 | 0.3173 | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||||||||||||
| c.426A>C | K142N 2D AIThe SynGAP1 missense variant K142N 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, 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 | 0.461924 | Structured | 0.558796 | Binding | 0.374 | 0.859 | 0.500 | -12.169 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.097 | Likely Benign | -3.13 | Deleterious | 0.700 | Possibly Damaging | 0.383 | Benign | 3.47 | Benign | 0.00 | Affected | 0.3586 | 0.1437 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.426A>T | K142N 2D AIThe SynGAP1 missense variant K142N 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, 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 | 0.461924 | Structured | 0.558796 | Binding | 0.374 | 0.859 | 0.500 | -12.169 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.096 | Likely Benign | -3.13 | Deleterious | 0.700 | Possibly Damaging | 0.383 | Benign | 3.47 | Benign | 0.00 | Affected | 0.3586 | 0.1437 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.73C>G | R25G 2D AIThe SynGAP1 missense variant R25G is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. When high‑accuracy tools are considered separately, AlphaMissense‑Optimized predicts a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome, and Foldetta data are unavailable. Overall, the majority of robust predictors lean toward a benign interpretation. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.461924 | Structured | 0.438941 | Uncertain | 0.373 | 0.890 | 0.375 | -3.533 | Likely Benign | 0.373 | Ambiguous | Likely Benign | 0.122 | Likely Benign | -1.69 | Neutral | 0.686 | Possibly Damaging | 0.630 | Possibly Damaging | 3.95 | Benign | 0.00 | Affected | 0.3621 | 0.3572 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.73C>T | R25W 2D AIThe SynGAP1 missense variant R25W is listed in ClinVar with an “Uncertain” status (ClinVar ID 2993054.0) and is present in gnomAD (ID 6‑33423482‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.461924 | Structured | 0.438941 | Uncertain | 0.373 | 0.890 | 0.375 | Uncertain | 2 | 6-33423482-C-T | 6 | 3.72e-6 | -5.133 | Likely Benign | 0.549 | Ambiguous | Likely Benign | 0.158 | Likely Benign | -1.60 | Neutral | 0.994 | Probably Damaging | 0.919 | Probably Damaging | 3.92 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1224 | 0.3938 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||
| c.74G>A | R25Q 2D AIThe SynGAP1 missense variant R25Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33423483‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.461924 | Structured | 0.438941 | Uncertain | 0.373 | 0.890 | 0.375 | Uncertain | 1 | 6-33423483-G-A | 15 | 9.29e-6 | -4.126 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -0.70 | Neutral | 0.829 | Possibly Damaging | 0.614 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3447 | 0.2566 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.74G>C | R25P 2D AIThe SynGAP1 missense variant R25P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.461924 | Structured | 0.438941 | Uncertain | 0.373 | 0.890 | 0.375 | -3.394 | Likely Benign | 0.424 | Ambiguous | Likely Benign | 0.155 | Likely Benign | -1.56 | Neutral | 0.841 | Possibly Damaging | 0.809 | Possibly Damaging | 3.94 | Benign | 0.00 | Affected | 0.2217 | 0.4571 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.74G>T | R25L 2D AIThe SynGAP1 missense variant R25L is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic impact. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools specifically highlight a benign prediction: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta data are missing. Taken together, the majority of robust predictors and the consensus analysis support a benign classification for R25L. This conclusion is consistent with the lack of ClinVar evidence and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.461924 | Structured | 0.438941 | Uncertain | 0.373 | 0.890 | 0.375 | -3.443 | Likely Benign | 0.484 | Ambiguous | Likely Benign | 0.121 | Likely Benign | -1.59 | Neutral | 0.686 | Possibly Damaging | 0.630 | Possibly Damaging | 3.97 | Benign | 0.00 | Affected | 0.2045 | 0.4792 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.754C>A | P252T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P252T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized and the SGM‑Consensus score (Likely Pathogenic). Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are treated as unavailable. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; Foldetta’s stability assessment is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -11.824 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.24 | Ambiguous | 0.1 | 1.89 | Ambiguous | 1.57 | Ambiguous | 0.71 | Ambiguous | 0.828 | Likely Pathogenic | -7.35 | Deleterious | 0.384 | Benign | 0.177 | Benign | 5.78 | Benign | 0.01 | Affected | 0.1514 | 0.4842 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.754C>G | P252A 2D 3DClick to see structure in 3D Viewer AISynGAP1 P252A is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: a single benign call from FATHMM, and a majority of pathogenic calls from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for P252A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -10.587 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.97 | Ambiguous | 0.1 | 1.74 | Ambiguous | 1.36 | Ambiguous | 0.69 | Ambiguous | 0.831 | Likely Pathogenic | -7.35 | Deleterious | 0.941 | Possibly Damaging | 0.607 | Possibly Damaging | 5.87 | Benign | 0.03 | Affected | 0.3490 | 0.4161 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.754C>T | P252S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P252S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. Predictions that are uncertain (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the evidence strongly favors a pathogenic effect for P252S, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -10.926 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.76 | Ambiguous | 0.1 | 1.81 | Ambiguous | 1.29 | Ambiguous | 0.79 | Ambiguous | 0.840 | Likely Pathogenic | -7.35 | Deleterious | 0.941 | Possibly Damaging | 0.531 | Possibly Damaging | 5.79 | Benign | 0.05 | Affected | 0.3508 | 0.4361 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.755C>A | P252H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P252H missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence indicates that P252H is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -11.991 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.06 | Ambiguous | 0.2 | 1.96 | Ambiguous | 1.51 | Ambiguous | 0.82 | Ambiguous | 0.845 | Likely Pathogenic | -8.27 | Deleterious | 0.999 | Probably Damaging | 0.936 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 0.1592 | 0.4128 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||
| c.755C>G | P252R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P252R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Computational predictors that classify the variant as benign are FoldX and FATHMM, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. Predictions that are inconclusive are Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that P252R is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -14.648 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 1.23 | Ambiguous | 0.82 | Ambiguous | 0.81 | Ambiguous | 0.890 | Likely Pathogenic | -8.27 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.80 | Benign | 0.00 | Affected | 0.1413 | 0.2848 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.755C>T | P252L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P252L missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign are premPS and FATHMM, while the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic effect. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore do not contribute to the overall assessment. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -10.181 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.93 | Ambiguous | 0.0 | 1.56 | Ambiguous | 1.25 | Ambiguous | 0.47 | Likely Benign | 0.794 | Likely Pathogenic | -9.19 | Deleterious | 0.991 | Probably Damaging | 0.781 | Possibly Damaging | 5.81 | Benign | 0.00 | Affected | 0.2027 | 0.6475 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.403C>G | R135G 2D AIThe SynGAP1 missense variant R135G is not reported in ClinVar and is absent from gnomAD. Consensus from standard in silico predictors shows a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM, while pathogenic calls come from PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments give a pathogenic result from AlphaMissense‑Optimized, an inconclusive SGM Consensus (a 2‑vs‑2 vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and no Foldetta data. Because the majority of tools predict benign and the high‑accuracy methods are either pathogenic or inconclusive, the overall evidence leans toward a benign effect. This conclusion does not conflict with the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.465241 | Structured | 0.676514 | Binding | 0.380 | 0.898 | 0.250 | -5.799 | Likely Benign | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.240 | Likely Benign | -3.17 | Deleterious | 0.000 | Benign | 0.000 | Benign | 3.69 | Benign | 0.01 | Affected | 0.3559 | 0.3273 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.404G>A | R135Q 2D AIThe SynGAP1 missense variant R135Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33432701‑G‑A). Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions come from SIFT, ESM1b, and AlphaMissense‑Default. The remaining high‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑to‑2 tie, and Foldetta stability analysis is not available. Overall, the balance of evidence favors a benign effect, and this conclusion does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.465241 | Structured | 0.676514 | Binding | 0.380 | 0.898 | 0.250 | Uncertain | 1 | 6-33432701-G-A | 5 | 3.84e-6 | -8.011 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 0.087 | Likely Benign | -1.94 | Neutral | 0.327 | Benign | 0.100 | Benign | 3.76 | Benign | 0.02 | Affected | 3.61 | 5 | 0.3153 | 0.2741 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||||||
| c.404G>C | R135P 2D AIThe SynGAP1 missense variant R135P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. In silico predictors that classify the variant as benign include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy tools give a pathogenic signal: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of predictions (seven pathogenic vs. three benign) indicate that the variant is most likely pathogenic, and this assessment 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 | 0.465241 | Structured | 0.676514 | Binding | 0.380 | 0.898 | 0.250 | -9.512 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.139 | Likely Benign | -3.19 | Deleterious | 0.609 | Possibly Damaging | 0.308 | Benign | 3.68 | Benign | 0.01 | Affected | 0.2052 | 0.4535 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.404G>T | R135L 2D AIThe SynGAP1 missense variant R135L 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized predicts pathogenicity. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic), also indicates pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions, including the high‑accuracy tools, support a pathogenic classification. 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. | 0.465241 | Structured | 0.676514 | Binding | 0.380 | 0.898 | 0.250 | -7.372 | In-Between | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.164 | Likely Benign | -3.61 | Deleterious | 0.308 | Benign | 0.122 | Benign | 3.70 | Benign | 0.01 | Affected | 0.1962 | 0.4727 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.421A>C | I141L 2D AIThe SynGAP1 missense variant I141L 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), SIFT, ESM1b, and FATHMM. Only AlphaMissense‑Default predicts a pathogenic outcome, while AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) is not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | -6.563 | Likely Benign | 0.787 | Likely Pathogenic | Ambiguous | 0.156 | Likely Benign | -1.00 | Neutral | 0.016 | Benign | 0.013 | Benign | 3.84 | Benign | 0.10 | Tolerated | 0.0742 | 0.3180 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.421A>G | I141V 2D AIThe SynGAP1 I141V missense variant is catalogued in gnomAD (ID 6‑33432718‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM) and pathogenic (SIFT, AlphaMissense‑Default). The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome. Foldetta, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the preponderance of evidence points to a benign effect, and this assessment aligns with the lack of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | 6-33432718-A-G | 1 | 6.42e-7 | -4.030 | Likely Benign | 0.785 | Likely Pathogenic | Ambiguous | 0.125 | Likely Benign | -0.58 | Neutral | 0.016 | Benign | 0.021 | Benign | 3.74 | Benign | 0.03 | Affected | 3.61 | 5 | 0.1101 | 0.3464 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.421A>T | I141F 2D AIThe SynGAP1 missense variant I141F is not 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, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2). Foldetta results are unavailable. Overall, the balance of evidence slightly favors a benign interpretation, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | -9.621 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.221 | Likely Benign | -1.82 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.57 | Benign | 0.01 | Affected | 0.0489 | 0.2775 | 1 | 0 | -1.7 | 34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.422T>A | I141N 2D AIThe SynGAP1 missense variant I141N is not reported in ClinVar and is absent from gnomAD. Consensus from standard prediction algorithms shows a split: benign predictions come from REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic. Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic impact for I141N. 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 | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | -12.417 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.258 | Likely Benign | -3.90 | Deleterious | 0.799 | Possibly Damaging | 0.424 | Benign | 3.54 | Benign | 0.00 | Affected | 0.1047 | 0.0270 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.422T>C | I141T 2D AIThe SynGAP1 missense variant I141T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its contribution is unavailable. Overall, the majority of computational 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 | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | -10.580 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.251 | Likely Benign | -2.81 | Deleterious | 0.272 | Benign | 0.167 | Benign | 3.57 | Benign | 0.00 | Affected | 0.1165 | 0.1214 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||||||
| c.422T>G | I141S 2D AIThe SynGAP1 missense variant I141S 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus also as Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic impact for I141S, 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 | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | -11.874 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.267 | Likely Benign | -3.28 | Deleterious | 0.567 | Possibly Damaging | 0.249 | Benign | 3.56 | Benign | 0.00 | Affected | 0.2885 | 0.0840 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.423C>G | I141M 2D AIThe SynGAP1 I141M variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are mixed, with an equal split between benign and pathogenic calls and no definitive evidence from Foldetta. Thus, the variant is most likely benign based on the current computational evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | -7.437 | In-Between | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.112 | Likely Benign | -1.54 | Neutral | 0.567 | Possibly Damaging | 0.332 | Benign | 3.57 | Benign | 0.01 | Affected | 0.0664 | 0.2661 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.559C>A | L187M 2D AIThe SynGAP1 missense variant L187M is not 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. Those 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, which would assess protein‑folding stability, has no available output for this variant. Overall, the majority of predictions (five pathogenic vs. three benign) lean toward pathogenicity, 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. | 0.465241 | Structured | 0.428046 | Uncertain | 0.367 | 0.625 | 0.375 | -8.814 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 0.136 | Likely Benign | -1.35 | Neutral | 0.971 | Probably Damaging | 0.641 | Possibly Damaging | 3.72 | Benign | 0.02 | Affected | 0.0848 | 0.3613 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.559C>G | L187V 2D AIThe SynGAP1 missense variant L187V is not 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, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign). High‑accuracy AlphaMissense‑Optimized predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of standard predictors lean toward a benign classification, but the single high‑accuracy tool indicates pathogenicity. Thus, the variant is most likely benign based on the collective evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.465241 | Structured | 0.428046 | Uncertain | 0.367 | 0.625 | 0.375 | -10.543 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.136 | Likely Benign | -2.24 | Neutral | 0.437 | Benign | 0.079 | Benign | 3.81 | Benign | 0.02 | Affected | 0.1525 | 0.3509 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.560T>A | L187Q 2D AIThe SynGAP1 missense variant L187Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas 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) all indicate likely pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence from multiple in silico predictors points to a pathogenic effect for the SynGAP1 L187Q 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 | 0.465241 | Structured | 0.428046 | Uncertain | 0.367 | 0.625 | 0.375 | -13.063 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.322 | Likely Benign | -4.31 | Deleterious | 0.917 | Possibly Damaging | 0.548 | Possibly Damaging | 3.72 | Benign | 0.00 | Affected | 0.1251 | 0.1060 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.560T>C | L187P 2D AIThe SynGAP1 missense variant L187P is listed in gnomAD (ID 6‑33435202‑T‑C) but has no ClinVar entry. Functional prediction tools split in two groups: benign predictions come from REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus classifies the variant as Likely Pathogenic. No Foldetta stability result is available, so it does not influence the overall assessment. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently reports no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.465241 | Structured | 0.428046 | Uncertain | 0.367 | 0.625 | 0.375 | 6-33435202-T-C | 1 | 6.20e-7 | -13.192 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.320 | Likely Benign | -5.17 | Deleterious | 0.917 | Possibly Damaging | 0.548 | Possibly Damaging | 3.70 | Benign | 0.01 | Affected | 3.47 | 9 | 0.3604 | 0.1484 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||
| c.560T>G | L187R 2D AIThe SynGAP1 missense variant L187R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a deleterious effect, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels the variant as 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 the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.465241 | Structured | 0.428046 | Uncertain | 0.367 | 0.625 | 0.375 | -14.118 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.332 | Likely Benign | -4.38 | Deleterious | 0.917 | Possibly Damaging | 0.467 | Possibly Damaging | 3.72 | Benign | 0.00 | Affected | 0.1481 | 0.0702 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.1105A>C | T369P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T369P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome, while FoldX and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for T369P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.468512 | Structured | 0.437011 | Uncertain | 0.417 | 0.707 | 0.500 | -2.743 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 1.20 | Ambiguous | 2.1 | 0.18 | Likely Benign | 0.69 | Ambiguous | 0.17 | Likely Benign | 0.138 | Likely Benign | -2.09 | Neutral | 0.396 | Benign | 0.142 | Benign | 1.83 | Pathogenic | 0.16 | Tolerated | 0.2589 | 0.6046 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1105A>G | T369A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T369A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and Foldetta are inconclusive. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that T369A is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.468512 | Structured | 0.437011 | Uncertain | 0.417 | 0.707 | 0.500 | -1.957 | Likely Benign | 0.056 | Likely Benign | Likely Benign | 0.09 | Likely Benign | 0.1 | 1.18 | Ambiguous | 0.64 | Ambiguous | 0.26 | Likely Benign | 0.090 | Likely Benign | -1.93 | Neutral | 0.012 | Benign | 0.016 | Benign | 1.72 | Pathogenic | 0.30 | Tolerated | 0.4538 | 0.5053 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1105A>T | T369S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T369S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No predictions or stability results are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.468512 | Structured | 0.437011 | Uncertain | 0.417 | 0.707 | 0.500 | -2.018 | Likely Benign | 0.071 | Likely Benign | Likely Benign | -0.07 | Likely Benign | 0.1 | 0.34 | Likely Benign | 0.14 | Likely Benign | 0.18 | Likely Benign | 0.097 | Likely Benign | -0.81 | Neutral | 0.001 | Benign | 0.001 | Benign | 1.78 | Pathogenic | 0.39 | Tolerated | 0.3746 | 0.4994 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1106C>A | T369K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T369K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FATHMM and AlphaMissense‑Default. Foldetta and Rosetta give uncertain results, which are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign vs two pathogenic). Foldetta’s stability prediction is uncertain. Overall, the majority of evidence (nine benign vs two pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.468512 | Structured | 0.437011 | Uncertain | 0.417 | 0.707 | 0.500 | -5.884 | Likely Benign | 0.616 | Likely Pathogenic | Likely Benign | -0.10 | Likely Benign | 0.1 | 1.13 | Ambiguous | 0.52 | Ambiguous | 0.27 | Likely Benign | 0.102 | Likely Benign | -1.87 | Neutral | 0.118 | Benign | 0.054 | Benign | 1.84 | Pathogenic | 0.34 | Tolerated | 0.1387 | 0.3855 | 0 | -1 | -3.2 | 27.07 | ||||||||||||||||||||||||||||||
| c.1106C>G | T369R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T369R is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438011‑C‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FATHMM and AlphaMissense‑Default. Rosetta and Foldetta are uncertain, so their results are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is also uncertain. Overall, the majority of evidence (nine benign vs two pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.468512 | Structured | 0.437011 | Uncertain | 0.417 | 0.707 | 0.500 | 6-33438011-C-G | 3 | 1.93e-6 | -6.772 | Likely Benign | 0.571 | Likely Pathogenic | Likely Benign | -0.27 | Likely Benign | 0.1 | 1.48 | Ambiguous | 0.61 | Ambiguous | 0.29 | Likely Benign | 0.148 | Likely Benign | -2.15 | Neutral | 0.244 | Benign | 0.107 | Benign | 1.72 | Pathogenic | 0.32 | Tolerated | 3.42 | 19 | 0.1217 | 0.3737 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||
| c.1106C>T | T369I 2D AIThe SynGAP1 missense variant T369I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact; there is no conflict with ClinVar status, which contains no entry for this variant. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.468512 | Structured | 0.437011 | Uncertain | 0.417 | 0.707 | 0.500 | -6.759 | Likely Benign | 0.289 | Likely Benign | Likely Benign | 0.60 | Ambiguous | 0.8 | 1.41 | Ambiguous | 1.01 | Ambiguous | -0.08 | Likely Benign | 0.078 | Likely Benign | -2.37 | Neutral | 0.396 | Benign | 0.142 | Benign | 1.72 | Pathogenic | 0.13 | Tolerated | 0.1106 | 0.7207 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.2164A>C | S722R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools and the high‑accuracy methods lean toward a pathogenic effect. Thus, the variant is most likely pathogenic based on current predictions, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -10.731 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.01 | Likely Benign | 0.72 | Ambiguous | 0.306 | Likely Benign | -2.66 | Deleterious | 0.999 | Probably Damaging | 0.948 | Probably Damaging | 2.52 | Benign | 0.09 | Tolerated | 0.0886 | 0.2797 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2164A>G | S722G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722G is not reported in ClinVar and is present in gnomAD (ID 6‑33441629‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and the protein‑folding stability method Foldetta. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. The consensus predictor SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as benign. No evidence from the high‑accuracy tools contradicts the benign predictions, but the consensus and several individual pathogenic predictors suggest a potential deleterious impact. Based on the overall pattern of predictions, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and the presence of multiple pathogenic signals. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | 6-33441629-A-G | 2 | 1.24e-6 | -9.141 | Likely Pathogenic | 0.214 | Likely Benign | Likely Benign | 0.24 | Likely Benign | 0.1 | 0.67 | Ambiguous | 0.46 | Likely Benign | 0.50 | Likely Benign | 0.270 | Likely Benign | -2.72 | Deleterious | 0.998 | Probably Damaging | 0.863 | Possibly Damaging | 2.49 | Pathogenic | 0.14 | Tolerated | 3.50 | 8 | 0.2202 | 0.3400 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||
| c.2164A>T | S722C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as benign. Overall, the majority of individual predictors and the high‑accuracy methods lean toward a benign impact, with only the SGM Consensus suggesting pathogenicity. Thus, the variant is most likely benign based on the available predictions, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -8.060 | Likely Pathogenic | 0.273 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.0 | -0.23 | Likely Benign | -0.01 | Likely Benign | 0.28 | Likely Benign | 0.362 | Likely Benign | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.968 | Probably Damaging | 2.46 | Pathogenic | 0.05 | Affected | 0.1132 | 0.4306 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.2165G>A | S722N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus classify the change as benign: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a neutral effect. No tool predicts pathogenicity; the only inconclusive results come from premPS and AlphaMissense‑Default, which are treated as unavailable evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign outcome, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a benign impact. Taken together, the evidence overwhelmingly supports a benign classification, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -4.399 | Likely Benign | 0.379 | Ambiguous | Likely Benign | 0.18 | Likely Benign | 0.1 | 0.15 | Likely Benign | 0.17 | Likely Benign | 0.79 | Ambiguous | 0.051 | Likely Benign | -0.91 | Neutral | 0.072 | Benign | 0.028 | Benign | 2.58 | Benign | 0.27 | Tolerated | 0.1258 | 0.3452 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||
| c.2165G>C | S722T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722T is reported in gnomAD (6‑33441630‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while FoldX is uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. No prediction or stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | 6-33441630-G-C | 1 | 6.20e-7 | -5.734 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.53 | Ambiguous | 0.0 | -0.32 | Likely Benign | 0.11 | Likely Benign | -0.12 | Likely Benign | 0.118 | Likely Benign | -0.57 | Neutral | 0.921 | Possibly Damaging | 0.414 | Benign | 2.57 | Benign | 1.00 | Tolerated | 3.50 | 8 | 0.1357 | 0.4363 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||
| c.2165G>T | S722I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S722I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, premPS, SIFT, and the folding‑stability method Foldetta, whereas pathogenic predictions are reported by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are provided by AlphaMissense‑Optimized, FoldX, and Rosetta. High‑accuracy analyses further clarify the picture: AlphaMissense‑Optimized remains inconclusive; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign impact on protein stability. Overall, the majority of evidence leans toward a pathogenic interpretation, and this conclusion does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -11.165 | Likely Pathogenic | 0.867 | Likely Pathogenic | Ambiguous | 0.69 | Ambiguous | 0.1 | -0.65 | Ambiguous | 0.02 | Likely Benign | 0.18 | Likely Benign | 0.232 | Likely Benign | -3.88 | Deleterious | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.48 | Pathogenic | 0.07 | Tolerated | 0.0776 | 0.4187 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.2166C>A | S722R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -10.731 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.01 | Likely Benign | 0.72 | Ambiguous | 0.221 | Likely Benign | -2.66 | Deleterious | 0.999 | Probably Damaging | 0.948 | Probably Damaging | 2.52 | Benign | 0.09 | Tolerated | 0.0886 | 0.2797 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2166C>G | S722R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign stability. Overall, the balance of evidence leans toward pathogenicity, and this conclusion does not contradict any ClinVar annotation (none is available). Thus, based on the current computational predictions, the S722R variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -10.731 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.01 | Likely Benign | 0.72 | Ambiguous | 0.220 | Likely Benign | -2.66 | Deleterious | 0.999 | Probably Damaging | 0.948 | Probably Damaging | 2.52 | Benign | 0.09 | Tolerated | 0.0886 | 0.2797 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.736C>A | L246M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L246M has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN and FATHMM, while a majority (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are uncertain. High‑accuracy methods are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Thus no high‑accuracy tool provides a definitive verdict. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any ClinVar status because no ClinVar record exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -11.386 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.65 | Ambiguous | 0.2 | 0.76 | Ambiguous | 0.71 | Ambiguous | 0.87 | Ambiguous | 0.661 | Likely Pathogenic | -1.79 | Neutral | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.72 | Benign | 0.01 | Affected | 0.0710 | 0.3511 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.736C>G | L246V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L246V is reported in gnomAD (variant ID 6‑33435587‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Only FATHMM predicts a benign outcome. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. The overwhelming majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | 6-33435587-C-G | 1 | 6.20e-7 | -12.092 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 2.09 | Destabilizing | 0.1 | 1.52 | Ambiguous | 1.81 | Ambiguous | 1.13 | Destabilizing | 0.736 | Likely Pathogenic | -2.60 | Deleterious | 0.930 | Possibly Damaging | 0.504 | Possibly Damaging | 4.71 | Benign | 0.01 | Affected | 3.41 | 14 | 0.1434 | 0.3607 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||
| c.737T>A | L246Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L246Q missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; Rosetta is uncertain and is not grouped. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the overwhelming majority of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -15.420 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.82 | Destabilizing | 0.3 | 1.79 | Ambiguous | 2.31 | Destabilizing | 1.69 | Destabilizing | 0.921 | Likely Pathogenic | -5.43 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.67 | Benign | 0.00 | Affected | 0.1092 | 0.0758 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.737T>C | L246P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L246P is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from FATHMM, while all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -16.581 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.42 | Destabilizing | 0.3 | 8.72 | Destabilizing | 7.57 | Destabilizing | 1.79 | Destabilizing | 0.944 | Likely Pathogenic | -6.30 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.67 | Benign | 0.00 | Affected | 0.3731 | 0.1582 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.737T>G | L246R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L246R missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -13.849 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.94 | Destabilizing | 0.8 | 2.77 | Destabilizing | 3.36 | Destabilizing | 1.72 | Destabilizing | 0.925 | Likely Pathogenic | -5.43 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.67 | Benign | 0.00 | Affected | 0.1266 | 0.0600 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2167A>C | T723P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723P is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity are SGM Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. premPS is uncertain and does not influence the overall assessment. Overall, the majority of tools and the high‑accuracy methods support a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.476583 | Structured | 0.458243 | Uncertain | 0.945 | 0.447 | 0.375 | -9.231 | Likely Pathogenic | 0.741 | Likely Pathogenic | Likely Benign | 3.98 | Destabilizing | 0.1 | 6.10 | Destabilizing | 5.04 | Destabilizing | 0.54 | Ambiguous | 0.085 | Likely Benign | -2.51 | Deleterious | 0.995 | Probably Damaging | 0.929 | Probably Damaging | 3.49 | Benign | 0.04 | Affected | 0.1826 | 0.4406 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.2167A>G | T723A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess sequence conservation, structural impact, or functional effect all converge on a benign outcome: SIFT, PolyPhen‑2 (HumDiv and HumVar), PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, REVEL, and the protein‑stability predictors FoldX, Rosetta, premPS, and Foldetta all indicate a benign effect. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Based on the uniform predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.476583 | Structured | 0.458243 | Uncertain | 0.945 | 0.447 | 0.375 | -4.572 | Likely Benign | 0.064 | Likely Benign | Likely Benign | -0.47 | Likely Benign | 0.0 | 0.16 | Likely Benign | -0.16 | Likely Benign | 0.25 | Likely Benign | 0.053 | Likely Benign | -0.91 | Neutral | 0.161 | Benign | 0.045 | Benign | 3.51 | Benign | 0.06 | Tolerated | 0.3902 | 0.3639 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.2167A>T | T723S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or tolerated. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The high‑accuracy consensus methods confirm the benign assessment: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Overall, the majority of evidence supports a benign impact for T723S, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.476583 | Structured | 0.458243 | Uncertain | 0.945 | 0.447 | 0.375 | -4.792 | Likely Benign | 0.091 | Likely Benign | Likely Benign | -0.26 | Likely Benign | 0.0 | 0.28 | Likely Benign | 0.01 | Likely Benign | 0.23 | Likely Benign | 0.037 | Likely Benign | -0.89 | Neutral | 0.673 | Possibly Damaging | 0.678 | Possibly Damaging | 3.55 | Benign | 0.06 | Tolerated | 0.3171 | 0.3731 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.2168C>A | T723K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, while FoldX and AlphaMissense‑Default are uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the preponderance of evidence supports a benign classification for T723K, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.476583 | Structured | 0.458243 | Uncertain | 0.945 | 0.447 | 0.375 | -4.624 | Likely Benign | 0.482 | Ambiguous | Likely Benign | -0.77 | Ambiguous | 0.1 | -0.04 | Likely Benign | -0.41 | Likely Benign | 0.25 | Likely Benign | 0.121 | Likely Benign | -1.40 | Neutral | 0.674 | Possibly Damaging | 0.118 | Benign | 3.46 | Benign | 0.51 | Tolerated | 0.0924 | 0.2798 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||
| c.2168C>G | T723R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify it as benign. Two tools (polyPhen‑2 HumDiv and HumVar) predict it to be pathogenic, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as likely benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign impact for T723R, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.476583 | Structured | 0.458243 | Uncertain | 0.945 | 0.447 | 0.375 | -3.654 | Likely Benign | 0.408 | Ambiguous | Likely Benign | -0.90 | Ambiguous | 0.1 | -0.13 | Likely Benign | -0.52 | Ambiguous | 0.44 | Likely Benign | 0.146 | Likely Benign | -1.50 | Neutral | 0.931 | Possibly Damaging | 0.458 | Possibly Damaging | 3.51 | Benign | 0.29 | Tolerated | 0.0794 | 0.2437 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||
| c.2168C>T | T723I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723I is listed in ClinVar as Benign (ClinVar ID 436924.0) and is observed in gnomAD (variant ID 6‑33441633‑C‑T). Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT classifies the change as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates a benign impact. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.476583 | Structured | 0.458243 | Uncertain | 0.945 | 0.447 | 0.375 | Likely Benign | 1 | 6-33441633-C-T | 2 | 1.24e-6 | -2.591 | Likely Benign | 0.120 | Likely Benign | Likely Benign | -0.39 | Likely Benign | 0.0 | -0.20 | Likely Benign | -0.30 | Likely Benign | 0.26 | Likely Benign | 0.045 | Likely Benign | -2.09 | Neutral | 0.088 | Benign | 0.030 | Benign | 3.39 | Benign | 0.03 | Affected | 3.50 | 8 | 0.0708 | 0.5803 | 0 | -1 | 5.2 | 12.05 | 252.3 | -31.6 | 0.0 | 0.0 | -0.2 | 0.2 | X | Uncertain | The hydroxyl group of Thr723, located on the outer surface of an α-helix (res. Leu714-Arg726), continuously forms hydrogen bonds with the backbone carbonyl of Asn719 in the WT simulations, potentially lowering the stability of the α-helix. In the variant simulations, the sec-butyl side chain of Ile723 cannot form any hydrogen bonds, which, in theory, could increase the helix stability. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | |||||||||||||
| c.2170G>A | A724T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A724T missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that indicate a benign effect include REVEL, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Predictions that are inconclusive are AlphaMissense‑Default, FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) suggest a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, as there is no existing classification to contradict. Thus, the variant is most likely pathogenic based on current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.476583 | Structured | 0.458050 | Uncertain | 0.923 | 0.483 | 0.250 | -8.047 | Likely Pathogenic | 0.456 | Ambiguous | Likely Benign | 0.95 | Ambiguous | 0.1 | 1.10 | Ambiguous | 1.03 | Ambiguous | 0.40 | Likely Benign | 0.273 | Likely Benign | -2.87 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 2.09 | Pathogenic | 0.01 | Affected | 0.1149 | 0.5897 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.2170G>C | A724P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A724P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: REVEL predicts a benign effect, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS [uncertain], PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a pathogenic score; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, classifies the variant as pathogenic. No tool suggests a benign outcome, and the single benign prediction (REVEL) is outweighed by the consensus of pathogenic predictions. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this mutation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.476583 | Structured | 0.458050 | Uncertain | 0.923 | 0.483 | 0.250 | -12.817 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.90 | Destabilizing | 0.3 | 6.35 | Destabilizing | 4.63 | Destabilizing | 0.52 | Ambiguous | 0.391 | Likely Benign | -3.88 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.04 | Pathogenic | 0.04 | Affected | 0.1642 | 0.4273 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.2170G>T | A724S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A724S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of evidence points to a benign impact for A724S, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.476583 | Structured | 0.458050 | Uncertain | 0.923 | 0.483 | 0.250 | -6.893 | Likely Benign | 0.204 | Likely Benign | Likely Benign | 0.93 | Ambiguous | 0.1 | 0.88 | Ambiguous | 0.91 | Ambiguous | 0.57 | Ambiguous | 0.265 | Likely Benign | -1.68 | Neutral | 0.983 | Probably Damaging | 0.993 | Probably Damaging | 2.20 | Pathogenic | 0.25 | Tolerated | 0.2308 | 0.4518 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.2171C>A | A724D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A724D is not reported in ClinVar or gnomAD. Prediction tools that indicate a benign effect include REVEL, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. Four methods (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for A724D, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.476583 | Structured | 0.458050 | Uncertain | 0.923 | 0.483 | 0.250 | -12.233 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 1.06 | Ambiguous | 0.2 | 0.86 | Ambiguous | 0.96 | Ambiguous | 0.60 | Ambiguous | 0.335 | Likely Benign | -4.44 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 0.1596 | 0.1812 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.2171C>G | A724G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A724G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.476583 | Structured | 0.458050 | Uncertain | 0.923 | 0.483 | 0.250 | -8.908 | Likely Pathogenic | 0.580 | Likely Pathogenic | Likely Benign | 1.45 | Ambiguous | 0.1 | 1.73 | Ambiguous | 1.59 | Ambiguous | 0.56 | Ambiguous | 0.286 | Likely Benign | -3.10 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.07 | Pathogenic | 0.08 | Tolerated | 0.2001 | 0.3609 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.2171C>T | A724V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A724V missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign, SGM Consensus predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. With no ClinVar annotation, there is no contradiction between the predictions and existing clinical data. Overall, the evidence is mixed, but the majority of high‑confidence tools lean toward a benign effect, suggesting the variant is most likely benign rather than pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.476583 | Structured | 0.458050 | Uncertain | 0.923 | 0.483 | 0.250 | -9.000 | Likely Pathogenic | 0.471 | Ambiguous | Likely Benign | 0.42 | Likely Benign | 0.1 | 0.35 | Likely Benign | 0.39 | Likely Benign | 0.24 | Likely Benign | 0.241 | Likely Benign | -3.28 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 2.07 | Pathogenic | 0.01 | Affected | 0.0872 | 0.5620 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.2446T>A | S816T 2D AIThe SynGAP1 missense variant S816T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. 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 | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -3.957 | Likely Benign | 0.408 | Ambiguous | Likely Benign | 0.064 | Likely Benign | -1.05 | Neutral | 0.990 | Probably Damaging | 0.846 | Possibly Damaging | 2.65 | Benign | 0.32 | Tolerated | 0.1573 | 0.5529 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2446T>C | S816P 2D AIThe SynGAP1 missense variant S816P is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) suggest pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus likewise indicates Likely Benign; Foldetta data are unavailable. Overall, the preponderance of evidence points to a benign effect for S816P, and this conclusion is not in conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -3.662 | Likely Benign | 0.510 | Ambiguous | Likely Benign | 0.160 | Likely Benign | -0.26 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.66 | Benign | 0.45 | Tolerated | 0.2298 | 0.5102 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2446T>G | S816A 2D AIThe SynGAP1 missense variant S816A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. 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 collective 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 | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -4.543 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.07 | Neutral | 0.953 | Possibly Damaging | 0.799 | Possibly Damaging | 2.67 | Benign | 0.59 | Tolerated | 0.5307 | 0.4532 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2447C>A | S816Y 2D AIThe SynGAP1 missense variant S816Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default, all of which classify the substitution as deleterious. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized yields an uncertain result, while Foldetta data are unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus, the variant is most likely pathogenic; this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -8.369 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | -2.83 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.60 | Benign | 0.03 | Affected | 0.0668 | 0.4741 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2447C>G | S816C 2D AIThe SynGAP1 missense variant S816C has no ClinVar record and is not present in gnomAD. Functional prediction tools fall into two groups: benign predictions come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the evidence is mixed, with an equal split between benign and pathogenic calls among general predictors and conflicting outcomes from the two high‑accuracy tools. The variant is most likely pathogenic based on the predominance of pathogenic predictions, and this assessment does not contradict ClinVar status, which currently has no entry for S816C. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -7.998 | In-Between | 0.605 | Likely Pathogenic | Likely Benign | 0.246 | Likely Benign | -2.75 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 2.59 | Benign | 0.06 | Tolerated | 0.1167 | 0.5472 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2447C>T | S816F 2D AIThe SynGAP1 missense variant S816F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. When predictions are grouped, two tools predict benign and six predict pathogenic. High‑accuracy assessment further supports a pathogenic interpretation: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both conventional and high‑accuracy predictors indicates that S816F is most likely pathogenic, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -8.804 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.232 | Likely Benign | -3.21 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.59 | Benign | 0.03 | Affected | 0.0605 | 0.5014 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3562G>A | D1188N 2D AIThe SynGAP1 D1188N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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 inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic classification for D1188N, 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. | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -5.621 | Likely Benign | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.340 | Likely Benign | -2.50 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 5.47 | Benign | 0.00 | Affected | 0.0767 | 0.4663 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3562G>C | D1188H 2D AIThe SynGAP1 D1188H missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, while those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -6.827 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.420 | Likely Benign | -3.27 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 5.41 | Benign | 0.00 | Affected | 0.0892 | 0.5242 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3562G>T | D1188Y 2D AIThe SynGAP1 D1188Y missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evaluated tools (seven pathogenic versus three benign) indicate a pathogenic impact. This prediction aligns with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -6.482 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.490 | Likely Benign | -4.49 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 5.40 | Benign | 0.00 | Affected | 0.0450 | 0.4714 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.3563A>C | D1188A 2D AIThe SynGAP1 D1188A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL, ESM1b, and FATHMM, while those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. This prediction 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. | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -4.369 | Likely Benign | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.439 | Likely Benign | -3.91 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 5.45 | Benign | 0.00 | Affected | 0.2768 | 0.4495 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.3563A>G | D1188G 2D AIThe SynGAP1 D1188G missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus method SGM, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a tie and is therefore inconclusive. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not conflict with any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -5.286 | Likely Benign | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.440 | Likely Benign | -3.69 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 5.47 | Benign | 0.00 | Affected | 0.2771 | 0.4880 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3563A>T | D1188V 2D AIThe SynGAP1 D1188V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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 inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the balance of evidence (seven pathogenic versus three benign predictions) indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -4.482 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.479 | Likely Benign | -4.13 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 5.49 | Benign | 0.00 | Affected | 0.0592 | 0.4651 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3564T>A | D1188E 2D AIThe SynGAP1 missense variant D1188E 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. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized model classifies the variant as pathogenic, whereas the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic interpretation. The variant is most likely pathogenic based on the consensus of computational tools, 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 Benign | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -2.517 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.382 | Likely Benign | -1.93 | Neutral | 0.992 | Probably Damaging | 0.992 | Probably Damaging | 5.50 | Benign | 0.00 | Affected | 0.0954 | 0.4616 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3564T>G | D1188E 2D AIThe SynGAP1 missense variant D1188E 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. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy predictors give a mixed picture: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this residue. Overall, five of the nine evaluated tools predict pathogenicity while four predict benignity, with the high‑accuracy AlphaMissense‑Optimized result supporting the pathogenic prediction. Therefore, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -2.517 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.382 | Likely Benign | -1.93 | Neutral | 0.992 | Probably Damaging | 0.992 | Probably Damaging | 5.50 | Benign | 0.00 | Affected | 0.0954 | 0.4616 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.418T>A | S140T 2D AIThe SynGAP1 missense variant S140T 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) remains Likely Benign. Foldetta predictions are unavailable. Overall, the balance of evidence, particularly the SGM‑Consensus and the majority of benign‑predicting tools, suggests that the variant is most likely benign. 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 Benign | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -6.336 | Likely Benign | 0.873 | Likely Pathogenic | Ambiguous | 0.132 | Likely Benign | -1.94 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 3.59 | Benign | 0.03 | Affected | 0.1069 | 0.5722 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.418T>C | S140P 2D AIThe SynGAP1 missense variant S140P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized as pathogenic, while SGM Consensus and Foldetta are unavailable. Overall, the majority of evidence points to a pathogenic impact for S140P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -4.089 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.287 | Likely Benign | -2.59 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.52 | Benign | 0.08 | Tolerated | 0.1726 | 0.5117 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||||||
| c.418T>G | S140A 2D AIThe SynGAP1 missense variant S140A is not 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. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. three benign) indicate a pathogenic impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -9.068 | Likely Pathogenic | 0.805 | Likely Pathogenic | Ambiguous | 0.141 | Likely Benign | -1.83 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 3.62 | Benign | 0.05 | Affected | 0.4449 | 0.4320 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||||
| c.419C>A | S140Y 2D AIThe SynGAP1 missense variant S140Y 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 and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the S140Y variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -13.071 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.252 | Likely Benign | -3.88 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 3.48 | Benign | 0.00 | Affected | 0.0597 | 0.5849 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.419C>G | S140C 2D AIThe SynGAP1 missense variant S140C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as 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 the S140C variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -10.103 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.170 | Likely Benign | -3.11 | Deleterious | 0.999 | Probably Damaging | 0.990 | Probably Damaging | 3.49 | Benign | 0.01 | Affected | 0.0811 | 0.5709 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.419C>T | S140F 2D AIThe SynGAP1 missense variant S140F 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 and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic or likely pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports “Likely Pathogenic.” High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote) also indicates likely pathogenic. Foldetta results are unavailable. Overall, the consensus of the available predictions points to a pathogenic effect for S140F, 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 | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -10.824 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.246 | Likely Benign | -3.83 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 3.48 | Benign | 0.00 | Affected | 0.0565 | 0.5988 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.466T>A | F156I 2D AIThe SynGAP1 missense variant F156I is not 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. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence predictors (six out of nine) indicate a pathogenic impact, whereas three predict benign. Consequently, the variant is most likely pathogenic based on current computational evidence, 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. | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | -10.505 | Likely Pathogenic | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.194 | Likely Benign | -2.38 | Neutral | 0.981 | Probably Damaging | 0.966 | Probably Damaging | 3.99 | Benign | 0.00 | Affected | 0.1960 | 0.1938 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.466T>C | F156L 2D AIThe SynGAP1 missense variant F156L is not 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 tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of conventional tools predict pathogenicity, but the high‑accuracy consensus is ambiguous. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | -7.437 | In-Between | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.180 | Likely Benign | -2.31 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.04 | Benign | 0.00 | Affected | 0.2067 | 0.3109 | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.466T>G | F156V 2D AIThe SynGAP1 missense variant F156V is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—classify the change as pathogenic. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, but the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic status. Foldetta, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence points to a pathogenic effect for F156V, and this conclusion does not conflict with the current ClinVar annotation, which is absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | -11.945 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.246 | Likely Benign | -2.91 | Deleterious | 0.981 | Probably Damaging | 0.954 | Probably Damaging | 4.03 | Benign | 0.00 | Affected | 0.2177 | 0.2166 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||||||||||||
| c.467T>A | F156Y 2D AIThe SynGAP1 missense variant F156Y is not 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 a majority of tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a tie (2 pathogenic vs. 2 benign) and thus unavailable; Foldetta predictions are not provided. Overall, the balance of evidence (5 pathogenic vs. 3 benign predictions) indicates that 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. | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | -11.811 | Likely Pathogenic | 0.869 | Likely Pathogenic | Ambiguous | 0.136 | Likely Benign | -1.51 | Neutral | 0.981 | Probably Damaging | 0.931 | Probably Damaging | 3.96 | Benign | 0.00 | Affected | 0.1363 | 0.1419 | 7 | 3 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||||||||||||
| c.467T>C | F156S 2D AIThe SynGAP1 missense variant F156S 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, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Pathogenic” based on a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (derived from the same set of high‑accuracy predictors) also indicates a likely pathogenic outcome. Foldetta results are unavailable, so they do not influence the overall assessment. 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 | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | -14.082 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.282 | Likely Benign | -3.62 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.97 | Benign | 0.00 | Affected | 0.5183 | 0.0200 | Weaken | -3 | -2 | -3.6 | -60.10 | ||||||||||||||||||||||||||||||||||||||
| c.467T>G | F156C 2D AIThe SynGAP1 missense variant F156C is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus reports it as “Likely Pathogenic.” No Foldetta stability analysis is available for this variant. Overall, the majority of predictions, including the high‑accuracy tools, indicate that F156C is most likely pathogenic, which is consistent with its ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | Uncertain | 1 | -13.658 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.297 | Likely Benign | -3.54 | Deleterious | 0.999 | Probably Damaging | 0.990 | Probably Damaging | 3.92 | Benign | 0.00 | Affected | 0.3030 | 0.1291 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||||
| c.468T>A | F156L 2D AIThe SynGAP1 missense variant F156L is not 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 tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of conventional tools predict pathogenicity, but the high‑accuracy consensus is ambiguous. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | -7.437 | In-Between | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.164 | Likely Benign | -2.31 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.04 | Benign | 0.00 | Affected | 0.2067 | 0.3109 | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.468T>G | F156L 2D AISynGAP1 missense variant F156L 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 tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (benign)—leans toward benign. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the preponderance of conventional tools indicates a pathogenic effect, and the high‑accuracy predictions are mixed; no ClinVar entry exists to contradict the assessment. Therefore, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | -7.437 | In-Between | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.163 | Likely Benign | -2.31 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.04 | Benign | 0.00 | Affected | 0.2067 | 0.3109 | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.547C>A | H183N 2D AIThe SynGAP1 H183N missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, tools that predict a pathogenic impact are PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the majority of predictions, including the high‑accuracy tools, point to a pathogenic effect, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -12.028 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.188 | Likely Benign | -4.97 | Deleterious | 0.012 | Benign | 0.006 | Benign | 3.81 | Benign | 0.01 | Affected | 0.1714 | 0.2589 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.547C>G | H183D 2D AIThe SynGAP1 missense variant H183D 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Pathogenic, and AlphaMissense‑Optimized independently predicts Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the majority of predictions (seven pathogenic vs. four benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for H183D. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -18.626 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.311 | Likely Benign | -6.55 | Deleterious | 0.421 | Benign | 0.107 | Benign | 3.81 | Benign | 0.01 | Affected | 0.2620 | 0.1817 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.547C>T | H183Y 2D AIThe SynGAP1 H183Y missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of computational evidence points to 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. | Likely Pathogenic | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -9.481 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.250 | Likely Benign | -4.48 | Deleterious | 0.818 | Possibly Damaging | 0.255 | Benign | 3.77 | Benign | 0.00 | Affected | 0.0831 | 0.4406 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.548A>C | H183P 2D AIThe SynGAP1 missense variant H183P 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, 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 also predicts Pathogenic, while the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic impact, 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 | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -18.527 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.410 | Likely Benign | -7.18 | Deleterious | 0.838 | Possibly Damaging | 0.276 | Benign | 3.79 | Benign | 0.01 | Affected | 0.2143 | 0.3712 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.548A>G | H183R 2D AIThe SynGAP1 H183R missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus (majority vote) also pathogenic; Foldetta stability analysis is unavailable. Based on the majority of computational evidence, 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 | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -10.937 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.368 | Likely Benign | -5.43 | Deleterious | 0.596 | Possibly Damaging | 0.142 | Benign | 3.90 | Benign | 0.13 | Tolerated | 0.1915 | 0.2249 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.548A>T | H183L 2D AIThe SynGAP1 missense variant H183L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Pathogenic” verdict (3 pathogenic vs. 1 benign votes). AlphaMissense‑Optimized alone also predicts pathogenic. 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 pathogenic 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 Pathogenic | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -12.898 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.325 | Likely Benign | -8.12 | Deleterious | 0.421 | Benign | 0.058 | Benign | 3.79 | Benign | 0.01 | Affected | 0.0911 | 0.5304 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.549T>A | H183Q 2D AIThe SynGAP1 missense variant H183Q 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, 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 | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -10.383 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.223 | Likely Benign | -5.43 | Deleterious | 0.838 | Possibly Damaging | 0.276 | Benign | 3.88 | Benign | 0.01 | Affected | 0.1470 | 0.3623 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.549T>G | H183Q 2D AIThe SynGAP1 missense variant H183Q 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, 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 | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -10.383 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.223 | Likely Benign | -5.43 | Deleterious | 0.838 | Possibly Damaging | 0.276 | Benign | 3.88 | Benign | 0.01 | Affected | 0.1470 | 0.3623 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2611C>A | H871N 2D AIThe SynGAP1 missense variant H871N is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -3.303 | Likely Benign | 0.046 | Likely Benign | Likely Benign | 0.100 | Likely Benign | 0.69 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.69 | Benign | 0.40 | Tolerated | 0.1626 | 0.2507 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.2611C>G | H871D 2D AIThe SynGAP1 missense variant H871D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -3.263 | Likely Benign | 0.257 | Likely Benign | Likely Benign | 0.245 | Likely Benign | -0.51 | Neutral | 0.016 | Benign | 0.026 | Benign | 2.80 | Benign | 0.31 | Tolerated | 0.2271 | 0.1617 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2611C>T | H871Y 2D AIThe SynGAP1 missense variant H871Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -4.070 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -1.44 | Neutral | 0.510 | Possibly Damaging | 0.206 | Benign | 2.63 | Benign | 0.08 | Tolerated | 0.0872 | 0.3945 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.2612A>C | H871P 2D AIThe SynGAP1 missense variant H871P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also reports 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 | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -3.420 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.207 | Likely Benign | -0.91 | Neutral | 0.510 | Possibly Damaging | 0.206 | Benign | 2.63 | Benign | 0.18 | Tolerated | 0.2163 | 0.3757 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2612A>G | H871R 2D AIThe SynGAP1 missense variant H871R is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -3.894 | Likely Benign | 0.243 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -0.90 | Neutral | 0.144 | Benign | 0.085 | Benign | 2.67 | Benign | 0.23 | Tolerated | 0.1632 | 0.2099 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.2612A>T | H871L 2D AIThe SynGAP1 missense variant H871L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -4.562 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -2.16 | Neutral | 0.069 | Benign | 0.054 | Benign | 2.65 | Benign | 0.14 | Tolerated | 0.0953 | 0.4714 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.2613C>A | H871Q 2D AIThe SynGAP1 missense variant H871Q is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign classification, and 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 Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -4.049 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -0.67 | Neutral | 0.255 | Benign | 0.113 | Benign | 2.69 | Benign | 0.17 | Tolerated | 3.88 | 3 | 0.1384 | 0.3357 | 0 | 3 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||
| c.2613C>G | H871Q 2D AIThe SynGAP1 missense variant H871Q is reported in gnomAD (ID 6‑33443165‑C‑G) and has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability predictor, was not available for this variant. Overall, the evidence strongly supports a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | 6-33443165-C-G | 1 | 6.20e-7 | -4.049 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -0.67 | Neutral | 0.255 | Benign | 0.113 | Benign | 2.69 | Benign | 0.17 | Tolerated | 3.88 | 3 | 0.1384 | 0.3357 | 0 | 3 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||
| c.34A>C | S12R 2D AIThe SynGAP1 missense variant S12R 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 this: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority of the four high‑accuracy tools) 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 points to a benign impact, 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 | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | -4.033 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.116 | Likely Benign | -0.30 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0944 | 0.3678 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.34A>G | S12G 2D AIThe SynGAP1 missense variant S12G is reported in gnomAD (ID 6‑33420298‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign status. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for S12G, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | 6-33420298-A-G | -4.229 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.079 | Likely Benign | 0.22 | Neutral | 0.103 | Benign | 0.015 | Benign | 4.11 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2876 | 0.5080 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||
| c.34A>T | S12C 2D AIThe SynGAP1 missense variant S12C is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools largely support a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, two tools—polyPhen‑2 HumDiv and SIFT—predict a pathogenic impact. High‑accuracy methods give a consistent benign signal: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is not in conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | -5.413 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.00 | Neutral | 0.872 | Possibly Damaging | 0.206 | Benign | 4.05 | Benign | 0.00 | Affected | 0.1025 | 0.6092 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.35G>A | S12N 2D AIThe SynGAP1 missense variant S12N is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6‑33420299‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | 6-33420299-G-A | -4.946 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.41 | Neutral | 0.208 | Benign | 0.018 | Benign | 4.10 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1405 | 0.5004 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||
| c.35G>C | S12T 2D AIThe SynGAP1 missense variant S12T 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. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a benign effect. AlphaMissense‑Optimized independently scores the variant as 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). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | -4.304 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.16 | Neutral | 0.208 | Benign | 0.024 | Benign | 4.14 | Benign | 0.00 | Affected | 0.1487 | 0.6303 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.35G>T | S12I 2D AIThe SynGAP1 missense variant S12I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | -4.838 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.121 | Likely Benign | 0.05 | Neutral | 0.659 | Possibly Damaging | 0.072 | Benign | 4.09 | Benign | 0.00 | Affected | 0.0964 | 0.6082 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.36C>A | S12R 2D AIThe SynGAP1 missense variant S12R is present in gnomAD (ID 6‑33420300‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score all report benign or likely benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | 6-33420300-C-A | -4.033 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.097 | Likely Benign | -0.30 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0944 | 0.3678 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.36C>G | S12R 2D AIThe SynGAP1 missense variant S12R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33420300‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign classification; Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | Uncertain | 1 | 6-33420300-C-G | 4 | 2.59e-6 | -4.033 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.097 | Likely Benign | -0.30 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0944 | 0.3678 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||
| c.472C>A | Q158K 2D AIThe SynGAP1 missense variant Q158K is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. 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 interpretation: 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. Overall, the computational evidence strongly suggests 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 | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -6.795 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.069 | Likely Benign | -0.86 | Neutral | 0.276 | Benign | 0.121 | Benign | 4.20 | Benign | 0.15 | Tolerated | 0.1851 | 0.3869 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.472C>G | Q158E 2D AIThe SynGAP1 missense variant Q158E 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), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only ESM1b predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -11.133 | Likely Pathogenic | 0.196 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.54 | Neutral | 0.143 | Benign | 0.078 | Benign | 4.20 | Benign | 0.09 | Tolerated | 0.1420 | 0.2223 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.473A>C | Q158P 2D AIThe SynGAP1 missense variant Q158P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for Q158P, 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 | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -6.120 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.192 | Likely Benign | -0.99 | Neutral | 0.851 | Possibly Damaging | 0.374 | Benign | 4.12 | Benign | 0.03 | Affected | 0.2167 | 0.4190 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.473A>G | Q158R 2D AIThe SynGAP1 missense variant Q158R 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, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The predictions do not contradict ClinVar status, as ClinVar contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -6.873 | Likely Benign | 0.438 | Ambiguous | Likely Benign | 0.090 | Likely Benign | -0.85 | Neutral | 0.276 | Benign | 0.121 | Benign | 4.14 | Benign | 0.11 | Tolerated | 0.1527 | 0.1498 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.473A>T | Q158L 2D AIThe SynGAP1 missense variant Q158L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for Q158L, 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 | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -5.965 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.141 | Likely Benign | -1.11 | Neutral | 0.652 | Possibly Damaging | 0.160 | Benign | 4.14 | Benign | 0.03 | Affected | 0.0711 | 0.4832 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.474G>C | Q158H 2D AIThe SynGAP1 missense variant Q158H is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the 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 | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -2.990 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.02 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.19 | Benign | 0.51 | Tolerated | 0.1403 | 0.3774 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.474G>T | Q158H 2D AIThe SynGAP1 missense variant Q158H is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the 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 | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -2.990 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.02 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.19 | Benign | 0.51 | Tolerated | 0.1403 | 0.3774 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.508C>G | R170G 2D AIThe SynGAP1 missense variant R170G is not reported in ClinVar and has no entries in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic impact for R170G, and this conclusion 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 | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | -10.092 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.196 | Likely Benign | -3.19 | Deleterious | 0.664 | Possibly Damaging | 0.137 | Benign | 3.88 | Benign | 0.00 | Affected | 0.3285 | 0.3004 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.508C>T | R170W 2D AIThe SynGAP1 missense variant R170W is listed in ClinVar (ID 1310195.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—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 a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus indicates it is likely pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect, 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 | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | Uncertain | 2 | -11.660 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.241 | Likely Benign | -4.28 | Deleterious | 0.999 | Probably Damaging | 0.849 | Possibly Damaging | 3.84 | Benign | 0.00 | Affected | 3.74 | 4 | 0.1026 | 0.3469 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.509G>A | R170Q 2D AISynGAP1 missense variant R170Q is listed in ClinVar as Pathogenic and is not reported in gnomAD. Computational predictors show a split: benign calls come from REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is Uncertain, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive; Foldetta stability analysis is unavailable. Thus, no single method or high‑accuracy consensus strongly supports pathogenicity. The variant is most likely benign according to the current computational evidence, which contradicts the ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | Pathogenic/Likely path. | 6 | -9.021 | Likely Pathogenic | 0.798 | Likely Pathogenic | Ambiguous | 0.221 | Likely Benign | -2.31 | Neutral | 0.947 | Possibly Damaging | 0.342 | Benign | 3.91 | Benign | 0.00 | Affected | 3.74 | 4 | 0.2524 | 0.2299 | 1 | 1 | 1.0 | -28.06 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||||||
| c.509G>C | R170P 2D AIThe SynGAP1 missense variant R170P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates 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 R170P 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 | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | -9.687 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.386 | Likely Benign | -3.96 | Deleterious | 0.966 | Probably Damaging | 0.599 | Possibly Damaging | 3.86 | Benign | 0.00 | Affected | 0.1967 | 0.3989 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.509G>T | R170L 2D AIThe SynGAP1 missense variant R170L has no ClinVar entry and is not reported in gnomAD. In silico predictors fall into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy tools further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) also indicates 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 pathogenic predictions, including the high‑accuracy consensus, suggests that R170L is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | -8.649 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.319 | Likely Benign | -4.02 | Deleterious | 0.798 | Possibly Damaging | 0.319 | Benign | 3.87 | Benign | 0.00 | Affected | 0.1561 | 0.4310 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2608C>A | L870M 2D AIThe SynGAP1 missense variant L870M 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‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.809 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -1.01 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.60 | Benign | 0.10 | Tolerated | 0.0757 | 0.3956 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2608C>G | L870V 2D AIThe SynGAP1 missense variant L870V is listed in ClinVar (ID 946946.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, PolyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with the ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | Uncertain | 1 | -4.123 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -1.19 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.64 | Benign | 0.12 | Tolerated | 3.88 | 3 | 0.1549 | 0.3977 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.2609T>A | L870Q 2D AIThe SynGAP1 missense variant L870Q is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus itself is labeled likely benign. No output is available from the Foldetta stability analysis, so it does not influence the overall assessment. Based on the aggregate predictions, the variant is most likely benign, and 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. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.029 | Likely Benign | 0.417 | Ambiguous | Likely Benign | 0.185 | Likely Benign | -1.90 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.63 | Benign | 0.02 | Affected | 0.1027 | 0.1003 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2609T>C | L870P 2D AIThe SynGAP1 missense variant L870P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, 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 Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.462 | Likely Benign | 0.402 | Ambiguous | Likely Benign | 0.194 | Likely Benign | -1.92 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.59 | Benign | 0.13 | Tolerated | 0.3795 | 0.1864 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2609T>G | L870R 2D AIThe SynGAP1 missense variant L870R is not reported in ClinVar and has no entries in 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 for this variant, and this conclusion does not contradict the ClinVar status, which currently contains no classification for L870R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.578 | Likely Benign | 0.636 | Likely Pathogenic | Likely Benign | 0.175 | Likely Benign | -1.97 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.63 | Benign | 0.02 | Affected | 0.1147 | 0.0846 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2773C>A | L925I 2D AIThe SynGAP1 missense variant L925I is not 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 ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, 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 combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of consensus tools (five pathogenic vs. three benign) lean toward a pathogenic interpretation. This prediction does not contradict ClinVar status, as the variant is not yet catalogued there. 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. | 0.483068 | Structured | 0.977963 | Binding | 0.290 | 0.852 | 0.125 | -5.266 | Likely Benign | 0.828 | Likely Pathogenic | Ambiguous | 0.205 | Likely Benign | -1.38 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.37 | Pathogenic | 0.00 | Affected | 0.1192 | 0.3405 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||||||
| c.2773C>G | L925V 2D AIThe SynGAP1 missense variant L925V is not 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 ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, 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 consensus tools predict a pathogenic impact, and this prediction does not contradict any ClinVar annotation (none exists). 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. | 0.483068 | Structured | 0.977963 | Binding | 0.290 | 0.852 | 0.125 | -3.977 | Likely Benign | 0.831 | Likely Pathogenic | Ambiguous | 0.244 | Likely Benign | -2.09 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.36 | Pathogenic | 0.00 | Affected | 0.1848 | 0.3230 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2773C>T | L925F 2D AIThe SynGAP1 missense variant L925F is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL and ESM1b, whereas the majority of tools predict it to be pathogenic: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of computational evidence points to a pathogenic impact for the L925F substitution, 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 | 0.483068 | Structured | 0.977963 | Binding | 0.290 | 0.852 | 0.125 | -4.147 | Likely Benign | 0.966 | Likely Pathogenic | Likely Pathogenic | 0.242 | Likely Benign | -3.04 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.32 | Pathogenic | 0.00 | Affected | 0.0897 | 0.2881 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2774T>A | L925H 2D AIThe SynGAP1 missense variant L925H 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 ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic.” No Foldetta stability result is available. Overall, the majority of evidence points to a pathogenic effect for L925H, 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 | 0.483068 | Structured | 0.977963 | Binding | 0.290 | 0.852 | 0.125 | -3.369 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.475 | Likely Benign | -5.24 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 0.1219 | 0.1494 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.2774T>C | L925P 2D AIThe SynGAP1 missense variant L925P 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 ESM1b, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from multiple in silico predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.977963 | Binding | 0.290 | 0.852 | 0.125 | -2.733 | Likely Benign | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.501 | Likely Pathogenic | -5.12 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 0.3083 | 0.1996 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2774T>G | L925R 2D AIThe SynGAP1 missense variant L925R 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 ESM1b, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized reports a pathogenic effect, and the SGM‑Consensus indicates a likely pathogenic classification. Foldetta results are not available for this variant. 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 reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.977963 | Binding | 0.290 | 0.852 | 0.125 | -2.340 | Likely Benign | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.519 | Likely Pathogenic | -4.54 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 0.1278 | 0.1294 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3520G>A | E1174K 2D AIThe SynGAP1 missense variant E1174K is listed in ClinVar with an uncertain significance (ClinVar ID 1905754.0) and is present in gnomAD (variant ID 6‑33444555‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, matching the reported SGM‑Consensus result. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. Taken together, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | Uncertain | 1 | 6-33444555-G-A | 2 | 1.24e-6 | -4.345 | Likely Benign | 0.898 | Likely Pathogenic | Ambiguous | 0.442 | Likely Benign | -1.59 | Neutral | 0.962 | Probably Damaging | 0.367 | Benign | 5.52 | Benign | 0.03 | Affected | 4.32 | 2 | 0.1852 | 0.6521 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||
| c.3520G>C | E1174Q 2D AIThe SynGAP1 missense variant E1174Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta results are unavailable. Based on the overall distribution of predictions and the consensus from high‑accuracy tools, the variant is most likely benign. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | -3.778 | Likely Benign | 0.603 | Likely Pathogenic | Likely Benign | 0.323 | Likely Benign | -1.04 | Neutral | 0.959 | Probably Damaging | 0.681 | Possibly Damaging | 5.43 | Benign | 0.03 | Affected | 0.0936 | 0.6268 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||
| c.3521A>C | E1174A 2D AIThe SynGAP1 missense variant E1174A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are not available, so they do not influence the conclusion. Overall, the majority of evidence points to a benign 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 Benign | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | -3.512 | Likely Benign | 0.737 | Likely Pathogenic | Likely Benign | 0.413 | Likely Benign | -2.24 | Neutral | 0.790 | Possibly Damaging | 0.353 | Benign | 5.44 | Benign | 0.02 | Affected | 0.3462 | 0.5889 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3521A>G | E1174G 2D AIThe SynGAP1 E1174G missense change 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, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and the Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect for E1174G, 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 | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | -4.197 | Likely Benign | 0.714 | Likely Pathogenic | Likely Benign | 0.397 | Likely Benign | -2.20 | Neutral | 0.818 | Possibly Damaging | 0.353 | Benign | 5.42 | Benign | 0.01 | Affected | 0.2665 | 0.5614 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||
| c.3521A>T | E1174V 2D AIThe SynGAP1 missense variant E1174V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from PROVEAN, ESM1b, and FATHMM, while pathogenic calls are made by REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. Grouping by consensus, the majority of tools (four out of six) predict a benign effect, whereas the remaining four predict pathogenicity. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence leans toward a benign impact for E1174V, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | -4.814 | Likely Benign | 0.877 | Likely Pathogenic | Ambiguous | 0.515 | Likely Pathogenic | -2.41 | Neutral | 0.965 | Probably Damaging | 0.703 | Possibly Damaging | 5.41 | Benign | 0.01 | Affected | 0.0539 | 0.6623 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||
| c.3522G>C | E1174D 2D AIThe SynGAP1 missense variant E1174D is reported in gnomAD (variant ID 6-33444557-G-C) and has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No tool predicts pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is likely benign; Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | 6-33444557-G-C | 1 | 6.20e-7 | -4.257 | Likely Benign | 0.253 | Likely Benign | Likely Benign | 0.234 | Likely Benign | -0.19 | Neutral | 0.002 | Benign | 0.006 | Benign | 5.45 | Benign | 0.36 | Tolerated | 4.32 | 2 | 0.1557 | 0.4226 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||
| c.3522G>T | E1174D 2D AIThe SynGAP1 missense change E1174D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the variant as benign. No tool predicts pathogenicity. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a “Likely Benign” verdict, while AlphaMissense‑Optimized also reports benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, every available prediction supports a benign effect, and this conclusion is consistent with the lack of a ClinVar classification. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | -4.257 | Likely Benign | 0.253 | Likely Benign | Likely Benign | 0.234 | Likely Benign | -0.19 | Neutral | 0.002 | Benign | 0.006 | Benign | 5.45 | Benign | 0.36 | Tolerated | 4.32 | 2 | 0.1557 | 0.4226 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.3811G>A | E1271K 2D AIThe SynGAP1 missense variant E1271K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further reveal AlphaMissense‑Optimized as benign, whereas Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the preponderance of evidence—both from general predictors and the SGM Consensus—leans toward pathogenicity. 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 | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -2.295 | Likely Benign | 0.689 | Likely Pathogenic | Likely Benign | 0.192 | Likely Benign | -3.24 | Deleterious | 0.905 | Possibly Damaging | 0.433 | Benign | 2.07 | Pathogenic | 0.00 | Affected | 0.1780 | 0.5888 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3811G>C | E1271Q 2D AIThe SynGAP1 missense variant E1271Q 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. 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 not available. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Thus, based on the available computational evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -3.085 | Likely Benign | 0.282 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -2.40 | Neutral | 0.951 | Possibly Damaging | 0.617 | Possibly Damaging | 2.06 | Pathogenic | 0.00 | Affected | 0.0955 | 0.5470 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3812A>C | E1271A 2D AIThe SynGAP1 missense variant E1271A is not 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, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessment shows AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of conventional tools and the high‑accuracy consensus favor a pathogenic interpretation. This prediction does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -3.817 | Likely Benign | 0.375 | Ambiguous | Likely Benign | 0.298 | Likely Benign | -4.79 | Deleterious | 0.951 | Possibly Damaging | 0.433 | Benign | 2.06 | Pathogenic | 0.00 | Affected | 0.2985 | 0.4959 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3812A>G | E1271G 2D AIThe SynGAP1 missense variant E1271G is catalogued in gnomAD (ID 6‑33447860‑A‑G) but has no entry in ClinVar. Functional prediction tools show a split consensus: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign effect, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (two pathogenic versus one benign vote). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence, including the SGM Consensus, indicates a pathogenic impact. This prediction is not contradicted by ClinVar, as no ClinVar classification exists for E1271G. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | 6-33447860-A-G | -4.857 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.288 | Likely Benign | -5.37 | Deleterious | 0.905 | Possibly Damaging | 0.538 | Possibly Damaging | 2.05 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2513 | 0.5485 | -2 | 0 | 3.1 | -72.06 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||||||||
| c.3812A>T | E1271V 2D AISynGAP1 missense variant E1271V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. AlphaMissense‑Optimized yields an uncertain result, and no Foldetta stability assessment is available. Considering the majority of high‑confidence tools and the consensus score, the variant is most likely pathogenic. This assessment does not contradict any ClinVar annotation, as no ClinVar entry exists for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -6.961 | Likely Benign | 0.848 | Likely Pathogenic | Ambiguous | 0.303 | Likely Benign | -5.64 | Deleterious | 0.995 | Probably Damaging | 0.846 | Possibly Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0.0620 | 0.6106 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3813G>C | E1271D 2D AIThe SynGAP1 missense variant E1271D is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign; the Foldetta stability prediction is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -4.816 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.59 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.26 | Pathogenic | 0.00 | Affected | 0.1729 | 0.3471 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3813G>T | E1271D 2D AIThe SynGAP1 missense variant E1271D is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign; the Foldetta stability prediction is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -4.816 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -1.59 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.26 | Pathogenic | 0.00 | Affected | 0.1729 | 0.3471 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3814G>A | E1272K 2D AIThe SynGAP1 E1272K missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions are made by REVEL and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion 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 | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | -4.227 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.312 | Likely Benign | -3.37 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.28 | Pathogenic | 0.00 | Affected | 0.1544 | 0.5488 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3814G>C | E1272Q 2D AIThe SynGAP1 E1272Q missense variant is catalogued in gnomAD (variant ID 6‑33447862‑G‑C) but has no ClinVar entry. Prediction tools cluster into two groups: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, a majority‑vote aggregator of 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 (a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the preponderance of evidence (seven pathogenic versus three benign predictions) indicates that the variant 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 | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | 6-33447862-G-C | 1 | 6.45e-7 | -3.000 | Likely Benign | 0.651 | Likely Pathogenic | Likely Benign | 0.207 | Likely Benign | -2.53 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.25 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.0746 | 0.5258 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||
| c.3815A>C | E1272A 2D AIThe SynGAP1 missense variant E1272A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus indicates a likely pathogenic outcome; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic impact for E1272A. This prediction is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | -0.783 | Likely Benign | 0.779 | Likely Pathogenic | Likely Benign | 0.261 | Likely Benign | -5.05 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.26 | Pathogenic | 0.00 | Affected | 0.3243 | 0.5547 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3815A>G | E1272G 2D AIThe SynGAP1 missense variant E1272G is catalogued in gnomAD (ID 6‑33447863‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score, which is labeled Likely Pathogenic. The high‑accuracy AlphaMissense‑Optimized assessment is uncertain, and the Foldetta protein‑folding stability analysis is not available for this residue. Overall, the majority of evidence points toward a deleterious effect, so the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for E1272G. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | 6-33447863-A-G | -1.919 | Likely Benign | 0.863 | Likely Pathogenic | Ambiguous | 0.287 | Likely Benign | -5.89 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2804 | 0.5072 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||
| c.3815A>T | E1272V 2D AIThe SynGAP1 missense variant E1272V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. 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. Based on the preponderance of pathogenic predictions and the SGM‑Consensus outcome, the variant is most likely pathogenic; this assessment does not contradict any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | -3.628 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.278 | Likely Benign | -5.90 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 0.0424 | 0.5894 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3816G>C | E1272D 2D AIThe SynGAP1 missense variant E1272D has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) all predict a pathogenic impact. High‑accuracy assessments further show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a pathogenic effect. There is no ClinVar classification to contradict this conclusion, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | -4.781 | Likely Benign | 0.751 | Likely Pathogenic | Likely Benign | 0.189 | Likely Benign | -2.53 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.27 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1450 | 0.3471 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||
| c.3816G>T | E1272D 2D AIThe SynGAP1 missense variant E1272D is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6‑33447864‑G‑T). Functional prediction tools show mixed results: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. The high‑accuracy AlphaMissense‑Optimized tool classifies the change as benign, while the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect. No Foldetta stability assessment is available for this variant. Overall, the majority of conventional predictors and the consensus score lean toward pathogenicity, which is consistent with the SGM‑Consensus designation but contradicts the benign calls from AlphaMissense‑Optimized and a few other tools. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion aligns with the SGM‑Consensus prediction rather than the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | 6-33447864-G-T | -4.781 | Likely Benign | 0.751 | Likely Pathogenic | Likely Benign | 0.188 | Likely Benign | -2.53 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.27 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1450 | 0.3471 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.469C>A | R157S 2D AIThe SynGAP1 R157S missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, while the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. ESM1b remains uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic majority vote (2 pathogenic, 1 benign, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that R157S is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.483068 | Structured | 0.523978 | Binding | 0.306 | 0.777 | 0.375 | -7.573 | In-Between | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.211 | Likely Benign | -2.82 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 3.85 | Benign | 0.00 | Affected | 0.3484 | 0.2563 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.469C>G | R157G 2D AIThe SynGAP1 R157G missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized yields an Uncertain result, SGM‑Consensus indicates Likely Pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.523978 | Binding | 0.306 | 0.777 | 0.375 | -9.125 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.252 | Likely Benign | -3.52 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 3.80 | Benign | 0.00 | Affected | 0.3892 | 0.2567 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.469C>T | R157C 2D AIThe SynGAP1 missense variant R157C is listed in gnomAD (ID 6‑33432766‑C‑T) but has no ClinVar entry. Functional prediction tools split in two groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (which is “Likely Pathogenic”). 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. High‑accuracy assessments therefore indicate a likely pathogenic consensus from SGM‑Consensus, an uncertain AlphaMissense‑Optimized score, and no Foldetta data. Overall, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.523978 | Binding | 0.306 | 0.777 | 0.375 | 6-33432766-C-T | 7 | 4.34e-6 | -11.524 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 0.237 | Likely Benign | -4.02 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 3.77 | Benign | 0.00 | Affected | 3.74 | 4 | 0.3696 | 0.2092 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||||||||||||||
| c.470G>A | R157H 2D AIThe SynGAP1 missense variant R157H (ClinVar ID 2065231.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33432767‑G‑A). 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 classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the balance of predictions leans toward pathogenic, but the high‑accuracy tools do not provide a definitive verdict. This assessment does not contradict the ClinVar status, which remains Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.483068 | Structured | 0.523978 | Binding | 0.306 | 0.777 | 0.375 | Uncertain | 1 | 6-33432767-G-A | 1 | 6.20e-7 | -10.235 | Likely Pathogenic | 0.604 | Likely Pathogenic | Likely Benign | 0.254 | Likely Benign | -2.23 | Neutral | 0.999 | Probably Damaging | 0.987 | Probably Damaging | 3.80 | Benign | 0.00 | Affected | 3.74 | 4 | 0.2981 | 0.1449 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||||||||
| c.470G>C | R157P 2D AIThe SynGAP1 missense variant R157P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus indicates it is likely pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.523978 | Binding | 0.306 | 0.777 | 0.375 | -11.463 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.450 | Likely Benign | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 3.79 | Benign | 0.00 | Affected | 0.2438 | 0.3438 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.470G>T | R157L 2D AIThe SynGAP1 missense variant R157L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default all classify the variant as damaging. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.523978 | Binding | 0.306 | 0.777 | 0.375 | -8.978 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.330 | Likely Benign | -3.13 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 3.81 | Benign | 0.00 | Affected | 0.2015 | 0.3709 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.49T>A | S17T 2D AIThe SynGAP1 missense variant S17T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this conclusion 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 | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | -3.782 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -0.58 | Neutral | 0.052 | Benign | 0.004 | Benign | 4.10 | Benign | 0.00 | Affected | 0.1667 | 0.6933 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.49T>C | S17P 2D AIThe SynGAP1 missense variant S17P 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. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a benign effect. AlphaMissense‑Optimized independently scores the variant as 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 consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | -3.251 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.210 | Likely Benign | -0.65 | Neutral | 0.212 | Benign | 0.010 | Benign | 4.01 | Benign | 0.00 | Affected | 0.2406 | 0.6473 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.49T>G | S17A 2D AIThe SynGAP1 missense variant S17A 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, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence points to a benign effect, 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 | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | -3.140 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -0.34 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.15 | Benign | 0.00 | Affected | 0.5276 | 0.5824 | Strenghten | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.50C>A | S17Y 2D AIThe SynGAP1 missense variant S17Y is listed in gnomAD (ID 6‑33420314‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: 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. No Foldetta stability data are available, so it does not influence the conclusion. Overall, the majority of evidence indicates that S17Y is most likely benign, and this assessment does not contradict any ClinVar status, as none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | 6-33420314-C-A | -4.492 | Likely Benign | 0.551 | Ambiguous | Likely Benign | 0.050 | Likely Benign | -1.06 | Neutral | 0.742 | Possibly Damaging | 0.047 | Benign | 3.99 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0818 | 0.6366 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| c.50C>G | S17C 2D AIThe SynGAP1 missense variant S17C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools (polyPhen‑2 HumDiv and SIFT) predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign; Foldetta results are unavailable. 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 | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | -4.364 | Likely Benign | 0.279 | Likely Benign | Likely Benign | 0.044 | Likely Benign | 0.17 | Neutral | 0.486 | Possibly Damaging | 0.048 | Benign | 3.99 | Benign | 0.00 | Affected | 0.1226 | 0.6721 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.50C>T | S17F 2D AIThe SynGAP1 missense variant S17F is listed in ClinVar with an “Uncertain” status (ClinVar ID 3451958.0) and is present in gnomAD (ID 6‑33420314‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | Uncertain | 1 | 6-33420314-C-T | 10 | 6.49e-6 | -3.888 | Likely Benign | 0.637 | Likely Pathogenic | Likely Benign | 0.048 | Likely Benign | -0.99 | Neutral | 0.486 | Possibly Damaging | 0.032 | Benign | 3.99 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0729 | 0.6468 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||
| c.52T>A | Y18N 2D AIThe SynGAP1 missense variant Y18N is listed in gnomAD (ID 6‑33420316‑T‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. 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 status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.446314 | Uncertain | 0.345 | 0.908 | 0.375 | 6-33420316-T-A | -3.094 | Likely Benign | 0.492 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -0.73 | Neutral | 0.872 | Possibly Damaging | 0.114 | Benign | 4.07 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2564 | 0.1253 | -2 | -2 | -2.2 | -49.07 | ||||||||||||||||||||||||||||||||||||
| c.52T>C | Y18H 2D AIThe SynGAP1 missense variant Y18H is listed in gnomAD (ID 6‑33420316‑T‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.446314 | Uncertain | 0.345 | 0.908 | 0.375 | 6-33420316-T-C | -2.871 | Likely Benign | 0.542 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.58 | Neutral | 0.872 | Possibly Damaging | 0.114 | Benign | 4.07 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2805 | 0.0993 | 2 | 0 | -1.9 | -26.03 | ||||||||||||||||||||||||||||||||||||
| c.52T>G | Y18D 2D AIThe SynGAP1 missense variant Y18D is not 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, ESM1b, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the computational evidence overwhelmingly suggests that Y18D is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.446314 | Uncertain | 0.345 | 0.908 | 0.375 | -2.783 | Likely Benign | 0.580 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | -0.44 | Neutral | 0.659 | Possibly Damaging | 0.072 | Benign | 4.06 | Benign | 0.00 | Affected | 0.4207 | 0.1253 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.53A>C | Y18S 2D AIThe SynGAP1 missense variant Y18S is reported in gnomAD (ID 6‑33420317‑A‑C) 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, while only SIFT predicts it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign impact for Y18S. This conclusion is consistent with the absence of a pathogenic ClinVar classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.446314 | Uncertain | 0.345 | 0.908 | 0.375 | 6-33420317-A-C | -1.061 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -0.50 | Neutral | 0.389 | Benign | 0.036 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 0.4961 | 0.2640 | -2 | -3 | 0.5 | -76.10 | ||||||||||||||||||||||||||||||||||||
| c.53A>G | Y18C 2D AIThe SynGAP1 missense variant Y18C is listed in ClinVar (ID 1967233) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33420317‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The high‑accuracy consensus (SGM‑Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome, 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, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.446314 | Uncertain | 0.345 | 0.908 | 0.375 | Uncertain | 2 | 6-33420317-A-G | 44 | 2.88e-5 | -2.658 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.56 | Neutral | 0.872 | Possibly Damaging | 0.206 | Benign | 4.04 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3293 | 0.2473 | 0 | -2 | 3.8 | -60.04 | ||||||||||||||||||||||||||||||||
| c.53A>T | Y18F 2D AIThe SynGAP1 missense variant Y18F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, 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 | 0.483068 | Structured | 0.446314 | Uncertain | 0.345 | 0.908 | 0.375 | -2.371 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -0.19 | Neutral | 0.115 | Benign | 0.018 | Benign | 4.18 | Benign | 0.00 | Affected | 0.2675 | 0.3322 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2428C>A | R810S 2D AIThe SynGAP1 R810S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. The high‑accuracy consensus from SGM (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors pathogenicity, while the lack of a Foldetta result leaves that evidence inconclusive. Overall, the preponderance of pathogenic predictions suggests that R810S is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -5.996 | Likely Benign | 0.950 | Likely Pathogenic | Ambiguous | 0.204 | Likely Benign | -3.20 | Deleterious | 0.996 | Probably Damaging | 0.900 | Possibly Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.3152 | 0.4556 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.2428C>G | R810G 2D AISynGAP1 missense variant R810G is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: a single benign call from REVEL, and six pathogenic calls from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Two tools (ESM1b and AlphaMissense‑Optimized) give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized remains uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic, and Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a pathogenic impact for R810G, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -7.190 | In-Between | 0.828 | Likely Pathogenic | Ambiguous | 0.202 | Likely Benign | -3.57 | Deleterious | 0.996 | Probably Damaging | 0.925 | Probably Damaging | 2.35 | Pathogenic | 0.01 | Affected | 0.3686 | 0.4207 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2428C>T | R810C 2D AIThe SynGAP1 missense variant R810C is listed in gnomAD (6‑33442980‑C‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. 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 | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | 6-33442980-C-T | 2 | 1.24e-6 | -8.925 | Likely Pathogenic | 0.839 | Likely Pathogenic | Ambiguous | 0.245 | Likely Benign | -4.91 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 2.32 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3517 | 0.4263 | -3 | -4 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||||
| c.2429G>A | R810H 2D AIThe SynGAP1 R810H missense variant is listed in gnomAD (ID 6‑33442981‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas a pathogenic consensus is reached by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as pathogenic, and Foldetta (FoldX‑MD/Rosetta stability analysis) is unavailable. Overall, the majority of tools predict pathogenicity, and the high‑accuracy subset is split, but the pathogenic signal dominates. 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. | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | 6-33442981-G-A | 3 | 1.86e-6 | -6.554 | Likely Benign | 0.550 | Ambiguous | Likely Benign | 0.239 | Likely Benign | -2.80 | Deleterious | 1.000 | Probably Damaging | 0.980 | Probably Damaging | 2.35 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3149 | 0.2631 | 0 | 2 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||||
| c.2429G>C | R810P 2D AIThe SynGAP1 missense variant R810P is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized indicates a benign effect, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels the variant as 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 multiple in silico predictors points to a pathogenic impact for R810P. This conclusion is not contradicted by 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 | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -4.120 | Likely Benign | 0.779 | Likely Pathogenic | Likely Benign | 0.316 | Likely Benign | -4.08 | Deleterious | 1.000 | Probably Damaging | 0.977 | Probably Damaging | 2.33 | Pathogenic | 0.01 | Affected | 0.2307 | 0.5478 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2429G>T | R810L 2D AIThe SynGAP1 R810L missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to REVEL, while the majority of algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome. Uncertain calls come from ESM1b and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence from multiple in‑silico predictors points to a pathogenic impact for R810L. 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 | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -7.172 | In-Between | 0.834 | Likely Pathogenic | Ambiguous | 0.338 | Likely Benign | -4.57 | Deleterious | 0.996 | Probably Damaging | 0.925 | Probably Damaging | 2.35 | Pathogenic | 0.01 | Affected | 0.2019 | 0.5271 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||
| c.25C>A | H9N 2D AIThe SynGAP1 missense variant H9N is reported in gnomAD (ID 6‑33420289‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions 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 | 0.486429 | Structured | 0.528099 | Binding | 0.394 | 0.916 | 0.750 | 6-33420289-C-A | -3.789 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -0.36 | Neutral | 0.024 | Benign | 0.003 | Benign | 4.23 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2327 | 0.3823 | 1 | 2 | -0.3 | -23.04 | ||||||||||||||||||||||||||||||||||||
| c.25C>G | H9D 2D AIThe SynGAP1 missense variant H9D has no ClinVar entry and is not reported in 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 variant as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority of the high‑accuracy tools) is benign, and the Foldetta stability analysis is unavailable. Overall, the consensus of available predictions indicates that the variant is most likely benign, with no conflict with ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.528099 | Binding | 0.394 | 0.916 | 0.750 | -2.912 | Likely Benign | 0.168 | Likely Benign | Likely Benign | 0.217 | Likely Benign | -0.11 | Neutral | 0.024 | Benign | 0.002 | Benign | 4.24 | Benign | 0.00 | Affected | 0.2823 | 0.2893 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.25C>T | H9Y 2D AIThe SynGAP1 missense variant H9Y is reported in gnomAD (ID 6‑33420289‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus itself is likely benign. Foldetta results are not available, so they do not influence the assessment. Overall, the preponderance of evidence points to the variant being 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 | 0.486429 | Structured | 0.528099 | Binding | 0.394 | 0.916 | 0.750 | 6-33420289-C-T | -3.833 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.14 | Neutral | 0.047 | Benign | 0.006 | Benign | 4.24 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1227 | 0.5024 | 2 | 0 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||||||||
| c.2614T>A | S872T 2D AIThe SynGAP1 missense variant S872T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for S872T, 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 | 0.486429 | Structured | 0.662664 | Binding | 0.262 | 0.865 | 0.125 | -5.129 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.20 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.65 | Benign | 0.17 | Tolerated | 0.1738 | 0.6234 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2614T>C | S872P 2D AIThe SynGAP1 missense variant S872P 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‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also predicts Likely Benign. Foldetta results are not available for this variant. Overall, the majority of evidence indicates that S872P 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 | 0.486429 | Structured | 0.662664 | Binding | 0.262 | 0.865 | 0.125 | -4.291 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.187 | Likely Benign | -1.91 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.59 | Benign | 0.13 | Tolerated | 0.2321 | 0.5581 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2614T>G | S872A 2D AIThe SynGAP1 missense variant S872A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign prediction: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for S872A, 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 | 0.486429 | Structured | 0.662664 | Binding | 0.262 | 0.865 | 0.125 | -4.574 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.91 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.77 | Benign | 0.28 | Tolerated | 0.5351 | 0.4945 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2615C>T | S872L 2D AIThe SynGAP1 missense variant S872L is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus likewise favors a benign classification; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect for S872L, and this assessment does not conflict with ClinVar, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.662664 | Binding | 0.262 | 0.865 | 0.125 | -6.450 | Likely Benign | 0.555 | Ambiguous | Likely Benign | 0.178 | Likely Benign | -2.28 | Neutral | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 2.61 | Benign | 0.04 | Affected | 0.1168 | 0.5283 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.26A>C | H9P 2D AIThe SynGAP1 missense variant H9P 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 prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.528099 | Binding | 0.394 | 0.916 | 0.750 | -2.838 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.224 | Likely Benign | -0.16 | Neutral | 0.107 | Benign | 0.006 | Benign | 4.19 | Benign | 0.00 | Affected | 0.2644 | 0.5169 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
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