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.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.861T>A | D287E 2D  3DClick to see structure in 3D Viewer AISynGAP1 D287E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, ESM1b, and the protein‑folding stability method Foldetta; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic), also reports it as pathogenic. In contrast, Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect on protein stability. No evidence is available from Rosetta alone. Overall, the majority of predictions, including the high‑accuracy methods, indicate a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.102787 | Structured | 0.389029 | Uncertain | 0.912 | 0.268 | 0.000 | -5.250 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.35 | Likely Benign | 0.2 | 0.54 | Ambiguous | 0.45 | Likely Benign | 0.50 | Likely Benign | 0.416 | Likely Benign | -3.68 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.54 | Pathogenic | 0.01 | Affected | 0.1541 | 0.7833 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.861T>G | D287E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D287E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, ESM1b, and the protein‑folding stability method Foldetta; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic), also reports it as pathogenic. In contrast, Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect on protein stability. No evidence is available from Rosetta alone. Overall, the majority of predictions, including the high‑accuracy methods, indicate a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.102787 | Structured | 0.389029 | Uncertain | 0.912 | 0.268 | 0.000 | -5.250 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.35 | Likely Benign | 0.2 | 0.54 | Ambiguous | 0.45 | Likely Benign | 0.50 | Likely Benign | 0.416 | Likely Benign | -3.68 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.54 | Pathogenic | 0.01 | Affected | 0.1541 | 0.7833 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.866T>C | M289T 2D  AIThe SynGAP1 missense variant M289T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a benign effect. Taken together, the majority of evidence indicates that M289T is most likely benign, and this conclusion does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.127496 | Structured | 0.403499 | Uncertain | 0.886 | 0.276 | 0.000 | Uncertain | 1 | -4.668 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.73 | Ambiguous | 0.1 | 0.17 | Likely Benign | 0.45 | Likely Benign | -0.01 | Likely Benign | 0.222 | Likely Benign | -0.47 | Neutral | 0.801 | Possibly Damaging | 0.315 | Benign | 1.83 | Pathogenic | 0.57 | Tolerated | 0.1657 | 0.1534 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||
| c.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.1184G>C | G395A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G395A is not 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, 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) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Consequently, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.513880 | Disordered | 0.396199 | Uncertain | 0.474 | 0.601 | 0.500 | -3.964 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 1.51 | Ambiguous | 0.3 | -0.59 | Ambiguous | 0.46 | Likely Benign | 0.08 | Likely Benign | 0.160 | Likely Benign | -0.72 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.24 | Benign | 0.15 | Tolerated | 0.3848 | 0.5047 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1312G>T | A438S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A438S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as benign. The only inconclusive results come from Rosetta and premPS, which are listed as uncertain. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. Overall, the evidence strongly supports 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 | GAP | 0.147574 | Structured | 0.290154 | Uncertain | 0.929 | 0.293 | 0.000 | -6.085 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.0 | 0.62 | Ambiguous | 0.46 | Likely Benign | 0.68 | Ambiguous | 0.012 | Likely Benign | -1.27 | Neutral | 0.042 | Benign | 0.035 | Benign | 4.14 | Benign | 0.15 | Tolerated | 0.2143 | 0.3995 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1388A>C | D463A 2D  3DClick to see structure in 3D Viewer AISynGAP1 D463A is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results are AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the predictions are split, with an equal number of benign and pathogenic calls, and the high‑accuracy methods provide conflicting outcomes. Therefore, the variant is most likely of uncertain significance, which does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | Uncertain | 1 | -8.607 | Likely Pathogenic | 0.894 | Likely Pathogenic | Ambiguous | -0.04 | Likely Benign | 0.1 | 0.96 | Ambiguous | 0.46 | Likely Benign | 0.43 | Likely Benign | 0.425 | Likely Benign | -6.96 | Deleterious | 0.978 | Probably Damaging | 0.602 | Possibly Damaging | 3.33 | Benign | 0.29 | Tolerated | 0.3591 | 0.5169 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||
| c.1430T>A | M477K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS and FATHMM. Predictions that are uncertain or inconclusive are FoldX, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to mixed or uncertain inputs. Overall, the majority of evidence points to a benign impact. Thus, the variant is most likely benign, and this conclusion does not contradict the current ClinVar status, which contains no report of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -7.519 | In-Between | 0.553 | Ambiguous | Likely Benign | 0.54 | Ambiguous | 0.1 | 0.37 | Likely Benign | 0.46 | Likely Benign | 1.12 | Destabilizing | 0.371 | Likely Benign | -1.32 | Neutral | 0.254 | Benign | 0.122 | Benign | -1.15 | Pathogenic | 0.14 | Tolerated | 0.1817 | 0.0847 | 0 | -1 | -5.8 | -3.02 | ||||||||||||||||||||||||||||||
| c.1433A>C | E478A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E478A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No predictions are missing or inconclusive. Overall, the majority of high‑confidence tools lean toward a benign classification, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -8.499 | Likely Pathogenic | 0.612 | Likely Pathogenic | Likely Benign | 0.46 | Likely Benign | 0.0 | 0.45 | Likely Benign | 0.46 | Likely Benign | 0.02 | Likely Benign | 0.342 | Likely Benign | -4.74 | Deleterious | 0.585 | Possibly Damaging | 0.505 | Possibly Damaging | 3.42 | Benign | 0.05 | Affected | 0.3516 | 0.5847 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1487A>C | E496A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E496A is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show mixed results: benign calls come from Rosetta, Foldetta, premPS, SIFT, and AlphaMissense‑Optimized, while pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX is inconclusive. High‑accuracy methods give a split verdict: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts pathogenic, and Foldetta predicts benign. Overall, the majority of predictions lean toward pathogenicity, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | Uncertain | 1 | -11.159 | Likely Pathogenic | 0.598 | Likely Pathogenic | Likely Benign | 0.68 | Ambiguous | 0.0 | 0.23 | Likely Benign | 0.46 | Likely Benign | 0.47 | Likely Benign | 0.681 | Likely Pathogenic | -4.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.41 | Pathogenic | 0.09 | Tolerated | 0.2806 | 0.3548 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||
| c.1688G>A | R563K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 R563K 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, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Predictions that are inconclusive are Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as benign. Based on the overall consensus of the available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.039760 | Structured | 0.031987 | Uncertain | 0.876 | 0.209 | 0.000 | -10.948 | Likely Pathogenic | 0.335 | Likely Benign | Likely Benign | 0.25 | Likely Benign | 0.0 | 0.66 | Ambiguous | 0.46 | Likely Benign | 0.70 | Ambiguous | 0.198 | Likely Benign | -2.37 | Neutral | 0.990 | Probably Damaging | 0.998 | Probably Damaging | 3.46 | Benign | 0.35 | Tolerated | 0.4434 | 0.2379 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||||
| c.1721T>G | L574R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L574R is not 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, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and FATHMM. Two tools remain inconclusive: Rosetta (Uncertain) and AlphaMissense‑Default (Uncertain). 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. three pathogenic) support a benign classification, 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. | GAP | 0.083462 | Structured | 0.026427 | Uncertain | 0.927 | 0.246 | 0.000 | -8.702 | Likely Pathogenic | 0.563 | Ambiguous | Likely Benign | 0.04 | Likely Benign | 0.2 | 0.88 | Ambiguous | 0.46 | Likely Benign | -0.12 | Likely Benign | 0.322 | Likely Benign | 0.30 | Neutral | 0.907 | Possibly Damaging | 0.292 | Benign | -1.22 | Pathogenic | 0.52 | Tolerated | 0.1419 | 0.0530 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||
| c.1851G>C | E617D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change E617D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a benign effect. Based on the preponderance of evidence from both general and high‑accuracy predictors, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | -1.349 | Likely Benign | 0.241 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.1 | 0.80 | Ambiguous | 0.46 | Likely Benign | 0.07 | Likely Benign | 0.322 | Likely Benign | -0.01 | Neutral | 0.994 | Probably Damaging | 0.979 | Probably Damaging | -1.35 | Pathogenic | 0.88 | Tolerated | 3.37 | 35 | 0.1854 | 0.3386 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||
| c.1851G>T | E617D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617D is listed in ClinVar with an uncertain significance (ID 2584916.0) and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score all indicate benign or likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact, while Rosetta remains inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the preponderance of evidence supports a benign classification, which does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | Uncertain | 1 | -1.349 | Likely Benign | 0.241 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.1 | 0.80 | Ambiguous | 0.46 | Likely Benign | 0.07 | Likely Benign | 0.322 | Likely Benign | -0.01 | Neutral | 0.994 | Probably Damaging | 0.979 | Probably Damaging | -1.35 | Pathogenic | 0.88 | Tolerated | 3.37 | 35 | 0.1854 | 0.3386 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||
| 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.2176A>T | R726W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R726W has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls from REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and 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 further reveal AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. No prediction or stability result is missing or inconclusive. Overall, the majority of tools (seven) predict a benign effect, but the SGM‑Consensus and several high‑accuracy methods indicate pathogenicity, leaving the variant’s clinical significance uncertain. The predictions do 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 | 0.521092 | Disordered | 0.449098 | Uncertain | 0.888 | 0.513 | 0.625 | -10.091 | Likely Pathogenic | 0.580 | Likely Pathogenic | Likely Benign | 0.46 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.46 | Likely Benign | 0.15 | Likely Benign | 0.217 | Likely Benign | -3.72 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.57 | Benign | 0.01 | Affected | 0.1161 | 0.4252 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||
| c.631A>T | S211C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Optimized, and premPS, whereas a separate group predicts pathogenicity: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Two tools (Rosetta and AlphaMissense‑Default) return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Because the consensus of the most reliable predictors is split (two benign, one pathogenic) and the overall tool distribution is evenly divided, the variant’s impact remains ambiguous. Based on the available predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -10.567 | Likely Pathogenic | 0.547 | Ambiguous | Likely Benign | 0.28 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.46 | Likely Benign | 0.11 | Likely Benign | 0.263 | Likely Benign | -4.14 | Deleterious | 0.999 | Probably Damaging | 0.908 | Possibly Damaging | 3.89 | Benign | 0.01 | Affected | 0.1292 | 0.5638 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.860A>G | D287G 2D  AIThe SynGAP1 missense variant D287G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Foldetta, premPS, and Rosetta, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict it to be pathogenic; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of predictions indicates a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.102787 | Structured | 0.389029 | Uncertain | 0.912 | 0.268 | 0.000 | -13.558 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.61 | Ambiguous | 1.1 | 0.31 | Likely Benign | 0.46 | Likely Benign | 0.38 | Likely Benign | 0.521 | Likely Pathogenic | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.59 | Pathogenic | 0.01 | Affected | 0.4688 | 0.7390 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.979C>A | L327M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 L327M missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, AlphaMissense‑Optimized, and Foldetta, whereas those that predict a pathogenic outcome are SGM‑Consensus, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta predicting a benign effect. Overall, the majority of tools indicate a pathogenic effect, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.409189 | Uncertain | 0.939 | 0.490 | 0.000 | -10.320 | Likely Pathogenic | 0.727 | Likely Pathogenic | Likely Benign | 0.20 | Likely Benign | 0.0 | 0.72 | Ambiguous | 0.46 | Likely Benign | 1.07 | Destabilizing | 0.320 | Likely Benign | -1.61 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.53 | Pathogenic | 0.01 | Affected | 0.0806 | 0.3807 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.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.1253A>C | K418T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K418T variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, premPS, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of tools (10 pathogenic vs. 5 benign) support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -11.994 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.39 | Likely Benign | 0.1 | 0.55 | Ambiguous | 0.47 | Likely Benign | 0.41 | Likely Benign | 0.392 | Likely Benign | -5.36 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.37 | Benign | 0.04 | Affected | 0.1975 | 0.1894 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1261G>A | A421T 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant A421T is not reported in ClinVar and is present in gnomAD (ID 6‑33438166‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” Uncertain results from FoldX and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of consensus predictions lean toward 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 Pathogenic | GAP | 0.067594 | Structured | 0.404927 | Uncertain | 0.965 | 0.257 | 0.000 | 6-33438166-G-A | 1 | 6.19e-7 | -9.217 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.75 | Ambiguous | 0.2 | 0.18 | Likely Benign | 0.47 | Likely Benign | 0.99 | Ambiguous | 0.179 | Likely Benign | -3.12 | Deleterious | 0.353 | Benign | 0.136 | Benign | 3.43 | Benign | 0.09 | Tolerated | 3.37 | 29 | 0.1346 | 0.4439 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||
| c.1290G>A | M430I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430I is catalogued in gnomAD (6‑33438195‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, premPS, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign. 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 | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | 6-33438195-G-A | 1 | 6.19e-7 | -4.655 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 1.22 | Ambiguous | 0.1 | -0.29 | Likely Benign | 0.47 | Likely Benign | 0.65 | Ambiguous | 0.068 | Likely Benign | -1.62 | Neutral | 0.134 | Benign | 0.025 | Benign | 3.54 | Benign | 0.40 | Tolerated | 3.37 | 29 | 0.1524 | 0.4116 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||
| c.1290G>C | M430I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the remaining predictions (FoldX, premPS, AlphaMissense‑Default) are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also classifies the variant as benign. Taken together, the consensus of both general and high‑accuracy predictors is that M430I is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -4.655 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 1.22 | Ambiguous | 0.1 | -0.29 | Likely Benign | 0.47 | Likely Benign | 0.65 | Ambiguous | 0.068 | Likely Benign | -1.62 | Neutral | 0.134 | Benign | 0.025 | Benign | 3.54 | Benign | 0.40 | Tolerated | 3.37 | 29 | 0.1524 | 0.4116 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1290G>T | M430I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. Predictions that are inconclusive are FoldX, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta’s combined FoldX‑MD/Rosetta output is unavailable due to the uncertain FoldX result. Overall, the evidence overwhelmingly supports a benign classification for M430I, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -4.655 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 1.22 | Ambiguous | 0.1 | -0.29 | Likely Benign | 0.47 | Likely Benign | 0.65 | Ambiguous | 0.068 | Likely Benign | -1.62 | Neutral | 0.134 | Benign | 0.025 | Benign | 3.54 | Benign | 0.40 | Tolerated | 3.37 | 29 | 0.1524 | 0.4116 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1295G>A | C432Y 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant C432Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while benign predictions are reported by REVEL, Rosetta, FATHMM, and Foldetta. Tools with uncertain or missing results (FoldX, premPS) are not considered evidence. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predict pathogenicity, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Overall, the majority of predictions support a pathogenic impact, and this conclusion does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -13.720 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.62 | Ambiguous | 0.3 | 0.31 | Likely Benign | 0.47 | Likely Benign | 0.71 | Ambiguous | 0.441 | Likely Benign | -10.50 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.45 | Benign | 0.02 | Affected | 0.0857 | 0.3438 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1573G>C | E525Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E525Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely disagree: benign predictions come from Rosetta, Foldetta, and FATHMM, while pathogenic predictions are returned by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta) as benign. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -13.722 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 1.05 | Ambiguous | 0.7 | -0.11 | Likely Benign | 0.47 | Likely Benign | 0.84 | Ambiguous | 0.516 | Likely Pathogenic | -2.98 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 2.68 | Benign | 0.00 | Affected | 0.1173 | 0.3962 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1745A>C | E582A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E582A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 benign. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.102787 | Structured | 0.033838 | Uncertain | 0.845 | 0.235 | 0.000 | -7.432 | In-Between | 0.661 | Likely Pathogenic | Likely Benign | 0.78 | Ambiguous | 0.2 | 0.15 | Likely Benign | 0.47 | Likely Benign | 0.27 | Likely Benign | 0.263 | Likely Benign | -2.99 | Deleterious | 0.998 | Probably Damaging | 0.999 | Probably Damaging | 3.19 | Benign | 0.26 | Tolerated | 0.3236 | 0.4000 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||
| c.1787G>T | R596L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 R596L missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect are Foldetta and premPS, whereas the remaining pathogenic‑predicting tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all indicate a deleterious impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (derived from the same four high‑confidence predictors) also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the preponderance of evidence points to a pathogenic effect for R596L, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.017797 | Structured | 0.135423 | Uncertain | 0.918 | 0.134 | 0.000 | Uncertain | 1 | -13.197 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.51 | Ambiguous | 0.3 | -0.58 | Ambiguous | 0.47 | Likely Benign | -0.02 | Likely Benign | 0.756 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.1755 | 0.3433 | -3 | -2 | 8.3 | -43.03 | 234.2 | 63.4 | -0.1 | 0.0 | -0.5 | 0.6 | X | X | Potentially Pathogenic | The guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).However, in the variant simulations, the branched hydrocarbon side chain of Leu596 cannot form any of the hydrogen bonds or salt bridges maintained by the considerably bulkier and positively charged Arg596 side chain. Instead, Leu596 packs hydrophobically with the phenyl ring of Phe484 in the linker loop or residues from the opposing helix (e.g., Ile494, Thr491).Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||
| c.2039A>C | E680A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E680A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic impact are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. AlphaMissense‑Optimized remains inconclusive. Overall, the majority of predictions lean toward pathogenicity, but the conflicting high‑accuracy results leave the classification uncertain. The variant is most likely pathogenic based on the prevailing evidence, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -11.338 | Likely Pathogenic | 0.819 | Likely Pathogenic | Ambiguous | 0.34 | Likely Benign | 0.2 | 0.59 | Ambiguous | 0.47 | Likely Benign | 0.30 | Likely Benign | 0.444 | Likely Benign | -5.22 | Deleterious | 0.935 | Possibly Damaging | 0.490 | Possibly Damaging | 3.47 | Benign | 0.09 | Tolerated | 0.3931 | 0.6989 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.2056G>C | G686R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G686R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, Foldetta, and FATHMM, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) all predict a pathogenic impact; FoldX is listed as uncertain and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.109221 | Structured | 0.177104 | Uncertain | 0.919 | 0.268 | 0.000 | -14.801 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.79 | Ambiguous | 0.3 | 0.15 | Likely Benign | 0.47 | Likely Benign | 1.10 | Destabilizing | 0.503 | Likely Pathogenic | -7.21 | Deleterious | 0.974 | Probably Damaging | 0.449 | Possibly Damaging | 3.46 | Benign | 0.00 | Affected | 0.0951 | 0.3580 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.2183C>T | P728L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P728L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, and premPS, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact; FoldX and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect for P728L. 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. | Likely Pathogenic | 0.632174 | Disordered | 0.434760 | Uncertain | 0.725 | 0.567 | 0.625 | -11.125 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.79 | Ambiguous | 0.0 | 0.15 | Likely Benign | 0.47 | Likely Benign | 0.20 | Likely Benign | 0.402 | Likely Benign | -8.27 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 0.66 | Pathogenic | 0.00 | Affected | 0.2321 | 0.4713 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
| c.614T>C | I205T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I205T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the remaining predictions (FoldX, premPS, AlphaMissense‑Default) are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, classifies the variant as benign. Taken together, the consensus of both general and high‑accuracy predictors indicates that I205T is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -6.869 | Likely Benign | 0.450 | Ambiguous | Likely Benign | 0.65 | Ambiguous | 0.0 | 0.28 | Likely Benign | 0.47 | Likely Benign | 0.81 | Ambiguous | 0.118 | Likely Benign | -2.19 | Neutral | 0.421 | Benign | 0.156 | Benign | 4.16 | Benign | 0.15 | Tolerated | 0.0933 | 0.0541 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| 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.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.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.1210G>T | A404S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a pathogenic outcome. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a benign effect. No inconclusive or missing predictions are present. Based on the unanimous benign predictions and the lack of ClinVar evidence, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -1.937 | Likely Benign | 0.194 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.0 | 0.83 | Ambiguous | 0.48 | Likely Benign | 0.28 | Likely Benign | 0.078 | Likely Benign | -0.07 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.18 | Benign | 0.22 | Tolerated | 0.2970 | 0.6178 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1245G>C | E415D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E415D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Predictions that are inconclusive or uncertain are FoldX, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while Foldetta predicts a benign effect. Overall, the balance of evidence leans toward a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -7.766 | In-Between | 0.952 | Likely Pathogenic | Ambiguous | 0.75 | Ambiguous | 0.1 | 0.21 | Likely Benign | 0.48 | Likely Benign | 0.49 | Likely Benign | 0.220 | Likely Benign | -2.60 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.22 | Benign | 0.04 | Affected | 0.1777 | 0.2075 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1245G>T | E415D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E415D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta indicates a benign effect. Overall, the majority of standard tools lean toward pathogenicity, and the high‑accuracy consensus also supports a pathogenic classification. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -7.766 | In-Between | 0.952 | Likely Pathogenic | Ambiguous | 0.75 | Ambiguous | 0.1 | 0.21 | Likely Benign | 0.48 | Likely Benign | 0.49 | Likely Benign | 0.220 | Likely Benign | -2.60 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.22 | Benign | 0.04 | Affected | 0.1777 | 0.2075 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1421A>T | D474V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D474V missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, Foldetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -12.999 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.77 | Ambiguous | 0.0 | 0.18 | Likely Benign | 0.48 | Likely Benign | 0.18 | Likely Benign | 0.866 | Likely Pathogenic | -7.69 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | -1.30 | Pathogenic | 0.04 | Affected | 0.0694 | 0.4510 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1457A>C | E486A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E486A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, premPS, SIFT, and FATHMM, whereas pathogenic predictions are made by SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore unavailable. Overall, the majority of evidence supports a pathogenic effect. The prediction aligns with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -11.902 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.63 | Ambiguous | 0.0 | 0.32 | Likely Benign | 0.48 | Likely Benign | -0.03 | Likely Benign | 0.398 | Likely Benign | -5.17 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.44 | Benign | 0.39 | Tolerated | 0.3561 | 0.5859 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1598C>G | A533G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533G resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome; Rosetta is uncertain and therefore not counted as evidence. High‑accuracy assessments—all of which are available—show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Benign, reinforcing the benign consensus. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -3.412 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.32 | Likely Benign | 0.1 | 0.64 | Ambiguous | 0.48 | Likely Benign | 0.33 | Likely Benign | 0.185 | Likely Benign | -1.94 | Neutral | 0.258 | Benign | 0.099 | Benign | -1.23 | Pathogenic | 0.23 | Tolerated | 0.2348 | 0.4737 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1750A>G | I584V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I584V is catalogued in gnomAD (ID 6‑33440802‑A‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, and FATHMM. Two tools (FoldX and ESM1b) returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign (2 benign vs. 1 pathogenic vote), and Foldetta predicts benign stability. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.059222 | Structured | 0.046673 | Uncertain | 0.846 | 0.244 | 0.000 | 6-33440802-A-G | 1 | 6.20e-7 | -7.562 | In-Between | 0.234 | Likely Benign | Likely Benign | 0.67 | Ambiguous | 0.1 | 0.29 | Likely Benign | 0.48 | Likely Benign | 1.16 | Destabilizing | 0.405 | Likely Benign | -0.95 | Neutral | 0.642 | Possibly Damaging | 0.349 | Benign | -1.18 | Pathogenic | 0.18 | Tolerated | 3.37 | 34 | 0.1007 | 0.2659 | 3 | 4 | -0.3 | -14.03 | |||||||||||||||||||||||||
| c.1852C>G | Q618E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, and there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -12.535 | Likely Pathogenic | 0.162 | Likely Benign | Likely Benign | 0.46 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.48 | Likely Benign | 0.33 | Likely Benign | 0.233 | Likely Benign | -1.16 | Neutral | 0.046 | Benign | 0.021 | Benign | -1.17 | Pathogenic | 0.26 | Tolerated | 0.1003 | 0.1469 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.1962G>C | E654D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E654D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the predictions are mixed, with a slight majority leaning toward benign, but the high‑accuracy tools conflict. The variant is most likely benign based on the aggregate predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.026892 | Structured | 0.303029 | Uncertain | 0.957 | 0.311 | 0.000 | -10.454 | Likely Pathogenic | 0.886 | Likely Pathogenic | Ambiguous | 0.44 | Likely Benign | 0.0 | 0.52 | Ambiguous | 0.48 | Likely Benign | 0.29 | Likely Benign | 0.166 | Likely Benign | -2.87 | Deleterious | 0.906 | Possibly Damaging | 0.429 | Benign | 3.38 | Benign | 0.11 | Tolerated | 0.1678 | 0.2583 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1962G>T | E654D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E654D has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain (treated as unavailable), SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. No other folding‑stability results are available. Overall, the balance of evidence leans toward a benign interpretation, and this assessment does not contradict ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.026892 | Structured | 0.303029 | Uncertain | 0.957 | 0.311 | 0.000 | -10.454 | Likely Pathogenic | 0.886 | Likely Pathogenic | Ambiguous | 0.44 | Likely Benign | 0.0 | 0.52 | Ambiguous | 0.48 | Likely Benign | 0.29 | Likely Benign | 0.166 | Likely Benign | -2.87 | Deleterious | 0.906 | Possibly Damaging | 0.429 | Benign | 3.38 | Benign | 0.11 | Tolerated | 0.1678 | 0.2583 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1984C>G | Q662E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q662E is 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, REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. High‑accuracy methods all support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta 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 assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.046336 | Structured | 0.103446 | Uncertain | 0.932 | 0.323 | 0.000 | -12.750 | Likely Pathogenic | 0.191 | Likely Benign | Likely Benign | 0.32 | Likely Benign | 0.0 | 0.64 | Ambiguous | 0.48 | Likely Benign | 0.24 | Likely Benign | 0.083 | Likely Benign | -1.25 | Neutral | 0.876 | Possibly Damaging | 0.147 | Benign | 3.52 | Benign | 0.27 | Tolerated | 0.1660 | 0.1823 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.2026A>C | S676R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676R is not 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, FATHMM, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing; all available data are reported. Overall, the balance of evidence (six benign versus four pathogenic predictions, with the high‑accuracy Foldetta supporting benign) indicates that the variant is most likely benign. 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. | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -10.665 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.22 | Likely Benign | 0.3 | 0.74 | Ambiguous | 0.48 | Likely Benign | 0.45 | Likely Benign | 0.136 | Likely Benign | -2.34 | Neutral | 0.891 | Possibly Damaging | 0.278 | Benign | 3.40 | Benign | 0.02 | Affected | 0.0962 | 0.3454 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| c.2028C>A | S676R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676R is not 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, FATHMM, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing; all available data are included. Overall, the balance of evidence (six benign versus four pathogenic predictions, with the high‑accuracy Foldetta supporting benign) indicates that the variant is most likely benign. 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. | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -10.665 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.22 | Likely Benign | 0.3 | 0.74 | Ambiguous | 0.48 | Likely Benign | 0.45 | Likely Benign | 0.157 | Likely Benign | -2.34 | Neutral | 0.891 | Possibly Damaging | 0.278 | Benign | 3.40 | Benign | 0.02 | Affected | 0.0962 | 0.3454 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| c.2028C>G | S676R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676R is not 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, FATHMM, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing; all available data are included. Overall, the balance of evidence (six benign versus four pathogenic predictions, with the high‑accuracy Foldetta supporting benign) indicates that the variant is most likely benign. 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. | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -10.665 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.22 | Likely Benign | 0.3 | 0.74 | Ambiguous | 0.48 | Likely Benign | 0.45 | Likely Benign | 0.156 | Likely Benign | -2.34 | Neutral | 0.891 | Possibly Damaging | 0.278 | Benign | 3.40 | Benign | 0.02 | Affected | 0.0962 | 0.3454 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| c.2111G>C | S704T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. Only polyPhen‑2 HumDiv predicts a pathogenic effect, while FoldX remains inconclusive. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Overall, the aggregate evidence indicates that S704T is most likely benign, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | Uncertain | 1 | -4.930 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.80 | Ambiguous | 0.0 | 0.15 | Likely Benign | 0.48 | Likely Benign | 0.29 | Likely Benign | 0.071 | Likely Benign | -1.72 | Neutral | 0.525 | Possibly Damaging | 0.107 | Benign | 3.45 | Benign | 0.07 | Tolerated | 3.47 | 10 | 0.1036 | 0.4674 | 1 | 1 | 0.1 | 14.03 | 201.7 | -18.0 | 0.0 | 0.0 | -0.2 | 0.7 | X | Potentially Benign | Ser704 is located at the end and outer surface of an α-helix (res. Thr704-Gly712), which is connected via a tight turn or loop to another α-helix (res. Asp684-Gln702). The hydroxyl side chain of Ser704 occasionally forms a hydrogen bond with the amide group of Ala707. Similarly, in the variant simulations, the hydroxyl side chain of Thr704 forms hydrogen bonds with the amide groups of Ala707 and Leu708. Thus, the residue swap does not cause any apparent structural change. | ||||||||||||||||
| c.682A>T | T228S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 T228S 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, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a benign stability change. Taken together, the overwhelming majority of evidence indicates a benign impact for T228S. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -2.028 | Likely Benign | 0.493 | Ambiguous | Likely Benign | 0.32 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.48 | Likely Benign | 0.05 | Likely Benign | 0.458 | Likely Benign | -0.50 | Neutral | 0.734 | Possibly Damaging | 0.138 | Benign | 5.65 | Benign | 1.00 | Tolerated | 0.3395 | 0.5107 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.759C>A | N253K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253K resides in the PH domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Functional prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, and FATHMM. In contrast, the majority of predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—label it pathogenic or likely pathogenic. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus also indicates likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect. This assessment is not contradicted by ClinVar, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -15.834 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.0 | 0.90 | Ambiguous | 0.48 | Likely Benign | 0.17 | Likely Benign | 0.663 | Likely Pathogenic | -5.21 | Deleterious | 0.993 | Probably Damaging | 0.979 | Probably Damaging | 5.53 | Benign | 0.03 | Affected | 0.2640 | 0.6592 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.759C>G | N253K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools fall into two groups: benign predictions come from FoldX, FATHMM, premPS, and Foldetta, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Benign. Overall, the majority of tools predict pathogenicity, and the two most reliable predictors also lean pathogenic, whereas only one high‑accuracy tool suggests benign. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -15.834 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.0 | 0.90 | Ambiguous | 0.48 | Likely Benign | 0.17 | Likely Benign | 0.663 | Likely Pathogenic | -5.21 | Deleterious | 0.993 | Probably Damaging | 0.979 | Probably Damaging | 5.53 | Benign | 0.03 | Affected | 0.2640 | 0.6592 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.866T>A | M289K 2D 3DClick to see structure in 3D Viewer AISynGAP1 M289K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Because the majority of consensus and individual predictors lean toward pathogenicity, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status since none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.127496 | Structured | 0.403499 | Uncertain | 0.886 | 0.276 | 0.000 | -12.192 | Likely Pathogenic | 0.738 | Likely Pathogenic | Likely Benign | 0.36 | Likely Benign | 0.2 | 0.60 | Ambiguous | 0.48 | Likely Benign | 0.94 | Ambiguous | 0.229 | Likely Benign | -2.52 | Deleterious | 0.891 | Possibly Damaging | 0.492 | Possibly Damaging | 1.94 | Pathogenic | 0.12 | Tolerated | 0.1271 | 0.0879 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.914C>T | T305I 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437819‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Overall, the balance of evidence from high‑confidence predictors leans toward a benign impact, and this assessment does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | Uncertain | 1 | 6-33437819-C-T | 1 | 6.20e-7 | -5.222 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.37 | Likely Benign | 0.2 | 0.58 | Ambiguous | 0.48 | Likely Benign | 0.25 | Likely Benign | 0.224 | Likely Benign | -2.90 | Deleterious | 0.997 | Probably Damaging | 0.929 | Probably Damaging | 1.70 | Pathogenic | 0.04 | Affected | 3.40 | 20 | 0.0939 | 0.5693 | -1 | 0 | 5.2 | 12.05 | |||||||||||||||||||||||
| c.1070A>G | H357R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 H357R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. Two tools remain uncertain: Rosetta and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority; and Foldetta also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.203355 | Structured | 0.399052 | Uncertain | 0.861 | 0.413 | 0.250 | -9.212 | Likely Pathogenic | 0.348 | Ambiguous | Likely Benign | -0.10 | Likely Benign | 0.3 | 1.07 | Ambiguous | 0.49 | Likely Benign | 0.32 | Likely Benign | 0.107 | Likely Benign | -1.03 | Neutral | 0.495 | Possibly Damaging | 0.095 | Benign | 4.22 | Benign | 0.59 | Tolerated | 0.2147 | 0.2818 | 2 | 0 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||
| c.1276A>G | N426D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N426D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Three tools (FoldX, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of predictions (six benign vs. four pathogenic) and the two high‑accuracy benign calls suggest the variant is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -11.159 | Likely Pathogenic | 0.554 | Ambiguous | Likely Benign | 0.80 | Ambiguous | 0.0 | 0.18 | Likely Benign | 0.49 | Likely Benign | 0.64 | Ambiguous | 0.173 | Likely Benign | -3.09 | Deleterious | 0.998 | Probably Damaging | 0.980 | Probably Damaging | 3.34 | Benign | 0.09 | Tolerated | 0.1730 | 0.1746 | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.1300G>C | V434L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools, Rosetta and AlphaMissense‑Default, give uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta, a protein‑folding stability method, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that V434L 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. | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -8.697 | Likely Pathogenic | 0.477 | Ambiguous | Likely Benign | -0.05 | Likely Benign | 0.0 | 1.02 | Ambiguous | 0.49 | Likely Benign | 0.20 | Likely Benign | 0.225 | Likely Benign | -2.30 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.64 | Benign | 0.27 | Tolerated | 0.0895 | 0.3813 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.1657A>C | K553Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K553Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Foldetta, and SIFT, whereas the majority of tools (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict it to be pathogenic; Rosetta is inconclusive and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, all pathogenic) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence (10 pathogenic vs. 3 benign predictions) indicates that K553Q is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.012270 | Structured | 0.006539 | Uncertain | 0.949 | 0.246 | 0.000 | -13.476 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.44 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.49 | Likely Benign | 1.01 | Destabilizing | 0.783 | Likely Pathogenic | -3.78 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.37 | Pathogenic | 0.07 | Tolerated | 0.3477 | 0.0830 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1804A>C | I602L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I602L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, PROVEAN, and AlphaMissense‑Optimized, whereas a majority of tools predict pathogenicity: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Three tools (Rosetta, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the balance of evidence leans toward pathogenicity, with no conflict with the ClinVar status because the variant is not yet classified in that database. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -9.660 | Likely Pathogenic | 0.558 | Ambiguous | Likely Benign | -0.15 | Likely Benign | 0.1 | 1.12 | Ambiguous | 0.49 | Likely Benign | 0.91 | Ambiguous | 0.631 | Likely Pathogenic | -1.99 | Neutral | 0.645 | Possibly Damaging | 0.718 | Possibly Damaging | -1.54 | Pathogenic | 0.04 | Affected | 0.1044 | 0.3199 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1903A>C | N635H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N635H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Three tools (FoldX, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; and Foldetta predicts benign. No prediction or folding‑stability result is missing or inconclusive. Based on the available evidence, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -12.507 | Likely Pathogenic | 0.419 | Ambiguous | Likely Benign | 1.07 | Ambiguous | 0.2 | -0.10 | Likely Benign | 0.49 | Likely Benign | 0.91 | Ambiguous | 0.429 | Likely Benign | -4.78 | Deleterious | 0.993 | Probably Damaging | 0.879 | Possibly Damaging | 2.90 | Benign | 0.00 | Affected | 0.1184 | 0.3720 | 2 | 1 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||
| c.1910C>T | S637F 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant S637F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, FoldX, Foldetta, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by Rosetta and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM‑Consensus) aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and yields a pathogenic verdict. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. AlphaMissense‑Optimized remains inconclusive. Overall, the majority of evidence points toward a pathogenic impact, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -13.266 | Likely Pathogenic | 0.831 | Likely Pathogenic | Ambiguous | 0.01 | Likely Benign | 0.1 | 0.96 | Ambiguous | 0.49 | Likely Benign | 0.49 | Likely Benign | 0.222 | Likely Benign | -3.92 | Deleterious | 0.985 | Probably Damaging | 0.681 | Possibly Damaging | 3.35 | Benign | 0.01 | Affected | 0.0780 | 0.4126 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.2159A>G | D720G 2D AISynGAP1 missense variant D720G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Foldetta, and premPS, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools remain inconclusive: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as benign. Overall, the balance of evidence favors a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.374039 | Structured | 0.450695 | Uncertain | 0.955 | 0.417 | 0.125 | -11.130 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.45 | Likely Benign | 0.4 | 0.53 | Ambiguous | 0.49 | Likely Benign | 0.46 | Likely Benign | 0.427 | Likely Benign | -5.67 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.15 | Pathogenic | 0.01 | Affected | 0.4027 | 0.5011 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.742C>T | R248W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248W is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Rosetta, Foldetta, and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results from FoldX and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | Uncertain | 1 | -11.647 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.17 | Ambiguous | 0.3 | -0.20 | Likely Benign | 0.49 | Likely Benign | 0.89 | Ambiguous | 0.699 | Likely Pathogenic | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.948 | Probably Damaging | 5.62 | Benign | 0.00 | Affected | 3.41 | 14 | 0.1124 | 0.4037 | 2 | -3 | 3.6 | 30.03 | 266.4 | 42.3 | 0.0 | 0.0 | 0.3 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg248, located on an α helix (res. Ala236-Val250), forms two very stable salt bridges with Asp255 (from a short α helical section, res. Lys254-Asn256) and Glu244 (from a nearby loop) in the WT simulations. In the variant simulations, the indole group of Trp248 cannot form any salt bridges, which could negatively affect the tertiary structure assembly of the PH domain. Instead, in the variant simulations, the indole ring of Trp248 stacks against Pro252, which makes a turn after the α helix. | ||||||||||||||||
| c.820C>A | L274M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, PROVEAN, and AlphaMissense‑Optimized, whereas those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Three tools (Rosetta, premPS, and ESM1b) returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting benign. Overall, the majority of predictions (seven pathogenic vs. four benign) and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.066181 | Structured | 0.377483 | Uncertain | 0.866 | 0.195 | 0.250 | -7.386 | In-Between | 0.658 | Likely Pathogenic | Likely Benign | 0.24 | Likely Benign | 0.2 | 0.74 | Ambiguous | 0.49 | Likely Benign | 0.81 | Ambiguous | 0.512 | Likely Pathogenic | -1.77 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.04 | Pathogenic | 0.01 | Affected | 0.0810 | 0.2202 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.943A>G | N315D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and FATHMM. The remaining tools (FoldX, premPS, AlphaMissense‑Default) are inconclusive. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority; and Foldetta predicts a benign stability change. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -5.667 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 1.27 | Ambiguous | 0.6 | -0.30 | Likely Benign | 0.49 | Likely Benign | 0.88 | Ambiguous | 0.229 | Likely Benign | -2.41 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.02 | Pathogenic | 0.45 | Tolerated | 0.1972 | 0.4488 | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.949C>A | L317M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L317M missense variant is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools show a split: benign calls come from REVEL, FoldX, Foldetta, and PROVEAN, whereas pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta predicts a benign effect on protein stability. No evidence from ClinVar contradicts these findings. Overall, the preponderance of pathogenic predictions and the SGM‑Consensus result suggest that the variant is most likely pathogenic, though the benign signal from Foldetta and other tools indicates uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.106997 | Structured | 0.394031 | Uncertain | 0.874 | 0.240 | 0.125 | -9.558 | Likely Pathogenic | 0.788 | Likely Pathogenic | Ambiguous | 0.14 | Likely Benign | 0.1 | 0.84 | Ambiguous | 0.49 | Likely Benign | 0.94 | Ambiguous | 0.250 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.71 | Pathogenic | 0.04 | Affected | 0.0937 | 0.3122 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1001A>C | K334T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K334T is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, and premPS. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive or uncertain are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts a likely pathogenic outcome, AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.377384 | Structured | 0.325972 | Uncertain | 0.544 | 0.414 | 0.500 | -8.313 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 0.78 | Ambiguous | 0.3 | 0.21 | Likely Benign | 0.50 | Ambiguous | 0.17 | Likely Benign | 0.320 | Likely Benign | -5.51 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.78 | Pathogenic | 0.02 | Affected | 0.2062 | 0.2978 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1001A>T | K334M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K334M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, and premPS. In contrast, the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as deleterious. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as Likely Pathogenic. Foldetta and Rosetta provide uncertain results. Focusing on high‑accuracy methods, AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus confirms a Likely Pathogenic status, and Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for K334M, and this assessment does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.377384 | Structured | 0.325972 | Uncertain | 0.544 | 0.414 | 0.500 | -10.530 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.44 | Likely Benign | 0.0 | 0.56 | Ambiguous | 0.50 | Ambiguous | 0.14 | Likely Benign | 0.323 | Likely Benign | -5.51 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.77 | Pathogenic | 0.01 | Affected | 0.1027 | 0.3690 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1273A>T | T425S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, Rosetta) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (five benign vs. four pathogenic) lean toward a benign interpretation, and this assessment does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -7.420 | In-Between | 0.676 | Likely Pathogenic | Likely Benign | 0.22 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.50 | Ambiguous | 0.63 | Ambiguous | 0.275 | Likely Benign | -3.05 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.42 | Benign | 0.07 | Tolerated | 0.2511 | 0.2324 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||
| c.1274C>A | T425N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions labeled uncertain (Foldetta, premPS, AlphaMissense‑Optimized, Rosetta) are treated as unavailable. High‑accuracy assessments further indicate a likely pathogenic outcome from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and an uncertain result from AlphaMissense‑Optimized and Foldetta. Overall, the majority of definitive predictions support a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -10.709 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.19 | Likely Benign | 0.1 | 0.81 | Ambiguous | 0.50 | Ambiguous | 0.82 | Ambiguous | 0.185 | Likely Benign | -3.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.44 | Benign | 0.04 | Affected | 0.1169 | 0.2843 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.1274C>G | T425S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, Rosetta) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (five benign vs. four pathogenic) lean toward a benign interpretation, and this assessment does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -7.420 | In-Between | 0.676 | Likely Pathogenic | Likely Benign | 0.22 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.50 | Ambiguous | 0.63 | Ambiguous | 0.184 | Likely Benign | -3.05 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.42 | Benign | 0.07 | Tolerated | 0.2511 | 0.2324 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||
| c.1521G>C | K507N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K507N is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, whereas a pathogenic signal is reported by REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta’s stability prediction is unavailable. Overall, the majority of tools (10 out of 14 with definitive calls) predict a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -10.682 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | 0.81 | Ambiguous | 0.1 | 0.18 | Likely Benign | 0.50 | Ambiguous | 1.06 | Destabilizing | 0.579 | Likely Pathogenic | -1.63 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.57 | Pathogenic | 0.11 | Tolerated | 0.2417 | 0.0764 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1521G>T | K507N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K507N is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, while those that predict a pathogenic effect comprise REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (10 pathogenic vs. 4 benign) predict a deleterious impact. Thus, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -10.682 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | 0.81 | Ambiguous | 0.1 | 0.18 | Likely Benign | 0.50 | Ambiguous | 1.06 | Destabilizing | 0.579 | Likely Pathogenic | -1.63 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.57 | Pathogenic | 0.11 | Tolerated | 0.2417 | 0.0764 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1741C>T | R581W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R581W is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only Rosetta, whereas the remaining pathogenic‑predicating tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—consistently classify the variant as deleterious. Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain”; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Pathogenic”; and Foldetta remains “Uncertain.” Overall, the preponderance of evidence points to a pathogenic impact, which contrasts with the ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.029544 | Uncertain | 0.829 | 0.236 | 0.000 | Uncertain | 2 | -12.855 | Likely Pathogenic | 0.920 | Likely Pathogenic | Ambiguous | 1.32 | Ambiguous | 0.1 | -0.32 | Likely Benign | 0.50 | Ambiguous | 0.68 | Ambiguous | 0.678 | Likely Pathogenic | -6.79 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.37 | Pathogenic | 0.01 | Affected | 3.37 | 34 | 0.1142 | 0.3043 | 2 | -3 | 3.6 | 30.03 | 257.8 | 36.0 | 0.1 | 0.1 | 0.1 | 0.3 | X | X | Potentially Pathogenic | Arg581 is located on a short α-α loop between two α helices (res. Arg563-Glu578 and res. Glu582-Ser604). In the WT simulations, the guanidinium group of Arg581 forms salt bridges with the carboxylate groups of Asp583 within the same helix, as well as with Glu478 and/or Glu480 in a slightly α-helical loop (res. Glu478-Thr488) preceding another α helix (res. Ala461-Phe476).In the variant simulations, the neutral indole ring of the Trp581 side chain cannot form any of these salt bridges. Instead, it packs hydrophobically against Met477 and Ile587 without forming any direct hydrogen bonds. The tendency of the loop (res. Asp477-Thr488) to acquire an α-helical structure seems to marginally increase, potentially due to Trp581's inability to coordinate stable hydrogen bonds with the loop residues (e.g., Glu478-Arg581 salt bridge). Additionally, the residue swap could weaken the tertiary structure assembly and negatively affect the overall protein folding process. | |||||||||||||||
| c.1981C>G | Q661E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q661E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Four tools (FoldX, 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 available predictions lean toward a benign impact. This conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.048328 | Structured | 0.117089 | Uncertain | 0.924 | 0.309 | 0.000 | -12.121 | Likely Pathogenic | 0.370 | Ambiguous | Likely Benign | 0.64 | Ambiguous | 0.1 | 0.35 | Likely Benign | 0.50 | Ambiguous | 0.61 | Ambiguous | 0.141 | Likely Benign | -2.15 | Neutral | 0.988 | Probably Damaging | 0.619 | Possibly Damaging | 3.42 | Benign | 0.03 | Affected | 0.1199 | 0.2439 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.2102C>A | P701H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 P701H missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions that are uncertain or inconclusive are FoldX, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict the ClinVar status, which contains no pathogenic assertion for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.074921 | Structured | 0.404318 | Uncertain | 0.918 | 0.345 | 0.000 | -8.786 | Likely Pathogenic | 0.553 | Ambiguous | Likely Benign | 1.40 | Ambiguous | 0.0 | -0.41 | Likely Benign | 0.50 | Ambiguous | 0.62 | Ambiguous | 0.141 | Likely Benign | -2.12 | Neutral | 0.936 | Possibly Damaging | 0.539 | Possibly Damaging | 3.38 | Benign | 0.03 | Affected | 0.1495 | 0.3495 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||
| c.635C>T | S212F 2D AIThe SynGAP1 missense variant S212F is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX, FATHMM, and premPS, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score (Likely Pathogenic) predict a pathogenic outcome. The remaining tools, Foldetta and Rosetta, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall consensus of the majority of predictors and the high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -14.029 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.11 | Likely Benign | 1.6 | 0.88 | Ambiguous | 0.50 | Ambiguous | -0.02 | Likely Benign | 0.820 | Likely Pathogenic | -5.15 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 0.0503 | 0.6259 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.670A>T | T224S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 (HumDiv) predicts a pathogenic outcome; the remaining tools (Foldetta, premPS, AlphaMissense‑Default, Rosetta) give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -5.928 | Likely Benign | 0.558 | Ambiguous | Likely Benign | 0.29 | Likely Benign | 0.1 | 0.70 | Ambiguous | 0.50 | Ambiguous | 0.71 | Ambiguous | 0.412 | Likely Benign | -2.09 | Neutral | 0.608 | Possibly Damaging | 0.079 | Benign | 5.56 | Benign | 0.66 | Tolerated | 0.3498 | 0.4994 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.671C>G | T224S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 (HumDiv) predicts a pathogenic outcome; the remaining tools (Foldetta, premPS, AlphaMissense‑Default, Rosetta) give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -5.928 | Likely Benign | 0.558 | Ambiguous | Likely Benign | 0.29 | Likely Benign | 0.1 | 0.70 | Ambiguous | 0.50 | Ambiguous | 0.71 | Ambiguous | 0.374 | Likely Benign | -2.09 | Neutral | 0.608 | Possibly Damaging | 0.079 | Benign | 5.56 | Benign | 0.66 | Tolerated | 0.3498 | 0.4994 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.720C>A | D240E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240E missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated predictors (seven pathogenic vs. four benign) lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -8.619 | Likely Pathogenic | 0.796 | Likely Pathogenic | Ambiguous | 0.49 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.50 | Ambiguous | 0.28 | Likely Benign | 0.713 | Likely Pathogenic | -3.43 | Deleterious | 0.984 | Probably Damaging | 0.967 | Probably Damaging | 5.84 | Benign | 0.10 | Tolerated | 0.1155 | 0.5066 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.720C>G | D240E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D240E is a missense change in the PH domain. No ClinVar entry exists for this variant, and it is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from SIFT, FoldX, premPS, and FATHMM, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—AlphaMissense‑Optimized, Rosetta, and Foldetta—are treated as unavailable. High‑accuracy assessments show the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifying the variant as Likely Pathogenic, whereas AlphaMissense‑Optimized and Foldetta provide no definitive verdict. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -8.619 | Likely Pathogenic | 0.796 | Likely Pathogenic | Ambiguous | 0.49 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.50 | Ambiguous | 0.28 | Likely Benign | 0.713 | Likely Pathogenic | -3.43 | Deleterious | 0.984 | Probably Damaging | 0.967 | Probably Damaging | 5.84 | Benign | 0.10 | Tolerated | 0.1155 | 0.5066 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.808G>C | E270Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E270Q missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, and premPS, whereas the majority of tools predict pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates several high‑accuracy predictors, classifies the variant as Likely Pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized is Uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is Uncertain. Rosetta alone is Uncertain, and Foldetta’s uncertainty reflects limited stability change evidence. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.382573 | Uncertain | 0.938 | 0.231 | 0.125 | -11.096 | Likely Pathogenic | 0.886 | Likely Pathogenic | Ambiguous | 0.00 | Likely Benign | 0.2 | 1.00 | Ambiguous | 0.50 | Ambiguous | 0.46 | Likely Benign | 0.418 | Likely Benign | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.65 | Pathogenic | 0.03 | Affected | 0.1044 | 0.4015 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.848A>T | E283V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E283V missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are FoldX and premPS, while the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give inconclusive results: Rosetta (Uncertain) and Foldetta (Uncertain). High‑accuracy methods specifically indicate that AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely pathogenic, whereas Foldetta’s stability assessment is uncertain. Taken together, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic effect for E283V. This conclusion is consistent with the absence of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.358602 | Uncertain | 0.950 | 0.249 | 0.000 | -13.602 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.44 | Likely Benign | 0.2 | 0.56 | Ambiguous | 0.50 | Ambiguous | 0.36 | Likely Benign | 0.558 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.83 | Pathogenic | 0.00 | Affected | 0.0874 | 0.6011 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.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.1051G>A | A351T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A351T missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Uncertain predictions come from Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta as inconclusive. Overall, the majority of evidence supports a benign impact for A351T, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -6.863 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.0 | 0.80 | Ambiguous | 0.51 | Ambiguous | 0.49 | Likely Benign | 0.040 | Likely Benign | -2.42 | Neutral | 0.524 | Possibly Damaging | 0.138 | Benign | 1.71 | Pathogenic | 0.06 | Tolerated | 0.1337 | 0.6713 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1183G>A | G395R 2D AIThe SynGAP1 missense variant G395R has no ClinVar record and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from SIFT, ESM1b, and AlphaMissense‑Default. Two tools, FoldX and Foldetta, yield uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta remains uncertain. Overall, the balance of evidence favors 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. | C2 | 0.513880 | Disordered | 0.396199 | Uncertain | 0.474 | 0.601 | 0.500 | -9.851 | Likely Pathogenic | 0.768 | Likely Pathogenic | Likely Benign | 1.26 | Ambiguous | 2.1 | -0.25 | Likely Benign | 0.51 | Ambiguous | 0.50 | Likely Benign | 0.430 | Likely Benign | -2.01 | Neutral | 0.037 | Benign | 0.027 | Benign | 4.23 | Benign | 0.02 | Affected | 0.0953 | 0.4313 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1183G>C | G395R 2D AIThe SynGAP1 missense variant G395R has no ClinVar record and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from SIFT, ESM1b, and AlphaMissense‑Default. Two tools, FoldX and Foldetta, yield uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta remains uncertain. Overall, the balance of evidence favors 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. | C2 | 0.513880 | Disordered | 0.396199 | Uncertain | 0.474 | 0.601 | 0.500 | -9.851 | Likely Pathogenic | 0.768 | Likely Pathogenic | Likely Benign | 1.26 | Ambiguous | 2.1 | -0.25 | Likely Benign | 0.51 | Ambiguous | 0.50 | Likely Benign | 0.430 | Likely Benign | -2.01 | Neutral | 0.037 | Benign | 0.027 | Benign | 4.23 | Benign | 0.02 | Affected | 0.0953 | 0.4313 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1315C>A | L439M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L439M is reported in gnomAD (variant ID 6‑33438220‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on benign impact include REVEL, FoldX, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from premPS, polyPhen‑2 (HumDiv and HumVar) and SIFT. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta as inconclusive. Overall, the majority of evidence points to a benign effect; there is no ClinVar classification to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | 6-33438220-C-A | 1 | 6.20e-7 | -5.840 | Likely Benign | 0.363 | Ambiguous | Likely Benign | -0.33 | Likely Benign | 0.1 | 1.34 | Ambiguous | 0.51 | Ambiguous | 1.01 | Destabilizing | 0.187 | Likely Benign | -1.43 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.24 | Benign | 0.02 | Affected | 3.38 | 25 | 0.0720 | 0.2753 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||
| c.1345A>G | S449G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449G is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (variant ID 6‑33438250‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as “Likely Benign,” and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | Uncertain | 1 | 6-33438250-A-G | 3 | 1.86e-6 | -5.936 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.47 | Likely Benign | 0.0 | 0.55 | Ambiguous | 0.51 | Ambiguous | 0.85 | Ambiguous | 0.116 | Likely Benign | -2.32 | Neutral | 0.948 | Possibly Damaging | 0.124 | Benign | 3.35 | Benign | 0.13 | Tolerated | 3.37 | 32 | 0.2600 | 0.3718 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||
| c.1424G>T | R475L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R475L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score, whereas only Rosetta predicts a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. With the preponderance of pathogenic calls and no conflicting evidence from ClinVar or population databases, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | -13.074 | Likely Pathogenic | 0.928 | Likely Pathogenic | Ambiguous | 1.49 | Ambiguous | 0.4 | -0.47 | Likely Benign | 0.51 | Ambiguous | 0.55 | Ambiguous | 0.806 | Likely Pathogenic | -6.40 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.40 | Pathogenic | 0.00 | Affected | 0.1580 | 0.3428 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1519A>G | K507E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K507E missense change is not listed in ClinVar and has no gnomAD allele, indicating it is not a common polymorphism. Functional prediction tools cluster into two groups: benign predictions come from Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, while pathogenic predictions arise from REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Four tools give uncertain results: FoldX, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments provide a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic, and Foldetta remains uncertain. Overall, the majority of standard predictors favor a pathogenic effect, and the high‑accuracy consensus also tilts toward pathogenicity, though not decisively. Therefore, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status because the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -11.507 | Likely Pathogenic | 0.448 | Ambiguous | Likely Benign | 0.70 | Ambiguous | 0.0 | 0.31 | Likely Benign | 0.51 | Ambiguous | 0.67 | Ambiguous | 0.536 | Likely Pathogenic | -0.84 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.45 | Pathogenic | 0.21 | Tolerated | 0.2537 | 0.0488 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||
| c.1622C>A | A541D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SIFT and FoldX, whereas a larger group—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | -11.510 | Likely Pathogenic | 0.864 | Likely Pathogenic | Ambiguous | 0.36 | Likely Benign | 0.0 | 0.65 | Ambiguous | 0.51 | Ambiguous | 0.65 | Ambiguous | 0.571 | Likely Pathogenic | -3.18 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.15 | Pathogenic | 0.14 | Tolerated | 0.1581 | 0.1902 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1730C>A | A577E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 A577E 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, PROVEAN, and SIFT, whereas those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain; Rosetta and premPS are inconclusive. Overall, the majority of evaluated tools (five pathogenic vs. four benign) and the SGM‑Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | -9.607 | Likely Pathogenic | 0.794 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.0 | 0.72 | Ambiguous | 0.51 | Ambiguous | 0.62 | Ambiguous | 0.419 | Likely Benign | -1.91 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.12 | Pathogenic | 0.76 | Tolerated | 0.1487 | 0.1799 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||
| c.1940G>A | G647D 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant G647D is reported in ClinVar as having no entry and is present in gnomAD (6‑33441199‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized all predict benign. Only AlphaMissense‑Default predicts pathogenic, while FoldX, Foldetta, premPS, and ESM1b are uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the consensus of most tools and the high‑accuracy predictions indicate that G647D is most likely benign, and this is consistent with the absence of a pathogenic ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.048328 | Structured | 0.325524 | Uncertain | 0.936 | 0.356 | 0.000 | 6-33441199-G-A | 1 | 6.20e-7 | -7.643 | In-Between | 0.582 | Likely Pathogenic | Likely Benign | 0.68 | Ambiguous | 0.1 | 0.33 | Likely Benign | 0.51 | Ambiguous | 0.56 | Ambiguous | 0.098 | Likely Benign | -1.63 | Neutral | 0.282 | Benign | 0.128 | Benign | 3.45 | Benign | 0.24 | Tolerated | 3.37 | 30 | 0.1630 | 0.1372 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||
| c.919T>G | F307V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F307V is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include Rosetta and premPS, whereas the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the consensus score SGM‑Consensus all classify the change as pathogenic or likely pathogenic. High‑accuracy methods give a pathogenic call from AlphaMissense‑Optimized, a likely pathogenic result from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an inconclusive result from Foldetta (combining FoldX‑MD and Rosetta). No prediction is missing or inconclusive enough to alter the overall assessment. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.298791 | Structured | 0.327302 | Uncertain | 0.900 | 0.315 | 0.125 | -12.262 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.91 | Ambiguous | 0.1 | 0.10 | Likely Benign | 0.51 | Ambiguous | 0.36 | Likely Benign | 0.605 | Likely Pathogenic | -6.43 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.29 | Pathogenic | 0.05 | Affected | 0.2523 | 0.3393 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1039A>G | T347A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347A is catalogued in gnomAD (ID 6‑33437944‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated. Only FATHMM predicts a pathogenic outcome, while Foldetta, premPS, and Rosetta are inconclusive. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta remains uncertain. Overall, the consensus of the majority of tools indicates the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | 6-33437944-A-G | 9 | 5.58e-6 | -5.858 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.34 | Likely Benign | 0.1 | 0.70 | Ambiguous | 0.52 | Ambiguous | 0.70 | Ambiguous | 0.093 | Likely Benign | -1.52 | Neutral | 0.031 | Benign | 0.016 | Benign | 1.68 | Pathogenic | 0.42 | Tolerated | 3.37 | 25 | 0.4032 | 0.4615 | 0 | 1 | 2.5 | -30.03 | ||||||||||||||||||||||||
| c.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.1257G>C | E419D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E419D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain or inconclusive predictions come from Foldetta, AlphaMissense‑Optimized, ESM1b, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain (treated as unavailable), the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta remains uncertain (unavailable). Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -7.036 | In-Between | 0.869 | Likely Pathogenic | Ambiguous | 0.17 | Likely Benign | 0.1 | 0.87 | Ambiguous | 0.52 | Ambiguous | 0.48 | Likely Benign | 0.170 | Likely Benign | -2.40 | Neutral | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.33 | Benign | 0.10 | Tolerated | 0.1966 | 0.4906 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1257G>T | E419D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E419D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain or inconclusive predictions come from Foldetta, AlphaMissense‑Optimized, ESM1b, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain (treated as unavailable), the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta remains uncertain (unavailable). Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -7.036 | In-Between | 0.869 | Likely Pathogenic | Ambiguous | 0.17 | Likely Benign | 0.1 | 0.87 | Ambiguous | 0.52 | Ambiguous | 0.48 | Likely Benign | 0.170 | Likely Benign | -2.40 | Neutral | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.33 | Benign | 0.10 | Tolerated | 0.1966 | 0.4906 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1385A>G | K462R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K462R is catalogued in gnomAD (ID 6‑33438290‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Three tools (Rosetta, Foldetta, premPS) yield uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic) and Foldetta is uncertain, so neither provides decisive evidence. Overall, the majority of reliable predictors lean toward a benign effect. This consensus does not contradict ClinVar status, which is currently absent. Thus, based on available predictions, K462R is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | 6-33438290-A-G | 1 | 6.20e-7 | -9.980 | Likely Pathogenic | 0.184 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.90 | Ambiguous | 0.52 | Ambiguous | 0.84 | Ambiguous | 0.246 | Likely Benign | -2.75 | Deleterious | 0.983 | Probably Damaging | 0.962 | Probably Damaging | 3.43 | Benign | 0.09 | Tolerated | 3.37 | 34 | 0.4995 | 0.1201 | 2 | 3 | -0.6 | 28.01 | |||||||||||||||||||||||||
| c.1558T>A | S520T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520T is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from premPS and PROVEAN, while pathogenic predictions are made by SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Four high‑accuracy methods were examined: AlphaMissense‑Optimized returned an uncertain result; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, was also uncertain. With three of the four high‑accuracy tools indicating pathogenicity and only two tools suggesting benign, the overall evidence points to a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -8.432 | Likely Pathogenic | 0.822 | Likely Pathogenic | Ambiguous | 0.52 | Ambiguous | 0.0 | 0.52 | Ambiguous | 0.52 | Ambiguous | 0.34 | Likely Benign | 0.565 | Likely Pathogenic | -2.41 | Neutral | 0.826 | Possibly Damaging | 0.872 | Possibly Damaging | -1.28 | Pathogenic | 0.02 | Affected | 0.1296 | 0.5199 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1823T>A | F608Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608Y is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a pathogenic effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus all predict pathogenicity, while only Rosetta predicts a benign effect. Tools with uncertain outcomes—FoldX, Foldetta, and AlphaMissense‑Optimized—do not provide decisive evidence. High‑accuracy assessments further support a deleterious impact: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic, whereas AlphaMissense‑Optimized and Foldetta remain inconclusive. Overall, the preponderance of evidence indicates that F608Y is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -13.249 | Likely Pathogenic | 0.812 | Likely Pathogenic | Ambiguous | 0.62 | Ambiguous | 0.1 | 0.41 | Likely Benign | 0.52 | Ambiguous | 1.05 | Destabilizing | 0.747 | Likely Pathogenic | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.976 | Probably Damaging | -1.44 | Pathogenic | 0.00 | Affected | 0.1504 | 0.1346 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1831A>C | M611L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome, while Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact, 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 | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -6.721 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.1 | 0.65 | Ambiguous | 0.52 | Ambiguous | 0.56 | Ambiguous | 0.229 | Likely Benign | -1.29 | Neutral | 0.059 | Benign | 0.017 | Benign | -1.07 | Pathogenic | 0.76 | Tolerated | 0.1130 | 0.3547 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1831A>T | M611L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611L 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, while Rosetta, Foldetta, and premPS are uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Likely Benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the preponderance of evidence points to a benign impact for M611L, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -6.721 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.1 | 0.65 | Ambiguous | 0.52 | Ambiguous | 0.56 | Ambiguous | 0.229 | Likely Benign | -1.29 | Neutral | 0.059 | Benign | 0.017 | Benign | -1.07 | Pathogenic | 0.76 | Tolerated | 0.1130 | 0.3547 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1854G>C | Q618H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q618H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, PROVEAN, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Four tools (FoldX, Foldetta, ESM1b, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and Foldetta is uncertain. Overall, the majority of evidence points toward a benign effect, and this conclusion does not contradict the lack of ClinVar annotation or gnomAD presence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -7.092 | In-Between | 0.489 | Ambiguous | Likely Benign | 0.59 | Ambiguous | 0.1 | 0.44 | Likely Benign | 0.52 | Ambiguous | 0.34 | Likely Benign | 0.475 | Likely Benign | -1.99 | Neutral | 0.946 | Possibly Damaging | 0.638 | Possibly Damaging | -1.35 | Pathogenic | 0.04 | Affected | 0.1015 | 0.2655 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1854G>T | Q618H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, PROVEAN, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Four tools (FoldX, Foldetta, ESM1b, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also uncertain. Overall, the balance of evidence leans toward a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -7.092 | In-Between | 0.489 | Ambiguous | Likely Benign | 0.59 | Ambiguous | 0.1 | 0.44 | Likely Benign | 0.52 | Ambiguous | 0.34 | Likely Benign | 0.475 | Likely Benign | -1.99 | Neutral | 0.946 | Possibly Damaging | 0.638 | Possibly Damaging | -1.35 | Pathogenic | 0.04 | Affected | 0.1015 | 0.2655 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1949A>C | N650T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, and FATHMM, whereas a larger group predicts pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results come from Foldetta, premPS, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -13.626 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.31 | Likely Benign | 0.1 | 0.73 | Ambiguous | 0.52 | Ambiguous | 0.69 | Ambiguous | 0.471 | Likely Benign | -5.98 | Deleterious | 0.986 | Probably Damaging | 0.710 | Possibly Damaging | 3.04 | Benign | 0.01 | Affected | 0.1700 | 0.4843 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.2012A>C | D671A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D671A missense variant is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence favors a pathogenic interpretation, with seven tools supporting pathogenicity versus four supporting benignity. This conclusion does not conflict with ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -11.709 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.25 | Likely Benign | 0.1 | 0.79 | Ambiguous | 0.52 | Ambiguous | 0.10 | Likely Benign | 0.245 | Likely Benign | -5.08 | Deleterious | 0.980 | Probably Damaging | 0.804 | Possibly Damaging | 3.34 | Benign | 0.03 | Affected | 0.4056 | 0.5895 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.2183C>G | P728R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P728R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FoldX, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further indicate a likely pathogenic status from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and an uncertain outcome from Foldetta (combining FoldX‑MD and Rosetta). AlphaMissense‑Optimized also remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, 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 | 0.632174 | Disordered | 0.434760 | Uncertain | 0.725 | 0.567 | 0.625 | -10.309 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 0.45 | Likely Benign | 0.1 | 0.59 | Ambiguous | 0.52 | Ambiguous | 0.70 | Ambiguous | 0.418 | Likely Benign | -7.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 0.66 | Pathogenic | 0.00 | Affected | 0.1728 | 0.2865 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||
| c.782A>T | D261V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, and FATHMM, while those that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.284882 | Structured | 0.422514 | Uncertain | 0.883 | 0.264 | 0.125 | -12.138 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | 1.72 | Ambiguous | 0.6 | -0.68 | Ambiguous | 0.52 | Ambiguous | -0.01 | Likely Benign | 0.869 | Likely Pathogenic | -5.50 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 5.73 | Benign | 0.08 | Tolerated | 0.0553 | 0.4734 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.994G>A | D332N 2D  3DClick to see structure in 3D Viewer AISynGAP1 D332N is not reported in ClinVar and is absent from gnomAD. Benign predictions come from REVEL, Rosetta, premPS, and SIFT, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default; SGM‑Consensus indicates a likely pathogenic outcome. FoldX and Foldetta give uncertain results. High‑accuracy tools show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, but the high‑accuracy AlphaMissense‑Optimized result is benign and Foldetta is inconclusive. Thus, the variant is most likely pathogenic based on the collective evidence, and this assessment does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -10.931 | Likely Pathogenic | 0.771 | Likely Pathogenic | Likely Benign | 1.20 | Ambiguous | 0.1 | -0.16 | Likely Benign | 0.52 | Ambiguous | 0.49 | Likely Benign | 0.396 | Likely Benign | -4.14 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.32 | Pathogenic | 0.11 | Tolerated | 0.0785 | 0.3963 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.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>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.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.1387G>C | D463H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant D463H is not reported in ClinVar and is absent from gnomAD. Consensus from standard prediction algorithms shows a split: benign predictions come from REVEL, FoldX, SIFT, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, SGM Consensus confirms Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains Uncertain. No evidence from ClinVar contradicts these findings. Overall, the preponderance of computational evidence indicates that D463H is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -13.151 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.20 | Likely Benign | 0.1 | 0.85 | Ambiguous | 0.53 | Ambiguous | 0.57 | Ambiguous | 0.356 | Likely Benign | -5.96 | Deleterious | 0.996 | Probably Damaging | 0.852 | Possibly Damaging | 3.35 | Benign | 0.11 | Tolerated | 0.1341 | 0.6156 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1532G>C | G511A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence (seven pathogenic versus three benign predictions) indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -9.621 | Likely Pathogenic | 0.844 | Likely Pathogenic | Ambiguous | 0.80 | Ambiguous | 0.2 | 0.25 | Likely Benign | 0.53 | Ambiguous | 0.55 | Ambiguous | 0.275 | Likely Benign | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.23 | Benign | 0.02 | Affected | 0.3793 | 0.2778 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1631G>A | R544Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R544Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438874‑G‑A). Prediction tools that classify the change as benign include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Foldetta and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, which is not contradictory to the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038858 | Structured | 0.016004 | Uncertain | 0.967 | 0.333 | 0.000 | Uncertain | 1 | 6-33438874-G-A | 1 | 6.20e-7 | -10.281 | Likely Pathogenic | 0.596 | Likely Pathogenic | Likely Benign | 0.19 | Likely Benign | 0.2 | 0.87 | Ambiguous | 0.53 | Ambiguous | 1.40 | Destabilizing | 0.542 | Likely Pathogenic | -2.41 | Neutral | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.40 | Pathogenic | 0.09 | Tolerated | 3.37 | 35 | 0.2103 | 0.1959 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||
| c.1925A>T | K642M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K642M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect fall into two broad groups: benign predictions come from FoldX, premPS, and FATHMM; pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give uncertain results: Rosetta and Foldetta. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments are as follows: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus also predicts pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence from multiple independent predictors indicates that K642M is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -13.557 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.43 | Likely Benign | 0.1 | 0.62 | Ambiguous | 0.53 | Ambiguous | 0.21 | Likely Benign | 0.510 | Likely Pathogenic | -5.88 | Deleterious | 1.000 | Probably Damaging | 0.941 | Probably Damaging | 2.81 | Benign | 0.00 | Affected | 0.1256 | 0.3589 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.2116G>C | E706Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E706Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are AlphaMissense‑Default and ESM1b. Rosetta and Foldetta provide uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta also yields an uncertain outcome. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.200174 | Structured | 0.377033 | Uncertain | 0.929 | 0.363 | 0.000 | -8.171 | Likely Pathogenic | 0.588 | Likely Pathogenic | Likely Benign | 0.44 | Likely Benign | 0.0 | 0.61 | Ambiguous | 0.53 | Ambiguous | -0.14 | Likely Benign | 0.059 | Likely Benign | -1.00 | Neutral | 0.433 | Benign | 0.051 | Benign | 4.13 | Benign | 0.31 | Tolerated | 0.0941 | 0.3831 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.910G>C | D304H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304H missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into three groups: benign predictions come from REVEL, Rosetta, and premPS; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; the remaining tools (FoldX, Foldetta, AlphaMissense‑Optimized) give uncertain results. High‑accuracy assessments reinforce this pattern: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which is currently absent. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -8.160 | Likely Pathogenic | 0.822 | Likely Pathogenic | Ambiguous | 0.89 | Ambiguous | 0.1 | 0.16 | Likely Benign | 0.53 | Ambiguous | 0.45 | Likely Benign | 0.417 | Likely Benign | -5.67 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.75 | Pathogenic | 0.01 | Affected | 0.1660 | 0.7498 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.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.1417G>A | V473I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438449‑G‑A). Functional prediction tools that agree on benign impact include REVEL, FoldX, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Pathogenic predictions are provided by both polyPhen‑2 HumDiv and HumVar. Predictions that are inconclusive are AlphaMissense‑Default, ESM1b, Foldetta, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to no majority, and Foldetta is uncertain. Overall, the balance of evidence favors a benign effect for V473I, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | Uncertain | 1 | 6-33438449-G-A | 1 | 6.20e-7 | -7.481 | In-Between | 0.418 | Ambiguous | Likely Benign | -0.12 | Likely Benign | 0.0 | 1.20 | Ambiguous | 0.54 | Ambiguous | -0.06 | Likely Benign | 0.203 | Likely Benign | -0.91 | Neutral | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.74 | Benign | 0.18 | Tolerated | 3.37 | 34 | 0.0568 | 0.3335 | 3 | 4 | 0.3 | 14.03 | |||||||||||||||||||||||
| c.1431G>A | M477I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, indicating no contradiction with existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -2.662 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.72 | Ambiguous | 0.1 | 0.36 | Likely Benign | 0.54 | Ambiguous | 0.45 | Likely Benign | 0.291 | Likely Benign | -1.57 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.21 | Pathogenic | 0.09 | Tolerated | 0.1368 | 0.3176 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1431G>C | M477I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta remains uncertain. Overall, the majority of evidence supports a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -2.662 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.72 | Ambiguous | 0.1 | 0.36 | Likely Benign | 0.54 | Ambiguous | 0.45 | Likely Benign | 0.290 | Likely Benign | -1.57 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.21 | Pathogenic | 0.09 | Tolerated | 0.1368 | 0.3176 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1431G>T | M477I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta remains uncertain. Overall, the majority of evidence supports a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -2.662 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.72 | Ambiguous | 0.1 | 0.36 | Likely Benign | 0.54 | Ambiguous | 0.45 | Likely Benign | 0.291 | Likely Benign | -1.57 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.21 | Pathogenic | 0.09 | Tolerated | 0.1368 | 0.3176 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1601C>G | S534C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is uncertain, so both are treated as unavailable. No other high‑accuracy predictions are available. Overall, the evidence is evenly split between benign and pathogenic predictions, leaving the variant’s clinical significance inconclusive. There is no ClinVar status to contradict this balanced prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -8.077 | Likely Pathogenic | 0.247 | Likely Benign | Likely Benign | 0.18 | Likely Benign | 0.1 | 0.90 | Ambiguous | 0.54 | Ambiguous | 0.56 | Ambiguous | 0.308 | Likely Benign | -4.05 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 3.25 | Benign | 0.00 | Affected | 0.0984 | 0.4861 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.1647G>C | L549F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L549F is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include Rosetta, premPS, and SIFT, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, which is consistent with its ClinVar “Uncertain” classification and does not contradict the available data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.007921 | Uncertain | 0.955 | 0.281 | 0.000 | Uncertain | 1 | -11.634 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.3 | 0.27 | Likely Benign | 0.54 | Ambiguous | 0.49 | Likely Benign | 0.514 | Likely Pathogenic | -3.42 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.29 | Pathogenic | 0.14 | Tolerated | 0.0724 | 0.1859 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||
| c.1647G>T | L549F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L549F is not reported in ClinVar and is absent from gnomAD. Benign predictions come from Rosetta, premPS, and SIFT, whereas pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score indicates likely pathogenic, while FoldX and Foldetta are uncertain. High‑accuracy tools specifically: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.007921 | Uncertain | 0.955 | 0.281 | 0.000 | -11.634 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.3 | 0.27 | Likely Benign | 0.54 | Ambiguous | 0.49 | Likely Benign | 0.514 | Likely Pathogenic | -3.42 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.29 | Pathogenic | 0.14 | Tolerated | 0.0724 | 0.1859 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1841A>T | Y614F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y614F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain or unavailable results come from Foldetta, premPS, and Rosetta. 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 unavailable. Overall, the majority of reliable predictors 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 | 0.314870 | Structured | 0.182134 | Uncertain | 0.852 | 0.254 | 0.000 | -5.584 | Likely Benign | 0.630 | Likely Pathogenic | Likely Benign | 0.09 | Likely Benign | 0.2 | 0.98 | Ambiguous | 0.54 | Ambiguous | 0.78 | Ambiguous | 0.364 | Likely Benign | -3.75 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.42 | Benign | 0.07 | Tolerated | 0.1909 | 0.2762 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||
| c.1864A>G | T622A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T622A is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FoldX, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools with uncertain or inconclusive results—AlphaMissense‑Optimized, Rosetta, Foldetta, and premPS—are treated as unavailable for pathogenicity assessment. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for T622A, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.071403 | Uncertain | 0.957 | 0.198 | 0.000 | -10.953 | Likely Pathogenic | 0.827 | Likely Pathogenic | Ambiguous | 0.03 | Likely Benign | 0.0 | 1.04 | Ambiguous | 0.54 | Ambiguous | 0.75 | Ambiguous | 0.893 | Likely Pathogenic | -4.58 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | -1.52 | Pathogenic | 0.01 | Affected | 0.3191 | 0.3091 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1918A>G | T640A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T640A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN, REVEL, FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), and SIFT all score the substitution as benign. No tool predicts pathogenicity; only Rosetta yields an uncertain result. High‑accuracy assessments corroborate this benign trend: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Taken together, the evidence overwhelmingly supports a benign classification for T640A, and this conclusion does not contradict any ClinVar annotation (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.066181 | Structured | 0.137043 | Uncertain | 0.893 | 0.284 | 0.000 | -3.068 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.14 | Likely Benign | 0.1 | 0.93 | Ambiguous | 0.54 | Ambiguous | -0.17 | Likely Benign | 0.078 | Likely Benign | 0.51 | Neutral | 0.009 | Benign | 0.001 | Benign | 3.51 | Benign | 0.42 | Tolerated | 0.3834 | 0.3202 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1928A>T | E643V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E643V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from Rosetta, premPS, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Three tools (FoldX, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show that the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic (3 pathogenic vs. 1 benign). AlphaMissense‑Optimized remains uncertain, and Foldetta also yields an uncertain stability change. Overall, the preponderance of evidence points to a pathogenic effect for E643V, and this conclusion does not contradict any existing ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -12.975 | Likely Pathogenic | 0.893 | Likely Pathogenic | Ambiguous | 1.13 | Ambiguous | 0.1 | -0.06 | Likely Benign | 0.54 | Ambiguous | -0.28 | Likely Benign | 0.554 | Likely Pathogenic | -6.85 | Deleterious | 0.727 | Possibly Damaging | 0.145 | Benign | 2.89 | Benign | 0.00 | Affected | 0.0948 | 0.6637 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2180A>T | N727I 2D  3DClick to see structure in 3D Viewer AISynGAP1 N727I is not reported in ClinVar and is absent from gnomAD. Benign predictions come from REVEL, FoldX, premPS, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Foldetta and Rosetta provide inconclusive results. High‑accuracy tools give a mixed picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts likely pathogenic, and Foldetta is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.538167 | Disordered | 0.442107 | Uncertain | 0.843 | 0.542 | 0.625 | -10.230 | Likely Pathogenic | 0.577 | Likely Pathogenic | Likely Benign | 0.17 | Likely Benign | 0.1 | 0.90 | Ambiguous | 0.54 | Ambiguous | 0.43 | Likely Benign | 0.319 | Likely Benign | -5.93 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.13 | Pathogenic | 0.03 | Affected | 0.0666 | 0.5917 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||
| c.667A>G | T223A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T223A is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33435518‑A‑G). Functional prediction tools that agree on a benign effect include FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL and PROVEAN. Predictions that are inconclusive are Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. 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. | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | Uncertain | 1 | 6-33435518-A-G | 3 | 1.86e-6 | -7.076 | In-Between | 0.316 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.54 | Ambiguous | 0.74 | Ambiguous | 0.574 | Likely Pathogenic | -3.36 | Deleterious | 0.231 | Benign | 0.058 | Benign | 5.74 | Benign | 0.09 | Tolerated | 3.41 | 13 | 0.2982 | 0.3031 | 1 | 0 | 2.5 | -30.03 | 186.4 | 44.0 | 0.0 | 0.0 | 0.0 | 0.0 | X | X | Uncertain | The introduced residue Ala223 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the hydroxyl group of the Thr223 side chain in the WT protein, the methyl side chain of Ala223 cannot form hydrogen bonds with nearby residues Thr228 and Lys207. Without these hydrogen-bonding interactions at the β sheet surface, the secondary structure element becomes unstable and partially unfolds in the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||
| c.757A>C | N253H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N253H is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include FoldX, FATHMM, and premPS, whereas a larger group predicts pathogenicity: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, while AlphaMissense‑Optimized and Foldetta provide inconclusive results and are treated as unavailable. No contradictory evidence is present in ClinVar. Overall, the preponderance of evidence from multiple in‑silico predictors points to a pathogenic effect for the variant, and this conclusion does not conflict with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -12.199 | Likely Pathogenic | 0.899 | Likely Pathogenic | Ambiguous | 0.31 | Likely Benign | 0.1 | 0.76 | Ambiguous | 0.54 | Ambiguous | -0.06 | Likely Benign | 0.832 | Likely Pathogenic | -4.39 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.51 | Benign | 0.01 | Affected | 0.1936 | 0.8033 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.804C>G | I268M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I268M missense variant is catalogued in gnomAD (ID 6‑33437709‑C‑G) but has no ClinVar entry. Functional prediction tools largely disagree: benign predictions come from FoldX and AlphaMissense‑Optimized, whereas the remaining evaluated algorithms (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all indicate pathogenicity. Rosetta and Foldetta provide inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it as likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the preponderance of evidence from the majority of prediction tools points to a pathogenic effect, which is consistent with the lack of a ClinVar classification but does not contradict any existing ClinVar status (none). Thus, the variant is most likely pathogenic, and this prediction does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | 6-33437709-C-G | 1 | 6.20e-7 | -9.721 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | 0.12 | Likely Benign | 0.2 | 0.95 | Ambiguous | 0.54 | Ambiguous | 1.32 | Destabilizing | 0.622 | Likely Pathogenic | -2.58 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.52 | Pathogenic | 0.01 | Affected | 3.38 | 19 | 0.0579 | 0.2145 | 1 | 2 | -2.6 | 18.03 | ||||||||||||||||||||||||
| c.855C>G | C285W 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant C285W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and Rosetta, whereas pathogenic predictions are made by SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy subset confirms this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta remains uncertain. No prediction tool is missing or inconclusive enough to alter the overall assessment. Consequently, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -9.017 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 3.35 | Destabilizing | 1.1 | -2.28 | Stabilizing | 0.54 | Ambiguous | 0.61 | Ambiguous | 0.327 | Likely Benign | -8.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.78 | Pathogenic | 0.11 | Tolerated | 0.1934 | 0.3697 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.958G>C | V320L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320L (gnomAD ID 6‑33437863‑G‑C) is listed in ClinVar as uncertain. Functional prediction tools show a predominance of benign calls: REVEL, FoldX, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come from polyPhen2_HumDiv and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain results. 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; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the balance of evidence favors a benign effect for V320L, which is consistent with its ClinVar designation of uncertain significance rather than a pathogenic classification. Based on the aggregate predictions, V320L is most likely benign, which does not contradict its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | Conflicting | 2 | 6-33437863-G-C | 6 | 3.72e-6 | -6.207 | Likely Benign | 0.362 | Ambiguous | Likely Benign | -0.26 | Likely Benign | 0.2 | 1.33 | Ambiguous | 0.54 | Ambiguous | 0.51 | Ambiguous | 0.096 | Likely Benign | -1.02 | Neutral | 0.900 | Possibly Damaging | 0.373 | Benign | 1.78 | Pathogenic | 0.92 | Tolerated | 3.38 | 23 | 0.0661 | 0.3863 | 2 | 1 | -0.4 | 14.03 | 245.8 | -10.2 | 0.3 | 0.9 | 0.1 | 0.3 | X | Potentially Benign | The isopropyl side chain of Val310, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Thr305-Asn315, res. Ala322-Asp330), hydrophobically packs with the side chains of nearby residues (e.g., Leu286, Val350, Pro318). The hydrophobic Leu320 side chain mostly forms the same interactions; hence, the residue swap does not seem to negatively affect the protein structure based on the variant simulations. | ||||||||||||||
| c.994G>T | D332Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D332Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and premPS, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a likely pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. Overall, the majority of evidence points to a pathogenic impact for D332Y, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -14.210 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 1.15 | Ambiguous | 0.6 | -0.07 | Likely Benign | 0.54 | Ambiguous | 0.41 | Likely Benign | 0.485 | Likely Benign | -7.33 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.20 | Pathogenic | 0.00 | Affected | 0.0372 | 0.4018 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1459A>T | N487Y 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N487Y has no ClinVar entry and is absent from gnomAD. Prediction tools that classify it as benign include Rosetta, premPS, and FATHMM, whereas the majority of algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—label it pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports it as likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for N487Y, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -14.921 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 1.15 | Ambiguous | 0.0 | -0.05 | Likely Benign | 0.55 | Ambiguous | 0.33 | Likely Benign | 0.652 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.69 | Benign | 0.00 | Affected | 0.0587 | 0.2946 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.1836G>C | Q612H 2D AIThe SynGAP1 missense variant Q612H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to Rosetta, which scores the variant as benign. All other evaluated predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM Consensus confirms a likely pathogenic status, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. FoldX and premPS are inconclusive, and Foldetta is unavailable for definitive interpretation. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.203988 | Uncertain | 0.822 | 0.263 | 0.000 | -9.733 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.70 | Ambiguous | 0.9 | 0.39 | Likely Benign | 0.55 | Ambiguous | 0.79 | Ambiguous | 0.550 | Likely Pathogenic | -4.55 | Deleterious | 0.991 | Probably Damaging | 0.986 | Probably Damaging | -1.26 | Pathogenic | 0.02 | Affected | 0.1379 | 0.3084 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.1836G>T | Q612H 2D AIThe SynGAP1 missense variant Q612H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to Rosetta, which scores the variant as benign. All other evaluated predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM Consensus confirms a likely pathogenic status, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. FoldX and premPS are inconclusive, and Foldetta is unavailable for definitive interpretation. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.203988 | Uncertain | 0.822 | 0.263 | 0.000 | -9.733 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.70 | Ambiguous | 0.9 | 0.39 | Likely Benign | 0.55 | Ambiguous | 0.79 | Ambiguous | 0.550 | Likely Pathogenic | -4.55 | Deleterious | 0.991 | Probably Damaging | 0.986 | Probably Damaging | -1.26 | Pathogenic | 0.02 | Affected | 0.1379 | 0.3084 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.1913A>C | K638T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K638T is not reported in ClinVar and is absent from gnomAD. Consensus from standard in silico predictors shows a split: benign calls come from REVEL, Rosetta, premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; FoldX and Foldetta are inconclusive. High‑accuracy assessments give AlphaMissense‑Optimized a benign score, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic effect for K638T. This prediction is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.098064 | Uncertain | 0.937 | 0.260 | 0.000 | -8.856 | Likely Pathogenic | 0.775 | Likely Pathogenic | Likely Benign | 0.87 | Ambiguous | 0.0 | 0.23 | Likely Benign | 0.55 | Ambiguous | 0.07 | Likely Benign | 0.404 | Likely Benign | -5.39 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.52 | Benign | 0.03 | Affected | 0.1632 | 0.2619 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1994A>T | Y665F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y665F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only ESM1b predicts a pathogenic outcome, while Rosetta and Foldetta are uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar claim; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.098513 | Structured | 0.086641 | Uncertain | 0.922 | 0.361 | 0.000 | -8.460 | Likely Pathogenic | 0.100 | Likely Benign | Likely Benign | 0.07 | Likely Benign | 0.1 | 1.03 | Ambiguous | 0.55 | Ambiguous | 0.38 | Likely Benign | 0.106 | Likely Benign | -1.23 | Neutral | 0.159 | Benign | 0.036 | Benign | 3.45 | Benign | 0.47 | Tolerated | 0.2277 | 0.3076 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||
| c.2057G>T | G686V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G686V has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on benign impact are Rosetta and FATHMM, while the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score (Likely Pathogenic) indicate a pathogenic effect. Uncertain results come from FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for G686V, 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 | 0.109221 | Structured | 0.177104 | Uncertain | 0.919 | 0.268 | 0.000 | -13.751 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.89 | Ambiguous | 0.5 | 0.21 | Likely Benign | 0.55 | Ambiguous | 0.74 | Ambiguous | 0.570 | Likely Pathogenic | -8.08 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | 0.1059 | 0.3646 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.2083C>A | L695I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L695I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic outcome. The remaining tools—AlphaMissense‑Default, Foldetta, premPS, and Rosetta—return uncertain results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, whereas Foldetta remains uncertain. Overall, the majority of reliable predictions support a benign classification, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.118441 | Structured | 0.373419 | Uncertain | 0.942 | 0.258 | 0.000 | -12.096 | Likely Pathogenic | 0.395 | Ambiguous | Likely Benign | 0.47 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.55 | Ambiguous | 0.93 | Ambiguous | 0.251 | Likely Benign | -2.00 | Neutral | 0.996 | Probably Damaging | 0.905 | Possibly Damaging | 3.24 | Benign | 0.08 | Tolerated | 0.0815 | 0.2759 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.2137C>T | P713S 2D  AIThe SynGAP1 missense variant P713S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, Rosetta, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are provided by FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight this ambiguity: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus indicates a likely pathogenic effect, and Foldetta likewise yields an uncertain stability change. Overall, the majority of tools lean toward a pathogenic interpretation, and this aligns with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.393235 | Uncertain | 0.961 | 0.371 | 0.000 | -8.496 | Likely Pathogenic | 0.846 | Likely Pathogenic | Ambiguous | 0.91 | Ambiguous | 0.7 | 0.19 | Likely Benign | 0.55 | Ambiguous | 0.62 | Ambiguous | 0.261 | Likely Benign | -6.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | 0.3234 | 0.3674 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.673T>G | S225A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S225A is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, premPS, 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 assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive (uncertain) and therefore does not alter the overall benign assessment. Consequently, the variant is most likely benign based on the available predictions, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.150080 | Structured | 0.344191 | Uncertain | 0.817 | 0.319 | 0.250 | -3.752 | Likely Benign | 0.052 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.3 | 0.79 | Ambiguous | 0.55 | Ambiguous | 0.11 | Likely Benign | 0.201 | Likely Benign | -1.52 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.79 | Benign | 0.58 | Tolerated | 0.4840 | 0.5897 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| 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.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.1436G>A | R479Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R479Q (gnomAD ID 6‑33438468‑G‑A) is listed in ClinVar as benign (ClinVar ID 2875625). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, and the SGM‑Consensus score (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Two tools predict a damaging outcome: polyPhen‑2 HumDiv and HumVar. Stability‑based methods (FoldX, Rosetta, Foldetta) return uncertain results. High‑accuracy predictors specifically give a benign call from AlphaMissense‑Optimized, a likely benign consensus from SGM‑Consensus, and an inconclusive result from Foldetta. Overall, the preponderance of evidence points to a benign effect, which is consistent with the ClinVar classification and does not contradict the database annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | Likely Benign | 1 | 6-33438468-G-A | 7 | 4.34e-6 | -7.109 | In-Between | 0.259 | Likely Benign | Likely Benign | 0.54 | Ambiguous | 0.1 | 0.57 | Ambiguous | 0.56 | Ambiguous | 0.49 | Likely Benign | 0.191 | Likely Benign | -1.16 | Neutral | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.42 | Benign | 0.31 | Tolerated | 3.39 | 32 | 0.2448 | 0.1812 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||
| c.1522G>C | D508H 2D AISynGAP1 D508H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show an even split: benign calls come from REVEL, FoldX, premPS, SIFT, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments give a pathogenic consensus from the SGM method (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), an uncertain outcome from AlphaMissense‑Optimized, and an uncertain outcome from Foldetta (combining FoldX‑MD and Rosetta). Overall, the balance of evidence leans toward pathogenicity, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -12.074 | Likely Pathogenic | 0.849 | Likely Pathogenic | Ambiguous | 0.15 | Likely Benign | 0.4 | 0.97 | Ambiguous | 0.56 | Ambiguous | -0.14 | Likely Benign | 0.336 | Likely Benign | -6.38 | Deleterious | 0.998 | Probably Damaging | 0.919 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 0.1804 | 0.5096 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1579G>T | D527Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D527Y is listed in ClinVar with an uncertain significance (ClinVar ID 1698369.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: the single benign prediction from premPS versus a consensus of pathogenic predictions from the remaining 12 tools (REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Protein‑stability calculations from FoldX and Rosetta are also uncertain. Overall, the preponderance of evidence indicates that D527Y is most likely pathogenic, which does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | Uncertain | 1 | -15.386 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | -0.77 | Ambiguous | 0.2 | 1.89 | Ambiguous | 0.56 | Ambiguous | -0.14 | Likely Benign | 0.905 | Likely Pathogenic | -8.79 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -2.41 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.0554 | 0.4229 | -4 | -3 | 2.2 | 48.09 | 270.9 | -45.7 | 0.1 | 0.1 | -0.1 | 0.0 | X | Potentially Pathogenic | Asp527 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the carboxylate group of the Asp527 side chain forms hydrogen bonds with the backbone atoms of loop residues (e.g., Ile529, Lys530) facing the membrane surface. In the variant simulations, Tyr527 is a bulkier residue that faces away from the loop and stacks with Phe646 in a nearby α-helix (res. Ser614-Ser668). Regardless, no negative structural effects are observed during the variant simulations. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||||||||
| c.1603A>G | S535G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for S535G, and this conclusion does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -4.619 | Likely Benign | 0.143 | Likely Benign | Likely Benign | 0.19 | Likely Benign | 0.0 | 0.93 | Ambiguous | 0.56 | Ambiguous | 0.64 | Ambiguous | 0.247 | Likely Benign | -1.75 | Neutral | 0.606 | Possibly Damaging | 0.114 | Benign | -1.30 | Pathogenic | 0.19 | Tolerated | 0.2858 | 0.4644 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.1667A>C | N556T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N556T is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SIFT, premPS, AlphaMissense‑Optimized, and Rosetta. Tools that predict a pathogenic effect are REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta reporting an uncertain stability change. FoldX‑MD and Foldetta results are inconclusive and are treated as unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.015078 | Structured | 0.008655 | Uncertain | 0.925 | 0.225 | 0.000 | -8.636 | Likely Pathogenic | 0.642 | Likely Pathogenic | Likely Benign | 1.03 | Ambiguous | 0.1 | 0.08 | Likely Benign | 0.56 | Ambiguous | 0.06 | Likely Benign | 0.695 | Likely Pathogenic | -4.73 | Deleterious | 0.996 | Probably Damaging | 0.990 | Probably Damaging | -1.36 | Pathogenic | 0.09 | Tolerated | 0.1189 | 0.3171 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.1769G>T | S590I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include FoldX, premPS, and FATHMM, whereas the majority of tools predict it to be pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give uncertain results: Rosetta and Foldetta. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that S590I is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -17.956 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | -0.04 | Likely Benign | 0.5 | 1.15 | Ambiguous | 0.56 | Ambiguous | 0.31 | Likely Benign | 0.686 | Likely Pathogenic | -5.78 | Deleterious | 0.998 | Probably Damaging | 0.948 | Probably Damaging | 3.05 | Benign | 0.02 | Affected | 0.0975 | 0.5025 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.2115G>C | K705N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K705N is listed in ClinVar (ID 872011.0) as Pathogenic and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, Rosetta, premPS, FATHMM) and pathogenic predictions (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default). Uncertain results come from FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as Likely Pathogenic, and Foldetta also yields an uncertain stability change. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, which aligns with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.379324 | Uncertain | 0.922 | 0.364 | 0.000 | Likely Pathogenic | 1 | -9.767 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.74 | Ambiguous | 0.0 | 0.37 | Likely Benign | 0.56 | Ambiguous | 0.44 | Likely Benign | 0.183 | Likely Benign | -3.12 | Deleterious | 0.996 | Probably Damaging | 0.876 | Possibly Damaging | 3.37 | Benign | 0.02 | Affected | 3.47 | 10 | 0.2480 | 0.1124 | 1 | 0 | 0.4 | -14.07 | 221.4 | -20.2 | 0.0 | 0.0 | 0.0 | 0.1 | X | Uncertain | The amino side chain of Lys705, located at the end and outer surface of an α-helix (res. Thr704-Gly712), does not form any interactions in the WT simulations. In the variant simulations, the carboxamide side chain of Asn705 briefly forms a salt bridge with Glu706. However, there is no apparent difference between the systems. Due to the model ending abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | ||||||||||||||||
| c.2115G>T | K705N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K705N is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Three tools (FoldX, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments further support a pathogenic interpretation: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic”; AlphaMissense‑Optimized remains uncertain, and Foldetta is also uncertain. Overall, the balance of evidence favors a pathogenic effect for K705N, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.379324 | Uncertain | 0.922 | 0.364 | 0.000 | -9.767 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.74 | Ambiguous | 0.0 | 0.37 | Likely Benign | 0.56 | Ambiguous | 0.44 | Likely Benign | 0.183 | Likely Benign | -3.12 | Deleterious | 0.996 | Probably Damaging | 0.876 | Possibly Damaging | 3.37 | Benign | 0.02 | Affected | 3.47 | 10 | 0.2480 | 0.1124 | 1 | 0 | 0.4 | -14.07 | 221.4 | -20.2 | 0.0 | 0.0 | 0.0 | 0.1 | X | Uncertain | The amino side chain of Lys705, located at the end and outer surface of an α-helix (res. Thr704-Gly712), does not form any interactions in the WT simulations. In the variant simulations, the carboxamide side chain of Asn705 briefly forms a salt bridge with Glu706. However, there is no apparent difference between the systems. Due to the model ending abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | ||||||||||||||||||
| c.2185A>C | N729H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from Rosetta (uncertain) and Foldetta (uncertain). High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign, while Foldetta remains uncertain. Overall, the evidence overwhelmingly supports a benign classification, 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 | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | -0.670 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.27 | Likely Benign | 0.0 | 0.84 | Ambiguous | 0.56 | Ambiguous | 0.00 | Likely Benign | 0.080 | Likely Benign | -0.92 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.28 | Benign | 0.17 | Tolerated | 0.1197 | 0.4602 | 2 | 1 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||
| c.605A>G | E202G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E202G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools with uncertain or inconclusive results are Rosetta, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward pathogenic (2 pathogenic, 1 benign, 1 uncertain). Foldetta remains uncertain. Overall, the majority of standard prediction tools suggest a benign effect, and this conclusion does not contradict the lack of ClinVar reporting. Thus, the variant is most likely benign based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -8.310 | Likely Pathogenic | 0.495 | Ambiguous | Likely Benign | 0.37 | Likely Benign | 0.0 | 0.74 | Ambiguous | 0.56 | Ambiguous | 0.27 | Likely Benign | 0.259 | Likely Benign | -4.70 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 4.01 | Benign | 0.07 | Tolerated | 0.3061 | 0.5405 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||
| c.847G>A | E283K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E283K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL and FoldX, whereas the majority of algorithms predict it to be pathogenic: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.358602 | Uncertain | 0.950 | 0.249 | 0.000 | -14.350 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.30 | Likely Benign | 0.1 | 0.82 | Ambiguous | 0.56 | Ambiguous | 0.62 | Ambiguous | 0.443 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.92 | Pathogenic | 0.01 | Affected | 0.2989 | 0.5714 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1099C>A | L367M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L367M variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and FATHMM. The remaining predictions are uncertain: Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also likely benign; Foldetta remains inconclusive. Overall, the majority of evidence supports a benign classification, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.370445 | Structured | 0.441805 | Uncertain | 0.790 | 0.657 | 0.250 | -4.968 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.1 | 0.92 | Ambiguous | 0.57 | Ambiguous | -0.04 | Likely Benign | 0.078 | Likely Benign | 0.12 | Neutral | 0.947 | Possibly Damaging | 0.360 | Benign | 1.63 | Pathogenic | 0.13 | Tolerated | 0.1402 | 0.3947 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1368G>C | Q456H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions lean toward a benign impact, and this does not contradict the lack of ClinVar annotation. Thus, based on the available computational evidence, the variant is most likely benign, though a high‑accuracy consensus suggests a possible pathogenic effect that warrants further investigation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -7.993 | In-Between | 0.598 | Likely Pathogenic | Likely Benign | 0.74 | Ambiguous | 0.1 | 0.39 | Likely Benign | 0.57 | Ambiguous | 0.32 | Likely Benign | 0.214 | Likely Benign | -4.07 | Deleterious | 0.996 | Probably Damaging | 0.974 | Probably Damaging | 3.37 | Benign | 0.19 | Tolerated | 0.0987 | 0.2358 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1368G>T | Q456H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions lean toward a benign impact, and this does not contradict the lack of ClinVar annotation. Thus, based on the available computational evidence, the variant is most likely benign, though a high‑accuracy consensus suggests a possible pathogenic effect that warrants further investigation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -7.993 | In-Between | 0.598 | Likely Pathogenic | Likely Benign | 0.74 | Ambiguous | 0.1 | 0.39 | Likely Benign | 0.57 | Ambiguous | 0.32 | Likely Benign | 0.214 | Likely Benign | -4.07 | Deleterious | 0.996 | Probably Damaging | 0.974 | Probably Damaging | 3.37 | Benign | 0.19 | Tolerated | 0.0987 | 0.2358 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1433A>G | E478G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E478G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. Uncertain predictions come from Rosetta, ESM1b, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to equal benign and pathogenic signals and two uncertain calls; Foldetta likewise yields an uncertain result. Overall, the majority of evaluated tools (seven benign vs. two pathogenic) support a benign classification. This consensus does not contradict any ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -7.897 | In-Between | 0.418 | Ambiguous | Likely Benign | 0.40 | Likely Benign | 0.0 | 0.73 | Ambiguous | 0.57 | Ambiguous | 0.02 | Likely Benign | 0.306 | Likely Benign | -4.91 | Deleterious | 0.923 | Possibly Damaging | 0.427 | Benign | 3.41 | Benign | 0.15 | Tolerated | 0.2758 | 0.5572 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||
| c.1503T>G | I501M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Predictions that are inconclusive or unavailable are FoldX, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Taken together, the majority of evidence points to a benign impact for I501M. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -7.452 | In-Between | 0.259 | Likely Benign | Likely Benign | 1.32 | Ambiguous | 0.2 | -0.19 | Likely Benign | 0.57 | Ambiguous | 0.95 | Ambiguous | 0.294 | Likely Benign | -2.32 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.36 | Benign | 0.01 | Affected | 0.0680 | 0.1589 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.1520A>C | K507T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K507T missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT, Rosetta, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifying it as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain result. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the absence of a ClinVar classification. **The variant is most likely pathogenic based on the current predictive evidence.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -10.244 | Likely Pathogenic | 0.468 | Ambiguous | Likely Benign | 0.82 | Ambiguous | 0.1 | 0.31 | Likely Benign | 0.57 | Ambiguous | 0.78 | Ambiguous | 0.724 | Likely Pathogenic | -2.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.55 | Pathogenic | 0.12 | Tolerated | 0.1501 | 0.2451 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1556A>G | E519G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519G missense variant is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, and premPS. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments: AlphaMissense‑Optimized is uncertain; SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; Foldetta is uncertain. Overall, the majority of available predictions (7 pathogenic vs. 4 benign) lean toward a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -10.835 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.22 | Likely Benign | 0.1 | 0.92 | Ambiguous | 0.57 | Ambiguous | 0.22 | Likely Benign | 0.458 | Likely Benign | -6.12 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.21 | Benign | 0.01 | Affected | 0.2729 | 0.3471 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1696A>C | K566Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K566Q has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT and Rosetta, whereas a majority of tools predict a pathogenic impact: REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, premPS, PROVEAN, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Because the preponderance of evidence points to a deleterious effect, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.047887 | Uncertain | 0.924 | 0.219 | 0.000 | -11.475 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 1.48 | Ambiguous | 0.1 | -0.35 | Likely Benign | 0.57 | Ambiguous | 1.25 | Destabilizing | 0.762 | Likely Pathogenic | -3.52 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.42 | Pathogenic | 0.07 | Tolerated | 0.3824 | 0.1282 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1993T>C | Y665H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y665H is not reported in ClinVar (ClinVar status: not reported) but is present in gnomAD (gnomAD ID: 6‑33441252‑T‑C). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools with uncertain or inconclusive results are FoldX, Foldetta, and AlphaMissense‑Default. High‑accuracy methods give a benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta remains uncertain. Overall, the majority of predictions (7 benign vs. 4 pathogenic) and the high‑accuracy consensus support a benign classification. This conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.098513 | Structured | 0.086641 | Uncertain | 0.922 | 0.361 | 0.000 | 6-33441252-T-C | 2 | 1.24e-6 | -9.303 | Likely Pathogenic | 0.389 | Ambiguous | Likely Benign | 0.85 | Ambiguous | 0.0 | 0.28 | Likely Benign | 0.57 | Ambiguous | 1.12 | Destabilizing | 0.129 | Likely Benign | -2.00 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.45 | Benign | 0.48 | Tolerated | 3.38 | 28 | 0.2122 | 0.0513 | 2 | 0 | -1.9 | -26.03 | |||||||||||||||||||||||||
| c.2012A>T | D671V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D671V missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods give a pathogenic signal: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the majority of predictions (seven pathogenic vs. three benign) support a pathogenic classification. There is no ClinVar entry to contradict this assessment, so the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -12.376 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.63 | Ambiguous | 0.1 | 0.51 | Ambiguous | 0.57 | Ambiguous | 0.14 | Likely Benign | 0.379 | Likely Benign | -6.08 | Deleterious | 0.975 | Probably Damaging | 0.885 | Possibly Damaging | 3.31 | Benign | 0.01 | Affected | 0.0820 | 0.6651 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.2027G>C | S676T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive results are from FoldX (Uncertain) and Foldetta (Uncertain). High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta remains Uncertain. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -5.621 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.79 | Ambiguous | 0.1 | 0.34 | Likely Benign | 0.57 | Ambiguous | -0.36 | Likely Benign | 0.098 | Likely Benign | 0.91 | Neutral | 0.050 | Benign | 0.017 | Benign | 3.52 | Benign | 1.00 | Tolerated | 0.1575 | 0.6286 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.635C>G | S212C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include FoldX, premPS, and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are inconclusive are Rosetta and Foldetta. The high‑accuracy consensus methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -11.656 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.16 | Likely Benign | 0.1 | 0.98 | Ambiguous | 0.57 | Ambiguous | 0.47 | Likely Benign | 0.840 | Likely Pathogenic | -4.29 | Deleterious | 0.999 | Probably Damaging | 0.990 | Probably Damaging | 5.73 | Benign | 0.00 | Affected | 0.0785 | 0.6270 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.743G>T | R248L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta and FATHMM, whereas the majority of algorithms predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions labeled uncertain are FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the consensus of the available evidence points to a pathogenic effect for R248L, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | -12.110 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 1.13 | Ambiguous | 0.5 | 0.01 | Likely Benign | 0.57 | Ambiguous | 0.67 | Ambiguous | 0.825 | Likely Pathogenic | -6.06 | Deleterious | 0.979 | Probably Damaging | 0.680 | Possibly Damaging | 5.66 | Benign | 0.03 | Affected | 0.1616 | 0.4741 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.795G>C | K265N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and Rosetta, whereas the majority of algorithms predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -8.759 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 0.16 | Likely Benign | 0.57 | Ambiguous | 0.85 | Ambiguous | 0.350 | Likely Benign | -3.26 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.86 | Pathogenic | 0.03 | Affected | 0.3691 | 0.1158 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.795G>T | K265N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and Rosetta, while the majority of algorithms predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain or inconclusive results are reported only for FoldX, Foldetta, and premPS, and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -8.759 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 0.16 | Likely Benign | 0.57 | Ambiguous | 0.85 | Ambiguous | 0.351 | Likely Benign | -3.26 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.86 | Pathogenic | 0.03 | Affected | 0.3691 | 0.1158 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.811G>A | A271T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining evidence—premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—consistently predict pathogenicity. FoldX, Rosetta, and Foldetta are inconclusive, and AlphaMissense‑Optimized also yields an uncertain result. High‑accuracy assessments show that the SGM‑Consensus (majority vote) predicts pathogenicity, while AlphaMissense‑Optimized and Foldetta remain unavailable. Taken together, the overwhelming majority of reliable predictors classify the variant as pathogenic, and this conclusion does not conflict with the ClinVar status, which currently has no entry for A271T. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.413873 | Uncertain | 0.939 | 0.220 | 0.125 | -9.564 | Likely Pathogenic | 0.934 | Likely Pathogenic | Ambiguous | 0.59 | Ambiguous | 0.1 | 0.54 | Ambiguous | 0.57 | Ambiguous | 1.00 | Destabilizing | 0.498 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 0.66 | Pathogenic | 0.01 | Affected | 0.1076 | 0.4691 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.929A>T | E310V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E310V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are Rosetta and premPS, while the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. FoldX and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that E310V is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | -15.494 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.08 | Ambiguous | 0.9 | 0.06 | Likely Benign | 0.57 | Ambiguous | 0.14 | Likely Benign | 0.871 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.12 | Pathogenic | 0.00 | Affected | 0.0849 | 0.8729 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.961C>T | R321C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33437866‑C‑T). Prediction tools that agree on a benign effect include REVEL, premPS, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Five tools (SGM‑Consensus, FoldX, Rosetta, AlphaMissense‑Default, and Foldetta) report uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (six out of eleven) support a pathogenic impact, while three support benign and five are inconclusive. Thus, the variant is most likely pathogenic based on current computational evidence, and this does not contradict its ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | Conflicting | 2 | 6-33437866-C-T | 9 | 5.58e-6 | -10.025 | Likely Pathogenic | 0.387 | Ambiguous | Likely Benign | 0.57 | Ambiguous | 0.1 | 0.56 | Ambiguous | 0.57 | Ambiguous | 0.18 | Likely Benign | 0.495 | Likely Benign | -4.59 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.89 | Pathogenic | 0.01 | Affected | 3.38 | 23 | 0.3313 | 0.2516 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||
| c.1007A>T | K336M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K336M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, premPS) and pathogenic predictions (SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized). The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Pathogenic.” Stability‑based assessments are inconclusive: Foldetta is uncertain, and Rosetta is also uncertain. High‑accuracy tools specifically indicate pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms pathogenic, while Foldetta remains uncertain. Based on the overall pattern of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.318242 | Structured | 0.338219 | Uncertain | 0.396 | 0.428 | 0.500 | -15.395 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.34 | Likely Benign | 0.1 | 0.82 | Ambiguous | 0.58 | Ambiguous | -0.23 | Likely Benign | 0.301 | Likely Benign | -5.07 | Deleterious | 0.989 | Probably Damaging | 0.832 | Possibly Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.1185 | 0.4760 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1014C>A | D338E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D338E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates a likely benign classification, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support from high‑accuracy methods, the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -5.264 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.85 | Ambiguous | 0.3 | 0.31 | Likely Benign | 0.58 | Ambiguous | -0.01 | Likely Benign | 0.080 | Likely Benign | -1.95 | Neutral | 0.002 | Benign | 0.005 | Benign | 1.85 | Pathogenic | 0.55 | Tolerated | 0.1584 | 0.5397 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1014C>G | D338E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D338E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates a likely benign classification, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support from high‑accuracy methods, the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -5.264 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.85 | Ambiguous | 0.3 | 0.31 | Likely Benign | 0.58 | Ambiguous | -0.01 | Likely Benign | 0.080 | Likely Benign | -1.95 | Neutral | 0.002 | Benign | 0.005 | Benign | 1.85 | Pathogenic | 0.55 | Tolerated | 0.1584 | 0.5397 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1036G>C | V346L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346L is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and SIFT, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta) give uncertain or inconclusive results and are not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of reliable predictors and the SGM‑Consensus support a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | -8.178 | Likely Pathogenic | 0.834 | Likely Pathogenic | Ambiguous | 0.05 | Likely Benign | 0.2 | 1.10 | Ambiguous | 0.58 | Ambiguous | 0.60 | Ambiguous | 0.384 | Likely Benign | -2.68 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.58 | Pathogenic | 0.09 | Tolerated | 0.1237 | 0.5348 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1036G>T | V346L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and SIFT, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a deleterious effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | -8.178 | Likely Pathogenic | 0.834 | Likely Pathogenic | Ambiguous | 0.05 | Likely Benign | 0.2 | 1.10 | Ambiguous | 0.58 | Ambiguous | 0.60 | Ambiguous | 0.386 | Likely Benign | -2.68 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.58 | Pathogenic | 0.09 | Tolerated | 0.1237 | 0.5348 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1121C>T | S374F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S374F missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv and SIFT. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates a likely benign outcome, while Foldetta’s stability analysis remains uncertain. Overall, the majority of evidence points to a benign effect, 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 | 0.642678 | Disordered | 0.428948 | Uncertain | 0.333 | 0.812 | 0.625 | -7.907 | In-Between | 0.268 | Likely Benign | Likely Benign | 0.55 | Ambiguous | 0.8 | 0.60 | Ambiguous | 0.58 | Ambiguous | -0.19 | Likely Benign | 0.202 | Likely Benign | -1.19 | Neutral | 0.875 | Possibly Damaging | 0.271 | Benign | 6.29 | Benign | 0.00 | Affected | 0.1045 | 0.6427 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.1253A>T | K418I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K418I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM. In contrast, the majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for K418I, 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 | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -14.895 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.51 | Ambiguous | 0.0 | 0.64 | Ambiguous | 0.58 | Ambiguous | 0.27 | Likely Benign | 0.428 | Likely Benign | -7.27 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.32 | Benign | 0.01 | Affected | 0.1297 | 0.2432 | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||
| c.1514A>T | Y505F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (five benign versus four pathogenic) lean toward a benign interpretation, and this is consistent with the lack of ClinVar evidence; thus the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -8.855 | Likely Pathogenic | 0.437 | Ambiguous | Likely Benign | 0.40 | Likely Benign | 0.0 | 0.76 | Ambiguous | 0.58 | Ambiguous | 0.69 | Ambiguous | 0.434 | Likely Benign | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.93 | Benign | 0.07 | Tolerated | 0.2409 | 0.2598 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||
| c.1720C>G | L574V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L574V is 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, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No other high‑confidence pathogenic predictions are present. Based on the preponderance of benign predictions and the lack of any ClinVar pathogenic annotation, the variant is most likely benign. This conclusion does not contradict any existing ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.083462 | Structured | 0.026427 | Uncertain | 0.927 | 0.246 | 0.000 | -5.559 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.78 | Ambiguous | 0.1 | 0.37 | Likely Benign | 0.58 | Ambiguous | 0.25 | Likely Benign | 0.149 | Likely Benign | -0.40 | Neutral | 0.004 | Benign | 0.003 | Benign | -1.27 | Pathogenic | 0.29 | Tolerated | 0.1481 | 0.2978 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1747G>C | D583H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D583H is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta and premPS, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome. FoldX and Foldetta provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.038478 | Uncertain | 0.805 | 0.247 | 0.000 | -9.191 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 1.22 | Ambiguous | 0.2 | -0.07 | Likely Benign | 0.58 | Ambiguous | -0.22 | Likely Benign | 0.713 | Likely Pathogenic | -6.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.43 | Pathogenic | 0.03 | Affected | 0.1217 | 0.4182 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1839G>C | E613D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E613D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, and SIFT, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Three tools—FoldX, Foldetta, and AlphaMissense‑Optimized—return uncertain or inconclusive results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic impact for E613D. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.193489 | Uncertain | 0.816 | 0.254 | 0.000 | -8.795 | Likely Pathogenic | 0.842 | Likely Pathogenic | Ambiguous | 0.67 | Ambiguous | 0.3 | 0.48 | Likely Benign | 0.58 | Ambiguous | 0.13 | Likely Benign | 0.474 | Likely Benign | -2.79 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | -1.27 | Pathogenic | 0.15 | Tolerated | 0.1998 | 0.4000 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1839G>T | E613D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E613D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, and SIFT, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Three tools—FoldX, Foldetta, and AlphaMissense‑Optimized—return uncertain or inconclusive results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic impact for E613D. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.193489 | Uncertain | 0.816 | 0.254 | 0.000 | -8.795 | Likely Pathogenic | 0.842 | Likely Pathogenic | Ambiguous | 0.67 | Ambiguous | 0.3 | 0.48 | Likely Benign | 0.58 | Ambiguous | 0.13 | Likely Benign | 0.474 | Likely Benign | -2.79 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | -1.27 | Pathogenic | 0.15 | Tolerated | 0.1998 | 0.4000 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1883A>C | K628T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K628T is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely converge on a deleterious effect: the majority—including REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—label the change as pathogenic or likely pathogenic. Only Rosetta predicts a benign outcome, while FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic, and Foldetta remains uncertain. Taken together, the preponderance of evidence indicates that K628T is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.035486 | Uncertain | 0.957 | 0.229 | 0.000 | -14.675 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.08 | Ambiguous | 0.1 | 0.07 | Likely Benign | 0.58 | Ambiguous | 0.61 | Ambiguous | 0.661 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.36 | Pathogenic | 0.00 | Affected | 0.1622 | 0.3541 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.2023A>G | N675D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N675D is not 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments give AlphaMissense‑Optimized a benign call, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) a pathogenic call, and Foldetta an uncertain result. With an equal split of general predictions but a pathogenic majority in the high‑accuracy consensus, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.129801 | Structured | 0.111024 | Uncertain | 0.513 | 0.333 | 0.000 | -12.829 | Likely Pathogenic | 0.497 | Ambiguous | Likely Benign | 1.41 | Ambiguous | 0.4 | -0.26 | Likely Benign | 0.58 | Ambiguous | 1.05 | Destabilizing | 0.246 | Likely Benign | -3.87 | Deleterious | 0.997 | Probably Damaging | 0.865 | Possibly Damaging | 3.53 | Benign | 0.17 | Tolerated | 0.1914 | 0.4901 | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.2047A>T | I683F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, while AlphaMissense‑Optimized and Foldetta are inconclusive and thus treated as unavailable evidence. Overall, the balance of evidence favors a pathogenic classification for I683F, and this assessment does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -12.781 | Likely Pathogenic | 0.828 | Likely Pathogenic | Ambiguous | 1.38 | Ambiguous | 0.1 | -0.23 | Likely Benign | 0.58 | Ambiguous | 0.59 | Ambiguous | 0.481 | Likely Benign | -3.99 | Deleterious | 0.971 | Probably Damaging | 0.499 | Possibly Damaging | 3.27 | Benign | 0.01 | Affected | 0.0770 | 0.2307 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.2093A>T | E698V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E698V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results are FoldX, Foldetta, and AlphaMissense‑Optimized. 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 a likely pathogenic outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports an uncertain result. Overall, the majority of evidence points to a pathogenic impact for E698V, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.120615 | Structured | 0.417514 | Uncertain | 0.922 | 0.315 | 0.000 | -12.797 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 0.76 | Ambiguous | 0.0 | 0.39 | Likely Benign | 0.58 | Ambiguous | 0.26 | Likely Benign | 0.480 | Likely Benign | -6.51 | Deleterious | 0.992 | Probably Damaging | 0.967 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 0.0577 | 0.4546 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2163C>G | I721M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant I721M is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, and PROVEAN, whereas pathogenic predictions are made by SGM‑Consensus, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Tools with inconclusive results are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of reliable predictors indicate a pathogenic effect, which aligns with the ClinVar designation of uncertain significance rather than contradicting it. Therefore, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | Uncertain | 1 | -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.650A>T | E217V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E217V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include Rosetta, FATHMM, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E217V. This conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | -10.194 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.76 | Ambiguous | 0.6 | 0.39 | Likely Benign | 0.58 | Ambiguous | 0.23 | Likely Benign | 0.723 | Likely Pathogenic | -4.84 | Deleterious | 0.900 | Possibly Damaging | 0.461 | Possibly Damaging | 5.79 | Benign | 0.03 | Affected | 0.0919 | 0.8340 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.898T>G | S300A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. Rosetta and Foldetta give uncertain results and are therefore not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign (3 benign vs. 1 pathogenic). Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -5.420 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.08 | Likely Benign | 0.3 | 1.07 | Ambiguous | 0.58 | Ambiguous | 0.08 | Likely Benign | 0.031 | Likely Benign | -1.18 | Neutral | 0.139 | Benign | 0.060 | Benign | 1.56 | Pathogenic | 0.20 | Tolerated | 0.5135 | 0.4949 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.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.1181A>G | K394R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K394R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. Only SIFT predicts a pathogenic outcome, while Rosetta and Foldetta are uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta remains uncertain. Overall, the preponderance of evidence supports a benign classification for K394R, and this conclusion does not contradict the absence of a ClinVar report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | -4.902 | Likely Benign | 0.097 | Likely Benign | Likely Benign | -0.01 | Likely Benign | 0.1 | 1.19 | Ambiguous | 0.59 | Ambiguous | 0.42 | Likely Benign | 0.335 | Likely Benign | -1.97 | Neutral | 0.141 | Benign | 0.091 | Benign | 5.11 | Benign | 0.03 | Affected | 0.5488 | 0.2075 | Weaken | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||
| c.1536A>C | E512D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E512D is not reported in ClinVar or gnomAD. Across a broad panel of in silico predictors, the majority indicate a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only the ESM1b model assigns a pathogenic label, while Rosetta and Foldetta provide uncertain results. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta remains inconclusive. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -8.354 | Likely Pathogenic | 0.198 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.3 | 1.05 | Ambiguous | 0.59 | Ambiguous | 0.00 | Likely Benign | 0.259 | Likely Benign | -2.10 | Neutral | 0.016 | Benign | 0.012 | Benign | 3.34 | Benign | 0.23 | Tolerated | 0.2055 | 0.3089 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1536A>T | E512D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change E512D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Across the broad panel of in‑silico predictors, the majority (REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all classify the variant as benign, whereas only ESM1b predicts it as pathogenic. The high‑accuracy tools give a consistent benign signal: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Overall, the evidence strongly supports a benign effect; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -8.354 | Likely Pathogenic | 0.198 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.3 | 1.05 | Ambiguous | 0.59 | Ambiguous | 0.00 | Likely Benign | 0.259 | Likely Benign | -2.10 | Neutral | 0.016 | Benign | 0.012 | Benign | 3.34 | Benign | 0.23 | Tolerated | 0.2055 | 0.3089 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1588A>C | K530Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (13/16) predict pathogenicity, whereas only three predict benign. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | -10.593 | Likely Pathogenic | 0.574 | Likely Pathogenic | Likely Benign | 0.31 | Likely Benign | 0.0 | 0.87 | Ambiguous | 0.59 | Ambiguous | 0.13 | Likely Benign | 0.524 | Likely Pathogenic | -3.18 | Deleterious | 0.698 | Possibly Damaging | 0.694 | Possibly Damaging | -1.61 | Pathogenic | 0.01 | Affected | 0.3001 | 0.0941 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1792C>A | L598I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L598I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and ESM1b. The remaining tools (FoldX, 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 reliable predictions indicate a benign impact. This conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.007259 | Structured | 0.147872 | Uncertain | 0.953 | 0.154 | 0.000 | -9.396 | Likely Pathogenic | 0.512 | Ambiguous | Likely Benign | 0.80 | Ambiguous | 0.0 | 0.38 | Likely Benign | 0.59 | Ambiguous | 0.78 | Ambiguous | 0.246 | Likely Benign | -1.96 | Neutral | 0.988 | Probably Damaging | 0.910 | Probably Damaging | 3.47 | Benign | 0.10 | Tolerated | 0.0792 | 0.2000 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.2125C>G | L709V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709V is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool that produced a definitive call classifies the variant as benign: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. The only inconclusive results are FoldX (uncertain) and Foldetta (uncertain), which are treated as unavailable evidence. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also benign; Foldetta remains uncertain. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.243554 | Structured | 0.365830 | Uncertain | 0.934 | 0.379 | 0.000 | -4.406 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.75 | Ambiguous | 0.0 | 0.42 | Likely Benign | 0.59 | Ambiguous | 0.03 | Likely Benign | 0.063 | Likely Benign | -0.36 | Neutral | 0.062 | Benign | 0.016 | Benign | 3.42 | Benign | 0.45 | Tolerated | 0.1162 | 0.2460 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.961C>G | R321G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, AlphaMissense‑Default, AlphaMissense‑Optimized, and premPS. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, while the high‑accuracy subset is mixed, with one benign, one pathogenic, and one uncertain result. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | -10.554 | Likely Pathogenic | 0.293 | Likely Benign | Likely Benign | 0.90 | Ambiguous | 0.1 | 0.28 | Likely Benign | 0.59 | Ambiguous | 0.49 | Likely Benign | 0.430 | Likely Benign | -3.70 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.92 | Pathogenic | 0.04 | Affected | 0.3224 | 0.2898 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1067G>C | R356P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 R356P missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FoldX, whereas a majority of tools (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive are AlphaMissense‑Optimized, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R356P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.219301 | Structured | 0.395028 | Uncertain | 0.802 | 0.373 | 0.250 | -12.956 | Likely Pathogenic | 0.919 | Likely Pathogenic | Ambiguous | 0.48 | Likely Benign | 0.1 | 0.72 | Ambiguous | 0.60 | Ambiguous | 1.05 | Destabilizing | 0.451 | Likely Benign | -6.23 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 1.72 | Pathogenic | 0.02 | Affected | 0.2213 | 0.5033 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1083G>C | Q361H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q361H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—FoldX, Rosetta, ESM1b, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also unavailable. Overall, the majority of conventional predictors lean toward pathogenicity, while the single high‑accuracy tool suggests benign. No ClinVar annotation exists to contradict these findings. Thus, based on the collective evidence, the variant is most likely pathogenic, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.305330 | Structured | 0.427593 | Uncertain | 0.945 | 0.534 | 0.250 | -7.269 | In-Between | 0.410 | Ambiguous | Likely Benign | 0.68 | Ambiguous | 0.1 | 0.52 | Ambiguous | 0.60 | Ambiguous | 0.32 | Likely Benign | 0.281 | Likely Benign | -2.73 | Deleterious | 0.996 | Probably Damaging | 0.986 | Probably Damaging | 1.79 | Pathogenic | 0.04 | Affected | 0.1352 | 0.4151 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1083G>T | Q361H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q361H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—FoldX, Rosetta, ESM1b, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also unavailable. Overall, the majority of conventional predictors (five pathogenic vs. three benign) lean toward a pathogenic interpretation, while the single high‑accuracy tool suggests benign. No ClinVar entry exists, so there is no contradiction with clinical database status. Based on the collective evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.305330 | Structured | 0.427593 | Uncertain | 0.945 | 0.534 | 0.250 | -7.269 | In-Between | 0.410 | Ambiguous | Likely Benign | 0.68 | Ambiguous | 0.1 | 0.52 | Ambiguous | 0.60 | Ambiguous | 0.32 | Likely Benign | 0.281 | Likely Benign | -2.73 | Deleterious | 0.996 | Probably Damaging | 0.986 | Probably Damaging | 1.79 | Pathogenic | 0.04 | Affected | 0.1352 | 0.4151 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1120T>A | S374T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S374T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on benign impact include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain but does not indicate destabilization. Overall, the evidence strongly favors a benign effect for S374T, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.642678 | Disordered | 0.428948 | Uncertain | 0.333 | 0.812 | 0.625 | -5.415 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.1 | 0.80 | Ambiguous | 0.60 | Ambiguous | -0.02 | Likely Benign | 0.176 | Likely Benign | -0.47 | Neutral | 0.118 | Benign | 0.049 | Benign | 5.32 | Benign | 0.12 | Tolerated | 0.2212 | 0.6466 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1175A>T | K392M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K392M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, ESM1b, and FATHMM, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The remaining tools—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—return uncertain or inconclusive results. High‑accuracy methods give no definitive signal: 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 (six pathogenic vs. three benign) lean toward a pathogenic impact. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.541878 | Disordered | 0.405672 | Uncertain | 0.319 | 0.702 | 0.750 | -3.856 | Likely Benign | 0.788 | Likely Pathogenic | Ambiguous | 0.52 | Ambiguous | 0.1 | 0.67 | Ambiguous | 0.60 | Ambiguous | -0.09 | Likely Benign | 0.665 | Likely Pathogenic | -3.24 | Deleterious | 0.952 | Possibly Damaging | 0.496 | Possibly Damaging | 4.59 | Benign | 0.00 | Affected | 0.1799 | 0.4941 | 0 | -1 | 5.8 | 3.02 | ||||||||||||||||||||||||||||||
| c.1221G>C | Q407H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q407H (C2 domain) has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict pathogenicity: premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is uncertain. No evidence from FoldX, Rosetta, or Foldetta supports a benign outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | -10.526 | Likely Pathogenic | 0.830 | Likely Pathogenic | Ambiguous | 0.59 | Ambiguous | 0.0 | 0.61 | Ambiguous | 0.60 | Ambiguous | 1.10 | Destabilizing | 0.206 | Likely Benign | -4.51 | Deleterious | 0.982 | Probably Damaging | 0.947 | Probably Damaging | 3.88 | Benign | 0.01 | Affected | 3.38 | 28 | 0.1205 | 0.3154 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||
| c.1221G>T | Q407H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q407H is listed in ClinVar with an uncertain significance (ClinVar ID 2772184.0) 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 premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions marked as uncertain include FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for Q407H. This conclusion does not conflict with the ClinVar designation of uncertain significance, which remains unresolved pending further evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | Uncertain | 1 | -10.526 | Likely Pathogenic | 0.830 | Likely Pathogenic | Ambiguous | 0.59 | Ambiguous | 0.0 | 0.61 | Ambiguous | 0.60 | Ambiguous | 1.10 | Destabilizing | 0.206 | Likely Benign | -4.51 | Deleterious | 0.982 | Probably Damaging | 0.947 | Probably Damaging | 3.88 | Benign | 0.01 | Affected | 3.38 | 28 | 0.1205 | 0.3154 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||
| c.1903A>G | N635D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N635D is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, and FATHMM. Those that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Predictions that are inconclusive are Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy methods give an uncertain result for AlphaMissense‑Optimized, a Likely Pathogenic verdict from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain outcome from Foldetta. Overall, the majority of computational evidence points to a pathogenic effect, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -14.453 | Likely Pathogenic | 0.799 | Likely Pathogenic | Ambiguous | 0.47 | Likely Benign | 0.1 | 0.73 | Ambiguous | 0.60 | Ambiguous | 1.26 | Destabilizing | 0.432 | Likely Benign | -4.71 | Deleterious | 0.955 | Possibly Damaging | 0.628 | Possibly Damaging | 2.92 | Benign | 0.01 | Affected | 0.1725 | 0.1937 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1928A>C | E643A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643A is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of tools lean toward a benign interpretation, and this assessment does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -12.562 | Likely Pathogenic | 0.733 | Likely Pathogenic | Likely Benign | 0.80 | Ambiguous | 0.2 | 0.39 | Likely Benign | 0.60 | Ambiguous | 0.21 | Likely Benign | 0.469 | Likely Benign | -5.81 | Deleterious | 0.771 | Possibly Damaging | 0.233 | Benign | 2.92 | Benign | 0.01 | Affected | 0.4074 | 0.6096 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.2104C>G | Q702E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q702E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Rosetta and Foldetta give uncertain results. High‑accuracy methods further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign; Foldetta remains inconclusive. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.074921 | Structured | 0.397258 | Uncertain | 0.907 | 0.345 | 0.000 | -10.974 | Likely Pathogenic | 0.230 | Likely Benign | Likely Benign | 0.48 | Likely Benign | 0.0 | 0.72 | Ambiguous | 0.60 | Ambiguous | 0.27 | Likely Benign | 0.196 | Likely Benign | -2.27 | Neutral | 0.989 | Probably Damaging | 0.930 | Probably Damaging | 3.55 | Benign | 0.15 | Tolerated | 0.1021 | 0.1609 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.2137C>G | P713A 2D  3DClick to see structure in 3D Viewer AISynGAP1 P713A is not reported in ClinVar and is absent from gnomAD. Benign predictions are provided by REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; the SGM‑Consensus score is labeled Likely Pathogenic. FoldX, Foldetta, and premPS give uncertain results. High‑accuracy tools: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; Foldetta remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.393235 | Uncertain | 0.961 | 0.371 | 0.000 | -8.535 | Likely Pathogenic | 0.689 | Likely Pathogenic | Likely Benign | 1.04 | Ambiguous | 0.1 | 0.15 | Likely Benign | 0.60 | Ambiguous | 0.75 | Ambiguous | 0.235 | Likely Benign | -6.80 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.34 | Benign | 0.00 | Affected | 0.3159 | 0.3475 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.613A>T | I205F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I205F missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, and polyPhen‑2 HumVar all classify it as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. Uncertain results from Foldetta, premPS, ESM1b, and Rosetta are treated as unavailable. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, while Foldetta remains uncertain. Overall, the consensus of the majority of tools indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -7.913 | In-Between | 0.271 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.3 | 0.89 | Ambiguous | 0.60 | Ambiguous | 0.52 | Ambiguous | 0.113 | Likely Benign | -1.80 | Neutral | 0.838 | Possibly Damaging | 0.368 | Benign | 4.08 | Benign | 0.10 | Tolerated | 0.0461 | 0.2205 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.815G>T | R272L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R272L missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and premPS. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the majority of evaluated tools predict a pathogenic impact. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.071867 | Structured | 0.425620 | Uncertain | 0.925 | 0.215 | 0.125 | -10.796 | Likely Pathogenic | 0.796 | Likely Pathogenic | Ambiguous | 1.66 | Ambiguous | 0.3 | -0.46 | Likely Benign | 0.60 | Ambiguous | 0.41 | Likely Benign | 0.470 | Likely Benign | -4.57 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.75 | Pathogenic | 0.01 | Affected | 0.1691 | 0.4230 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.971G>A | R324Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R324Q is listed in ClinVar with an uncertain significance (ClinVar ID 2572558.0) and is present in gnomAD (ID 6‑33437876‑G‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. Protein‑stability predictions from FoldX, Rosetta, and the combined Foldetta method are all uncertain. Overall, the consensus of available computational evidence points to a benign effect for R324Q, which is consistent with its ClinVar status of uncertain significance rather than a pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.257454 | Structured | 0.426893 | Uncertain | 0.954 | 0.397 | 0.000 | Uncertain | 3 | 6-33437876-G-A | 3 | 1.86e-6 | -5.001 | Likely Benign | 0.173 | Likely Benign | Likely Benign | 0.56 | Ambiguous | 0.1 | 0.63 | Ambiguous | 0.60 | Ambiguous | 1.02 | Destabilizing | 0.307 | Likely Benign | -1.17 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.92 | Pathogenic | 0.41 | Tolerated | 3.39 | 22 | 0.3804 | 0.3214 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||
| c.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.1154C>G | S385W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S385W is listed in ClinVar as Benign (ClinVar ID 218691.0) and is present in gnomAD (ID 6‑33438059‑C‑G). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, 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 ESM1b. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM Consensus as Benign, and Foldetta as Uncertain. Taken together, the majority of evidence points to a benign impact, which aligns with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.733139 | Disordered | 0.425480 | Uncertain | 0.341 | 0.925 | 0.750 | Benign | 1 | 6-33438059-C-G | -9.353 | Likely Pathogenic | 0.362 | Ambiguous | Likely Benign | 0.53 | Ambiguous | 0.2 | 0.69 | Ambiguous | 0.61 | Ambiguous | 0.00 | Likely Benign | 0.373 | Likely Benign | -0.84 | Neutral | 0.986 | Probably Damaging | 0.968 | Probably Damaging | 4.63 | Benign | 0.00 | Affected | 4.32 | 3 | 0.1272 | 0.6670 | -2 | -3 | -0.1 | 99.14 | 260.4 | -71.2 | 0.5 | 1.3 | 0.7 | 0.4 | Uncertain | Ser385 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like tryptophan are rarely tolerated. Although no major negative structural effects are observed in the variant simulations, Trp385 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effects on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||
| c.1226T>A | M409K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409K has no ClinVar record and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, SIFT, and FATHMM, while pathogenic calls arise from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is inconclusive; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also inconclusive. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -13.618 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 0.93 | Ambiguous | 0.3 | 0.29 | Likely Benign | 0.61 | Ambiguous | 1.45 | Destabilizing | 0.490 | Likely Benign | -4.26 | Deleterious | 0.769 | Possibly Damaging | 0.750 | Possibly Damaging | 4.18 | Benign | 0.40 | Tolerated | 0.1318 | 0.0656 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.1277A>C | N426T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change N426T lies in the GAP domain. It is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Predictions that are uncertain or inconclusive are FoldX, Foldetta, and ESM1b. 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 and is not taken as evidence. Overall, the majority of tools, including the high‑accuracy methods, predict a benign effect. This consensus 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. | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -7.389 | In-Between | 0.194 | Likely Benign | Likely Benign | 0.84 | Ambiguous | 0.0 | 0.38 | Likely Benign | 0.61 | Ambiguous | 0.12 | Likely Benign | 0.126 | Likely Benign | -3.14 | Deleterious | 0.983 | Probably Damaging | 0.926 | Probably Damaging | 3.47 | Benign | 0.10 | Tolerated | 0.1090 | 0.3002 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||
| c.1289T>A | M430K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430K is not 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, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and ESM1b. The remaining tools—FoldX, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized classifies the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors a pathogenic outcome; Foldetta remains uncertain. Overall, the majority of individual predictors lean toward a benign interpretation, whereas the SGM Consensus suggests pathogenicity. Given the lack of ClinVar evidence, there is no contradiction with existing clinical annotations. Based on the aggregate predictions, the variant is most likely benign, and this assessment does not conflict with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -10.816 | Likely Pathogenic | 0.494 | Ambiguous | Likely Benign | 0.78 | Ambiguous | 0.1 | 0.44 | Likely Benign | 0.61 | Ambiguous | 0.86 | Ambiguous | 0.149 | Likely Benign | -2.66 | Deleterious | 0.134 | Benign | 0.033 | Benign | 3.47 | Benign | 0.32 | Tolerated | 0.1660 | 0.1271 | 0 | -1 | -5.8 | -3.02 | ||||||||||||||||||||||||||||||
| c.1388A>T | D463V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D463V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain predictions come from Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points toward a pathogenic impact for D463V, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -12.374 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 0.23 | Likely Benign | 0.1 | 0.98 | Ambiguous | 0.61 | Ambiguous | 0.33 | Likely Benign | 0.521 | Likely Pathogenic | -7.95 | Deleterious | 0.973 | Probably Damaging | 0.658 | Possibly Damaging | 3.31 | Benign | 0.09 | Tolerated | 0.0713 | 0.5526 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1477G>A | A493T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A493T missense variant is not reported in ClinVar and is absent from gnomAD. Consensus among most in silico predictors indicates a deleterious effect: REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, premPS, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as pathogenic or likely pathogenic. Only Rosetta predicts a benign outcome; FoldX, Foldetta, and AlphaMissense‑Optimized are uncertain or unavailable. High‑accuracy tools give the following: AlphaMissense‑Optimized – uncertain; SGM Consensus – likely pathogenic; Foldetta – uncertain. Taken together, the preponderance of evidence supports a pathogenic effect for A493T. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -10.366 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.82 | Ambiguous | 0.0 | 0.39 | Likely Benign | 0.61 | Ambiguous | 1.10 | Destabilizing | 0.727 | Likely Pathogenic | -3.41 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.36 | Pathogenic | 0.04 | Affected | 0.0964 | 0.3972 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1808T>G | M603R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M603R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FoldX, which scores the variant as benign. All other evaluated predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No other tools provide conflicting evidence. Based on the preponderance of pathogenic predictions and the absence of benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -14.968 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.08 | Likely Benign | 0.0 | 1.13 | Ambiguous | 0.61 | Ambiguous | 0.65 | Ambiguous | 0.935 | Likely Pathogenic | -5.64 | Deleterious | 0.963 | Probably Damaging | 0.943 | Probably Damaging | -1.35 | Pathogenic | 0.00 | Affected | 0.1516 | 0.0837 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||
| c.1835A>G | Q612R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q612R is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are SIFT and FoldX. Tools that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while AlphaMissense‑Optimized and Foldetta are uncertain. No high‑accuracy tool provides a benign prediction. Overall, the majority of available evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.203988 | Uncertain | 0.822 | 0.263 | 0.000 | -10.571 | Likely Pathogenic | 0.837 | Likely Pathogenic | Ambiguous | -0.35 | Likely Benign | 0.2 | 1.56 | Ambiguous | 0.61 | Ambiguous | 0.78 | Ambiguous | 0.683 | Likely Pathogenic | -3.85 | Deleterious | 0.956 | Probably Damaging | 0.969 | Probably Damaging | -1.29 | Pathogenic | 0.10 | Tolerated | 0.1480 | 0.2196 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1849G>C | E617Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E617Q missense variant is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Foldetta and Rosetta give uncertain results, which are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (derived from a majority of high‑confidence predictors) indicates a likely pathogenic outcome. Foldetta’s stability prediction is inconclusive. Overall, the balance of evidence leans toward a pathogenic impact for E617Q, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | -8.650 | Likely Pathogenic | 0.747 | Likely Pathogenic | Likely Benign | 0.20 | Likely Benign | 0.2 | 1.01 | Ambiguous | 0.61 | Ambiguous | 0.21 | Likely Benign | 0.481 | Likely Benign | -2.39 | Neutral | 0.996 | Probably Damaging | 0.986 | Probably Damaging | -1.39 | Pathogenic | 0.29 | Tolerated | 0.1050 | 0.5951 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1855A>G | T619A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T619A missense variant is not reported in ClinVar and has no gnomAD entry. Consensus prediction tools cluster into two groups: benign predictions come from SIFT, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized classifying the change as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it as likely pathogenic; Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.219301 | Structured | 0.119723 | Uncertain | 0.929 | 0.237 | 0.000 | -6.341 | Likely Benign | 0.672 | Likely Pathogenic | Likely Benign | 0.59 | Ambiguous | 0.1 | 0.62 | Ambiguous | 0.61 | Ambiguous | 0.53 | Ambiguous | 0.613 | Likely Pathogenic | -4.21 | Deleterious | 0.996 | Probably Damaging | 0.989 | Probably Damaging | -1.27 | Pathogenic | 0.17 | Tolerated | 0.3915 | 0.3109 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.712G>C | E238Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two consensus groups: benign predictions come from SIFT and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Stability‑based methods (FoldX, Rosetta, premPS) and Foldetta give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -11.476 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.63 | Ambiguous | 0.5 | 0.59 | Ambiguous | 0.61 | Ambiguous | 0.52 | Ambiguous | 0.723 | Likely Pathogenic | -2.72 | Deleterious | 0.996 | Probably Damaging | 0.891 | Possibly Damaging | 5.44 | Benign | 0.06 | Tolerated | 0.1372 | 0.5412 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.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.862G>T | D288Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288Y missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, and premPS; pathogenic predictions from SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from the available tools suggests a benign effect. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -15.269 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.11 | Likely Benign | 0.2 | 1.10 | Ambiguous | 0.61 | Ambiguous | 0.10 | Likely Benign | 0.472 | Likely Benign | -7.11 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.64 | Pathogenic | 0.00 | Affected | 0.0635 | 0.5009 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.956C>T | A319V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A319V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is also inconclusive. Overall, the majority of evidence points to a benign effect, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | -8.179 | Likely Pathogenic | 0.141 | Likely Benign | Likely Benign | 0.58 | Ambiguous | 0.4 | 0.63 | Ambiguous | 0.61 | Ambiguous | 0.23 | Likely Benign | 0.329 | Likely Benign | -2.32 | Neutral | 0.989 | Probably Damaging | 0.824 | Possibly Damaging | 1.88 | Pathogenic | 0.10 | Tolerated | 0.1094 | 0.6390 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.994G>C | D332H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D332H has no ClinVar entry and is absent from gnomAD. Functional prediction tools that agree on a benign effect are Rosetta and premPS, whereas the majority of predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify the change as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Taken together, the preponderance of evidence indicates that D332H is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -13.255 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 1.50 | Ambiguous | 0.4 | -0.28 | Likely Benign | 0.61 | Ambiguous | 0.22 | Likely Benign | 0.505 | Likely Pathogenic | -5.63 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.23 | Pathogenic | 0.01 | Affected | 0.1005 | 0.4542 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1075A>T | T359S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T359S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only FATHMM predicts a pathogenic outcome, while FoldX, Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also favors benign. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is uncertain. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.281712 | Structured | 0.414952 | Uncertain | 0.939 | 0.480 | 0.250 | -4.624 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.0 | 0.73 | Ambiguous | 0.62 | Ambiguous | 0.66 | Ambiguous | 0.100 | Likely Benign | -1.87 | Neutral | 0.146 | Benign | 0.024 | Benign | 1.76 | Pathogenic | 0.27 | Tolerated | 0.3637 | 0.4996 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1401C>A | D467E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D467E is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (gnomAD ID: 6‑33438433‑C‑A). Prediction tools that agree on a benign effect include only FoldX. Tools that agree on a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). Uncertain or inconclusive predictions come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of reliable predictors indicate a pathogenic effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | 6-33438433-C-A | 2 | 1.24e-6 | -9.774 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.36 | Likely Benign | 0.1 | 0.87 | Ambiguous | 0.62 | Ambiguous | 0.60 | Ambiguous | 0.576 | Likely Pathogenic | -3.63 | Deleterious | 0.887 | Possibly Damaging | 0.938 | Probably Damaging | -1.08 | Pathogenic | 0.04 | Affected | 3.37 | 31 | 0.1061 | 0.4564 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||
| c.1401C>G | D467E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D467E missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive predictions come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -9.774 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.36 | Likely Benign | 0.1 | 0.87 | Ambiguous | 0.62 | Ambiguous | 0.60 | Ambiguous | 0.576 | Likely Pathogenic | -3.63 | Deleterious | 0.887 | Possibly Damaging | 0.938 | Probably Damaging | -1.08 | Pathogenic | 0.04 | Affected | 3.37 | 31 | 0.1061 | 0.4564 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||
| c.1567A>G | N523D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 N523D missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the predictions are mixed, but the majority of high‑confidence tools lean toward pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -8.955 | Likely Pathogenic | 0.641 | Likely Pathogenic | Likely Benign | 0.14 | Likely Benign | 0.2 | 1.10 | Ambiguous | 0.62 | Ambiguous | 0.56 | Ambiguous | 0.272 | Likely Benign | -3.57 | Deleterious | 0.112 | Benign | 0.079 | Benign | -1.25 | Pathogenic | 0.22 | Tolerated | 0.1553 | 0.1866 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1633A>G | M545V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545V is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include SIFT and Rosetta, while a majority of tools predict a pathogenic outcome: PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus. Tools with inconclusive results (FoldX, Foldetta, premPS, ESM1b) are considered unavailable for interpretation. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for M545V. This conclusion is not contradicted by ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | -7.481 | In-Between | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.91 | Ambiguous | 0.1 | 0.33 | Likely Benign | 0.62 | Ambiguous | 0.94 | Ambiguous | 0.688 | Likely Pathogenic | -3.54 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.26 | Pathogenic | 0.34 | Tolerated | 0.2454 | 0.2953 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||
| c.1921T>A | S641T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S641T 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 score the variant as benign. Rosetta also predicts a benign outcome, while FoldX and Foldetta are inconclusive (marked “Uncertain”). 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 benign; Foldetta remains uncertain. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.125101 | Structured | 0.157322 | Uncertain | 0.786 | 0.270 | 0.000 | -6.637 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.83 | Ambiguous | 0.3 | 0.41 | Likely Benign | 0.62 | Ambiguous | 0.13 | Likely Benign | 0.043 | Likely Benign | -1.50 | Neutral | 0.008 | Benign | 0.003 | Benign | 3.39 | Benign | 0.09 | Tolerated | 0.1505 | 0.5888 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1968A>C | E656D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E656D has no ClinVar entry and is not reported in gnomAD. Prediction tools show mixed results: benign predictions come from REVEL, FoldX, premPS, polyPhen‑2 HumVar, SIFT, and FATHMM, while pathogenic predictions arise from 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 further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus confirms Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Uncertain. No evidence from Foldetta or Rosetta is available to refute pathogenicity. Overall, the majority of high‑confidence tools predict a pathogenic impact, and this is consistent with the absence of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.032017 | Structured | 0.242242 | Uncertain | 0.963 | 0.264 | 0.000 | -11.992 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.22 | Likely Benign | 0.1 | 1.02 | Ambiguous | 0.62 | Ambiguous | 0.39 | Likely Benign | 0.275 | Likely Benign | -2.72 | Deleterious | 0.985 | Probably Damaging | 0.426 | Benign | 3.41 | Benign | 0.06 | Tolerated | 0.2052 | 0.4120 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1968A>T | E656D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E656D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign calls (REVEL, FoldX, premPS, polyPhen‑2 HumVar, SIFT, FATHMM) and pathogenic calls (PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized). The SGM‑Consensus score is “Likely Pathogenic,” while Foldetta and Rosetta outputs are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta remains inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.032017 | Structured | 0.242242 | Uncertain | 0.963 | 0.264 | 0.000 | -11.992 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.22 | Likely Benign | 0.1 | 1.02 | Ambiguous | 0.62 | Ambiguous | 0.39 | Likely Benign | 0.273 | Likely Benign | -2.72 | Deleterious | 0.985 | Probably Damaging | 0.426 | Benign | 3.41 | Benign | 0.06 | Tolerated | 0.2052 | 0.4120 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.2026A>T | S676C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen2_HumVar, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen2_HumDiv, SIFT, and ESM1b. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -9.230 | Likely Pathogenic | 0.132 | Likely Benign | Likely Benign | 0.47 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.62 | Ambiguous | 0.15 | Likely Benign | 0.164 | Likely Benign | -2.45 | Neutral | 0.959 | Probably Damaging | 0.431 | Benign | 3.35 | Benign | 0.01 | Affected | 0.1113 | 0.6352 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.673T>A | S225T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S225T 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 is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign; Foldetta, which integrates FoldX‑MD and Rosetta stability 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 | PH | 0.150080 | Structured | 0.344191 | Uncertain | 0.817 | 0.319 | 0.250 | -6.351 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.64 | Ambiguous | 0.4 | 0.59 | Ambiguous | 0.62 | Ambiguous | 0.03 | Likely Benign | 0.244 | Likely Benign | -1.98 | Neutral | 0.118 | Benign | 0.049 | Benign | 5.73 | Benign | 0.55 | Tolerated | 0.1419 | 0.7395 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1178G>C | G393A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G393A is 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 predictions indicate a benign effect, and there is no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.538167 | Disordered | 0.402365 | Uncertain | 0.333 | 0.670 | 0.625 | -4.507 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 1.93 | Ambiguous | 0.5 | -0.68 | Ambiguous | 0.63 | Ambiguous | 0.22 | Likely Benign | 0.381 | Likely Benign | -1.89 | Neutral | 0.176 | Benign | 0.039 | Benign | 1.33 | Pathogenic | 0.08 | Tolerated | 0.4143 | 0.5193 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1246C>A | L416I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L416I missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, and FATHMM. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Predictions that remain inconclusive are FoldX, Rosetta, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign prediction. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the preponderance of evidence points to a benign effect. This conclusion is not contradicted by any ClinVar annotation, as the variant has no existing ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.104810 | Structured | 0.336105 | Uncertain | 0.935 | 0.227 | 0.000 | -8.613 | Likely Pathogenic | 0.396 | Ambiguous | Likely Benign | 0.57 | Ambiguous | 0.0 | 0.69 | Ambiguous | 0.63 | Ambiguous | 0.50 | Likely Benign | 0.127 | Likely Benign | -1.28 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 3.38 | Benign | 0.37 | Tolerated | 0.1073 | 0.3480 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1288A>G | M430V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or tolerated changes. Only polyPhen‑2 HumDiv flags it as pathogenic, while the SGM‑Consensus score is Likely Benign. Stability‑based methods are inconclusive: FoldX and premPS return Uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports Uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta remains Uncertain. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -3.555 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 1.48 | Ambiguous | 0.1 | -0.23 | Likely Benign | 0.63 | Ambiguous | 0.87 | Ambiguous | 0.103 | Likely Benign | -1.35 | Neutral | 0.918 | Possibly Damaging | 0.185 | Benign | 3.53 | Benign | 0.51 | Tolerated | 0.3397 | 0.4953 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||
| c.1303T>A | L435M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L435M missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -4.705 | Likely Benign | 0.534 | Ambiguous | Likely Benign | 0.24 | Likely Benign | 0.0 | 1.02 | Ambiguous | 0.63 | Ambiguous | 1.05 | Destabilizing | 0.233 | Likely Benign | -1.74 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.17 | Benign | 0.01 | Affected | 0.0675 | 0.2753 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1308G>C | E436D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E436D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions are limited to FATHMM, while the remaining nine tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are treated as unavailable. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic (3 pathogenic vs. 1 benign). Foldetta’s stability prediction is uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -10.355 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.55 | Ambiguous | 0.1 | 0.71 | Ambiguous | 0.63 | Ambiguous | 0.73 | Ambiguous | 0.554 | Likely Pathogenic | -2.85 | Deleterious | 0.986 | Probably Damaging | 0.921 | Probably Damaging | 4.61 | Benign | 0.01 | Affected | 0.1938 | 0.3553 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1308G>T | E436D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E436D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions are limited to FATHMM, while the remaining nine tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are treated as unavailable. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic (3 pathogenic vs. 1 benign). Foldetta’s stability prediction is uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -10.355 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.55 | Ambiguous | 0.1 | 0.71 | Ambiguous | 0.63 | Ambiguous | 0.73 | Ambiguous | 0.554 | Likely Pathogenic | -2.85 | Deleterious | 0.986 | Probably Damaging | 0.921 | Probably Damaging | 4.61 | Benign | 0.01 | Affected | 0.1938 | 0.3553 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1430T>G | M477R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, and FATHMM. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta remains uncertain and is not taken as evidence. Overall, the majority of reliable predictors indicate a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -6.786 | Likely Benign | 0.552 | Ambiguous | Likely Benign | 0.48 | Likely Benign | 0.2 | 0.77 | Ambiguous | 0.63 | Ambiguous | 1.24 | Destabilizing | 0.442 | Likely Benign | -1.12 | Neutral | 0.720 | Possibly Damaging | 0.242 | Benign | -1.22 | Pathogenic | 0.11 | Tolerated | 0.1901 | 0.0828 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||
| c.1453C>T | R485C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485C (gnomAD ID 6‑33438485‑C‑T) is listed in ClinVar with an uncertain significance. Functional prediction tools largely disagree: benign calls come from Rosetta and premPS, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus is labeled likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. With the majority of evidence pointing to pathogenicity and no contradictory data from ClinVar, the variant is most likely pathogenic, although ClinVar has not yet reached a definitive classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | Uncertain | 2 | 6-33438485-C-T | 9 | 5.58e-6 | -14.294 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 0.26 | Likely Benign | 0.63 | Ambiguous | 0.44 | Likely Benign | 0.597 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.90 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.3350 | 0.2762 | -4 | -3 | 7.0 | -53.05 | 225.5 | 99.6 | -0.1 | 0.0 | -0.3 | 0.2 | X | Uncertain | The guanidinium group of Arg485 is located in a short helical structure (res. Glu480-Leu482) within an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. The side chain of Arg485 acts as the “arginine finger” of SynGAP, playing a crucial role in Ras-GTPase activation. Consequently, the residue swap inhibits the conversion of GTP to GDP at the enzyme’s active site. Although no negative effects on the protein structure are observed during the simulations, no definite conclusions can be drawn due to the critical role of Arg485 in GTPase activation. | |||||||||||||
| c.1462A>T | T488S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T488S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, and Rosetta) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of standard tools lean toward a benign interpretation, but the high‑accuracy consensus is split, leaving the variant’s impact ambiguous. No ClinVar annotation contradicts these predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -7.662 | In-Between | 0.745 | Likely Pathogenic | Likely Benign | 0.35 | Likely Benign | 0.1 | 0.90 | Ambiguous | 0.63 | Ambiguous | 0.77 | Ambiguous | 0.257 | Likely Benign | -3.51 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.73 | Benign | 0.31 | Tolerated | 0.2256 | 0.2813 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||
| c.1542C>G | I514M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514M is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, while the SGM‑Consensus (majority of the four high‑accuracy inputs) remains Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is Uncertain. Overall, seven of the twelve evaluated tools predict pathogenicity versus four predicting benign, with no evidence from ClinVar to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -9.753 | Likely Pathogenic | 0.727 | Likely Pathogenic | Likely Benign | 0.48 | Likely Benign | 0.2 | 0.78 | Ambiguous | 0.63 | Ambiguous | 1.13 | Destabilizing | 0.335 | Likely Benign | -2.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.88 | Benign | 0.00 | Affected | 0.0647 | 0.1816 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.1659G>C | K553N 2D 3DClick to see structure in 3D Viewer AISynGAP1 K553N is not reported in ClinVar and is present in gnomAD (6-33438902-G-C). Functional prediction tools largely agree on a deleterious effect: SIFT is the sole benign predictor, whereas REVEL, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. FoldX, Rosetta, and Foldetta return uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta remains uncertain. Overall, the consensus of the majority of tools indicates that K553N is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.012270 | Structured | 0.006539 | Uncertain | 0.949 | 0.246 | 0.000 | 6-33438902-G-C | 1 | 6.20e-7 | -13.664 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.63 | Ambiguous | 0.0 | 0.62 | Ambiguous | 0.63 | Ambiguous | 1.11 | Destabilizing | 0.566 | Likely Pathogenic | -4.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.24 | Pathogenic | 0.11 | Tolerated | 3.37 | 35 | 0.2758 | 0.0926 | 0 | 1 | 0.4 | -14.07 | ||||||||||||||||||||||||
| c.1659G>T | K553N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K553N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the majority of algorithms (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, Rosetta, and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.012270 | Structured | 0.006539 | Uncertain | 0.949 | 0.246 | 0.000 | -13.664 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.63 | Ambiguous | 0.0 | 0.62 | Ambiguous | 0.63 | Ambiguous | 1.11 | Destabilizing | 0.566 | Likely Pathogenic | -4.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.24 | Pathogenic | 0.11 | Tolerated | 3.37 | 35 | 0.2758 | 0.0926 | 0 | 1 | 0.4 | -14.07 | |||||||||||||||||||||||||||
| c.1850A>C | E617A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617A is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome; Rosetta and Foldetta are uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized indicates benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic interpretation. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | -8.704 | Likely Pathogenic | 0.769 | Likely Pathogenic | Likely Benign | 0.37 | Likely Benign | 0.1 | 0.89 | Ambiguous | 0.63 | Ambiguous | 0.18 | Likely Benign | 0.627 | Likely Pathogenic | -4.75 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.37 | Pathogenic | 0.46 | Tolerated | 0.3033 | 0.5317 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1951G>A | E651K 2D AIThe SynGAP1 E651K missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign calls (REVEL, FoldX, premPS, polyPhen‑2 HumVar, SIFT, FATHMM) and pathogenic calls (PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default). Three tools (Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is uncertain; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.365409 | Uncertain | 0.955 | 0.340 | 0.000 | -8.714 | Likely Pathogenic | 0.818 | Likely Pathogenic | Ambiguous | 0.11 | Likely Benign | 0.4 | 1.15 | Ambiguous | 0.63 | Ambiguous | 0.08 | Likely Benign | 0.211 | Likely Benign | -2.92 | Deleterious | 0.921 | Possibly Damaging | 0.303 | Benign | 3.39 | Benign | 0.17 | Tolerated | 0.2768 | 0.5803 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1998G>C | E666D 2D 3DClick to see structure in 3D Viewer AISynGAP1 E666D is listed in ClinVar with an uncertain significance (ID 587483.0) and is not reported in gnomAD. Functional prediction tools show a mixed signal: benign calls come from REVEL, SIFT, FATHMM, AlphaMissense‑Optimized, and Rosetta; pathogenic calls come from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as likely pathogenic. High‑accuracy assessments give AlphaMissense‑Optimized a benign prediction, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the balance of evidence slightly favors a pathogenic interpretation, but the predictions are not unequivocal. Thus, the variant is most likely pathogenic according to the current computational data, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.086870 | Uncertain | 0.925 | 0.387 | 0.000 | Uncertain | 1 | -8.820 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | 0.88 | Ambiguous | 0.0 | 0.37 | Likely Benign | 0.63 | Ambiguous | 1.05 | Destabilizing | 0.197 | Likely Benign | -2.69 | Deleterious | 0.992 | Probably Damaging | 0.603 | Possibly Damaging | 3.43 | Benign | 0.06 | Tolerated | 3.38 | 28 | 0.1926 | 0.3092 | 3 | 2 | 0.0 | -14.03 | 237.2 | 16.5 | 0.0 | 0.0 | -0.3 | 0.1 | X | Potentially Pathogenic | The carboxylate group of Glu666, located on the α-helix (res. Ser641-Glu666), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), such as Lys566, Thr672, and Asn669, in the WT simulations. In the variant simulations, the shorter side chain of Asp666 cannot maintain these interactions as efficiently as Glu666 in the WT, resulting in a less coordinated hydrogen-bond network. | ||||||||||||||||
| c.1998G>T | E666D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E666D missense variant is not reported in ClinVar (ClinVar ID: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, Rosetta, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX alone is also uncertain, so these results are treated as unavailable. Overall, the balance of evidence leans toward a pathogenic impact for E666D, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.086870 | Uncertain | 0.925 | 0.387 | 0.000 | -8.820 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | 0.88 | Ambiguous | 0.0 | 0.37 | Likely Benign | 0.63 | Ambiguous | 1.05 | Destabilizing | 0.197 | Likely Benign | -2.69 | Deleterious | 0.992 | Probably Damaging | 0.603 | Possibly Damaging | 3.43 | Benign | 0.06 | Tolerated | 3.38 | 28 | 0.1926 | 0.3092 | 3 | 2 | 0.0 | -14.03 | 237.2 | 16.5 | 0.0 | 0.0 | -0.3 | 0.1 | X | Potentially Pathogenic | The carboxylate group of Glu666, located on the α-helix (res. Ser641-Glu666), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), such as Lys566, Thr672, and Asn669, in the WT simulations. In the variant simulations, the shorter side chain of Asp666 cannot maintain these interactions as efficiently as Glu666 in the WT, resulting in a less coordinated hydrogen-bond network. | ||||||||||||||||||
| c.637A>G | I213V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213V missense variant is not reported in ClinVar (no ClinVar ID) 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‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts a pathogenic outcome. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta’s stability analysis is uncertain. Overall, the evidence strongly favors a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -6.133 | Likely Benign | 0.364 | Ambiguous | Likely Benign | 0.67 | Ambiguous | 0.2 | 0.58 | Ambiguous | 0.63 | Ambiguous | 0.47 | Likely Benign | 0.413 | Likely Benign | -0.69 | Neutral | 0.128 | Benign | 0.048 | Benign | 5.82 | Benign | 0.10 | Tolerated | 0.1008 | 0.2959 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.682A>G | T228A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T228A variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and the SGM‑Consensus score (which is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are REVEL, SIFT, and AlphaMissense‑Default. Predictions that are inconclusive or uncertain are Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as benign (majority of its constituent predictors are benign), and Foldetta as uncertain. Overall, the balance of evidence favors a benign interpretation; this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -5.190 | Likely Benign | 0.793 | Likely Pathogenic | Ambiguous | 0.44 | Likely Benign | 0.0 | 0.82 | Ambiguous | 0.63 | Ambiguous | 0.58 | Ambiguous | 0.520 | Likely Pathogenic | -2.30 | Neutral | 0.363 | Benign | 0.138 | Benign | 5.63 | Benign | 0.04 | Affected | 0.4072 | 0.5014 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.955G>A | A319T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict a pathogenic effect are polyPhen2_HumDiv and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of reliable predictors classify the variant as benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | -7.841 | In-Between | 0.098 | Likely Benign | Likely Benign | 0.55 | Ambiguous | 0.3 | 0.70 | Ambiguous | 0.63 | Ambiguous | 0.30 | Likely Benign | 0.116 | Likely Benign | -1.35 | Neutral | 0.775 | Possibly Damaging | 0.306 | Benign | 1.92 | Pathogenic | 0.09 | Tolerated | 0.1274 | 0.6083 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.998A>T | K333I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K333I missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX and premPS, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta and Foldetta give uncertain results. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.311707 | Structured | 0.330781 | Uncertain | 0.537 | 0.447 | 0.500 | -14.517 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.30 | Likely Benign | 0.0 | 0.95 | Ambiguous | 0.63 | Ambiguous | 0.43 | Likely Benign | 0.544 | Likely Pathogenic | -6.49 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.89 | Pathogenic | 0.03 | Affected | 0.0931 | 0.3521 | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||
| c.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.1447A>G | I483V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions are reported by premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions marked as uncertain include FoldX, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, whereas Foldetta remains uncertain. Overall, the balance of evidence from both general and high‑accuracy tools leans toward a benign effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | Conflicting | 2 | -10.121 | Likely Pathogenic | 0.523 | Ambiguous | Likely Benign | 1.00 | Ambiguous | 0.0 | 0.27 | Likely Benign | 0.64 | Ambiguous | 1.02 | Destabilizing | 0.228 | Likely Benign | -0.86 | Neutral | 0.914 | Possibly Damaging | 0.921 | Probably Damaging | 3.23 | Benign | 0.03 | Affected | 3.37 | 32 | 0.0876 | 0.2691 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||||
| c.1474A>C | K492Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K492Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and FATHMM, whereas pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM Consensus confirms a likely pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from ClinVar contradicts these findings. Therefore, the variant is most likely pathogenic based on the collective predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.685 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.34 | Likely Benign | 0.0 | 0.93 | Ambiguous | 0.64 | Ambiguous | 1.13 | Destabilizing | 0.463 | Likely Benign | -3.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.02 | Affected | 0.3534 | 0.0830 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1484A>C | E495A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E495A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include FoldX, while the remaining evaluated algorithms (REVEL, SIFT, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and the SGM‑Consensus) all predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. No contradictory evidence is present from ClinVar or population databases. Overall, the preponderance of predictions supports a pathogenic classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -9.229 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.42 | Likely Benign | 0.1 | 0.85 | Ambiguous | 0.64 | Ambiguous | 0.69 | Ambiguous | 0.834 | Likely Pathogenic | -5.84 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.38 | Pathogenic | 0.01 | Affected | 0.2711 | 0.4259 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1610C>G | A537G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict pathogenic. Uncertain results come from Rosetta, Foldetta, and premPS. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized reports benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Benign, and Foldetta’s stability prediction is inconclusive. Overall, the majority of evidence supports a benign impact for A537G, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | -4.302 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.40 | Likely Benign | 0.0 | 0.88 | Ambiguous | 0.64 | Ambiguous | 0.68 | Ambiguous | 0.290 | Likely Benign | -1.85 | Neutral | 0.977 | Probably Damaging | 0.672 | Possibly Damaging | -1.30 | Pathogenic | 0.36 | Tolerated | 0.2289 | 0.3387 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1691A>T | E564V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E564V has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on benign effect include premPS and SIFT, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E564V, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023534 | Structured | 0.038418 | Uncertain | 0.891 | 0.208 | 0.000 | -15.163 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.53 | Ambiguous | 0.0 | 0.75 | Ambiguous | 0.64 | Ambiguous | 0.23 | Likely Benign | 0.812 | Likely Pathogenic | -6.90 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | -1.37 | Pathogenic | 0.11 | Tolerated | 0.0571 | 0.5503 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2117A>C | E706A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E706A has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only polyPhen2_HumDiv suggests pathogenicity, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy methods reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of ClinVar classification or gnomAD observation. Thus, the variant is most likely benign, and this is consistent with the lack of ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.200174 | Structured | 0.377033 | Uncertain | 0.929 | 0.363 | 0.000 | -4.604 | Likely Benign | 0.443 | Ambiguous | Likely Benign | 0.80 | Ambiguous | 0.0 | 0.48 | Likely Benign | 0.64 | Ambiguous | -0.12 | Likely Benign | 0.117 | Likely Benign | -0.81 | Neutral | 0.613 | Possibly Damaging | 0.180 | Benign | 4.20 | Benign | 0.65 | Tolerated | 0.3413 | 0.4089 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.650A>C | E217A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E217A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, polyPhen‑2 HumVar, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, and ESM1b) returned uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; Foldetta’s stability prediction is uncertain. Overall, the majority of available predictions support a pathogenic impact for E217A. 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. | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | -7.294 | In-Between | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.67 | Ambiguous | 0.5 | 0.61 | Ambiguous | 0.64 | Ambiguous | 0.50 | Likely Benign | 0.619 | Likely Pathogenic | -3.88 | Deleterious | 0.900 | Possibly Damaging | 0.307 | Benign | 5.81 | Benign | 0.12 | Tolerated | 0.4442 | 0.8090 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||
| c.727A>G | I243V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243V is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. FoldX and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -8.237 | Likely Pathogenic | 0.314 | Likely Benign | Likely Benign | 1.09 | Ambiguous | 0.1 | 0.19 | Likely Benign | 0.64 | Ambiguous | 0.39 | Likely Benign | 0.445 | Likely Benign | -0.39 | Neutral | 0.617 | Possibly Damaging | 0.140 | Benign | 5.71 | Benign | 0.15 | Tolerated | 0.1019 | 0.2591 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.932A>G | H311R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, SIFT, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and premPS. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized indicates benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -9.825 | Likely Pathogenic | 0.719 | Likely Pathogenic | Likely Benign | 0.43 | Likely Benign | 0.1 | 0.85 | Ambiguous | 0.64 | Ambiguous | 0.70 | Ambiguous | 0.532 | Likely Pathogenic | -5.72 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.94 | Pathogenic | 0.14 | Tolerated | 0.1931 | 0.2490 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||
| c.1131G>A | M377I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377I (ClinVar ID 3803473.0, status = Uncertain) is present in gnomAD (ID = 6‑33438036‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the computational evidence strongly favors a benign classification, which does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.675549 | Disordered | 0.431183 | Uncertain | 0.324 | 0.884 | 0.625 | Uncertain | 1 | 6-33438036-G-A | 1 | 6.23e-7 | -2.895 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.76 | Ambiguous | 0.3 | 0.54 | Ambiguous | 0.65 | Ambiguous | 0.24 | Likely Benign | 0.227 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.46 | Benign | 0.26 | Tolerated | 4.32 | 12 | 0.2240 | 0.4133 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||
| c.1131G>C | M377I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus classify the change as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result and is therefore not considered evidence for pathogenicity. Overall, the collective evidence points to a benign impact for M377I, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.675549 | Disordered | 0.431183 | Uncertain | 0.324 | 0.884 | 0.625 | -2.895 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.76 | Ambiguous | 0.3 | 0.54 | Ambiguous | 0.65 | Ambiguous | 0.24 | Likely Benign | 0.227 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.46 | Benign | 0.26 | Tolerated | 4.32 | 12 | 0.2240 | 0.4133 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1131G>T | M377I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus classify the change as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result and is therefore not considered evidence for pathogenicity. Overall, the evidence overwhelmingly supports a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.675549 | Disordered | 0.431183 | Uncertain | 0.324 | 0.884 | 0.625 | -2.895 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.76 | Ambiguous | 0.3 | 0.54 | Ambiguous | 0.65 | Ambiguous | 0.24 | Likely Benign | 0.227 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.46 | Benign | 0.26 | Tolerated | 4.32 | 12 | 0.2240 | 0.4133 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1335G>C | E445D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E445D is reported in gnomAD (ID 6‑33438240‑G‑C) but has no ClinVar entry. Functional prediction tools show a split verdict: benign calls come from REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, and premPS. 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 remains uncertain. Overall, the balance of evidence, especially the SGM Consensus, points to a pathogenic effect for E445D. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | 6-33438240-G-C | 4 | 2.48e-6 | -10.238 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 0.81 | Ambiguous | 0.0 | 0.49 | Likely Benign | 0.65 | Ambiguous | 0.91 | Ambiguous | 0.136 | Likely Benign | -2.86 | Deleterious | 0.977 | Probably Damaging | 0.921 | Probably Damaging | 3.54 | Benign | 0.09 | Tolerated | 3.38 | 31 | 0.1437 | 0.3526 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||
| c.1335G>T | E445D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E445D is not reported in ClinVar (status: none) and is absent from gnomAD. Prediction tools that agree on benign include REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized; those that agree on pathogenic include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain or unavailable results come from FoldX, Foldetta, and premPS. High‑accuracy methods give a split view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta is uncertain. Overall, the predictions are inconclusive, with an equal number of benign and pathogenic calls. Thus, the variant is most likely benign based on the current evidence, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -10.238 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 0.81 | Ambiguous | 0.0 | 0.49 | Likely Benign | 0.65 | Ambiguous | 0.91 | Ambiguous | 0.136 | Likely Benign | -2.86 | Deleterious | 0.977 | Probably Damaging | 0.921 | Probably Damaging | 3.54 | Benign | 0.09 | Tolerated | 3.38 | 31 | 0.1437 | 0.3526 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||
| c.1387G>A | D463N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D463N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic impact are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Predictions that are uncertain (Foldetta, AlphaMissense‑Optimized, Rosetta) are treated as unavailable and do not influence the overall assessment. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; Foldetta is uncertain. Overall, the majority of available predictions lean toward a benign effect, and this conclusion does not contradict any ClinVar status (none reported). Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -11.428 | Likely Pathogenic | 0.812 | Likely Pathogenic | Ambiguous | 0.10 | Likely Benign | 0.1 | 1.19 | Ambiguous | 0.65 | Ambiguous | 0.40 | Likely Benign | 0.217 | Likely Benign | -4.37 | Deleterious | 0.880 | Possibly Damaging | 0.430 | Benign | 3.33 | Benign | 0.10 | Tolerated | 0.1152 | 0.5531 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1568A>G | N523S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and FATHMM. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) returned uncertain or inconclusive results. For high‑accuracy assessment, AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports an uncertain folding‑stability change. Taken together, the majority of evidence (five benign versus three pathogenic predictions) points to a benign effect, and this conclusion does not contradict any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -6.188 | Likely Benign | 0.552 | Ambiguous | Likely Benign | 0.64 | Ambiguous | 0.2 | 0.66 | Ambiguous | 0.65 | Ambiguous | 0.17 | Likely Benign | 0.492 | Likely Benign | -4.31 | Deleterious | 0.976 | Probably Damaging | 0.410 | Benign | -1.27 | Pathogenic | 0.27 | Tolerated | 0.2213 | 0.4178 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||
| c.1757A>C | D586A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D586A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include FoldX, SIFT, and premPS, whereas a majority of predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains inconclusive. No evidence from the uncertain tools (Rosetta, Foldetta) alters this consensus. Consequently, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -9.955 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.41 | Likely Benign | 0.2 | 0.88 | Ambiguous | 0.65 | Ambiguous | 0.25 | Likely Benign | 0.693 | Likely Pathogenic | -4.58 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.22 | Pathogenic | 0.31 | Tolerated | 0.3397 | 0.4673 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1826G>A | G609E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609E has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools (Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -10.470 | Likely Pathogenic | 0.421 | Ambiguous | Likely Benign | 2.95 | Destabilizing | 0.4 | -1.65 | Ambiguous | 0.65 | Ambiguous | 0.61 | Ambiguous | 0.531 | Likely Pathogenic | -2.28 | Neutral | 0.916 | Possibly Damaging | 0.588 | Possibly Damaging | -1.41 | Pathogenic | 0.17 | Tolerated | 0.1709 | 0.4491 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.1909T>G | S637A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S637A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, SIFT, polyPhen‑2 (HumDiv and HumVar), REVEL, FoldX, and premPS. No tool predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is inconclusive (Uncertain). Taken together, the overwhelming majority of evidence indicates a benign effect. The variant’s status 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 | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -4.186 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.1 | 0.99 | Ambiguous | 0.65 | Ambiguous | 0.22 | Likely Benign | 0.078 | Likely Benign | -0.64 | Neutral | 0.120 | Benign | 0.182 | Benign | 3.41 | Benign | 1.00 | Tolerated | 0.4853 | 0.2996 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| 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>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.694G>C | A232P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, SIFT, and FATHMM. Tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from Rosetta, premPS, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, and Foldetta remains uncertain. Overall, the majority of evaluated tools predict a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -12.697 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.8 | 1.25 | Ambiguous | 0.65 | Ambiguous | 0.71 | Ambiguous | 0.748 | Likely Pathogenic | -2.75 | Deleterious | 0.917 | Possibly Damaging | 0.502 | Possibly Damaging | 5.78 | Benign | 0.06 | Tolerated | 0.2163 | 0.5259 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.709G>A | A237T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A237T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 (HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv), and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) return uncertain results. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split; Foldetta also yields an inconclusive stability assessment. Overall, the majority of evidence leans toward a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -8.664 | Likely Pathogenic | 0.213 | Likely Benign | Likely Benign | 0.74 | Ambiguous | 0.3 | 0.55 | Ambiguous | 0.65 | Ambiguous | 0.71 | Ambiguous | 0.539 | Likely Pathogenic | -2.66 | Deleterious | 0.900 | Possibly Damaging | 0.348 | Benign | 5.80 | Benign | 0.06 | Tolerated | 0.0975 | 0.5737 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.898T>C | S300P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The remaining tools—FoldX, Foldetta, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -7.379 | In-Between | 0.110 | Likely Benign | Likely Benign | 1.24 | Ambiguous | 1.0 | 0.06 | Likely Benign | 0.65 | Ambiguous | 0.50 | Likely Benign | 0.086 | Likely Benign | -2.46 | Neutral | 0.784 | Possibly Damaging | 0.390 | Benign | 1.54 | Pathogenic | 0.02 | Affected | 0.2192 | 0.5585 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.1061C>A | A354D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A354D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. Those that predict a pathogenic effect are FATHMM and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, and Rosetta) return uncertain results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors a pathogenic interpretation. Foldetta’s stability prediction is uncertain. Overall, the majority of consensus tools lean toward a benign effect, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | -7.914 | In-Between | 0.725 | Likely Pathogenic | Likely Benign | 0.22 | Likely Benign | 0.1 | 1.10 | Ambiguous | 0.66 | Ambiguous | 0.57 | Ambiguous | 0.087 | Likely Benign | -1.49 | Neutral | 0.255 | Benign | 0.053 | Benign | 1.75 | Pathogenic | 0.07 | Tolerated | 0.1759 | 0.1345 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||
| c.1081C>G | Q361E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q361E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain predictions come from Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta remains uncertain. Taken together, the majority of evidence supports a benign impact for Q361E, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.305330 | Structured | 0.427593 | Uncertain | 0.945 | 0.534 | 0.250 | -7.544 | In-Between | 0.289 | Likely Benign | Likely Benign | 0.29 | Likely Benign | 0.0 | 1.02 | Ambiguous | 0.66 | Ambiguous | 0.21 | Likely Benign | 0.153 | Likely Benign | -0.89 | Neutral | 0.969 | Probably Damaging | 0.930 | Probably Damaging | 1.70 | Pathogenic | 0.26 | Tolerated | 0.1217 | 0.3018 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.1255G>A | E419K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E419K 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, premPS, SIFT, and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Foldetta and Rosetta give uncertain results and are not counted in either group. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus predicts likely pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact for E419K. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -12.257 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.01 | Likely Benign | 0.1 | 1.30 | Ambiguous | 0.66 | Ambiguous | -0.03 | Likely Benign | 0.399 | Likely Benign | -3.75 | Deleterious | 0.998 | Probably Damaging | 0.975 | Probably Damaging | 3.36 | Benign | 0.07 | Tolerated | 0.2759 | 0.6899 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1400A>T | D467V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D467V missense variant is not reported in ClinVar or gnomAD. Prediction tools cluster into two groups: benign predictions come from Rosetta and premPS, while the majority—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label the change as pathogenic. Two tools, FoldX and Foldetta, give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta remains uncertain. Overall, the consensus of high‑confidence predictors points to a pathogenic effect, and this conclusion is consistent with the absence of any ClinVar annotation or gnomAD observation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -15.041 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.24 | Ambiguous | 0.1 | 0.08 | Likely Benign | 0.66 | Ambiguous | 0.02 | Likely Benign | 0.893 | Likely Pathogenic | -8.70 | Deleterious | 0.997 | Probably Damaging | 0.997 | Probably Damaging | -1.28 | Pathogenic | 0.02 | Affected | 0.0644 | 0.5274 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1435C>T | R479W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R479W is not reported in ClinVar and is present in gnomAD (ID 6‑33438467‑C‑T). Functional prediction tools show a split opinion: benign calls come from REVEL, premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely pathogenic; Foldetta remains inconclusive. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | 6-33438467-C-T | 6 | 3.72e-6 | -11.356 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 0.60 | Ambiguous | 0.1 | 0.72 | Ambiguous | 0.66 | Ambiguous | 0.42 | Likely Benign | 0.249 | Likely Benign | -4.75 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 3.35 | Benign | 0.02 | Affected | 3.39 | 32 | 0.1046 | 0.2933 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||
| c.1876A>C | I626L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I626L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, and FATHMM, whereas polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default predict a pathogenic outcome. Three tools—Foldetta, premPS, and Rosetta—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta also yields an uncertain stability prediction. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.109221 | Structured | 0.040732 | Uncertain | 0.970 | 0.223 | 0.000 | -10.696 | Likely Pathogenic | 0.622 | Likely Pathogenic | Likely Benign | 0.32 | Likely Benign | 0.1 | 1.00 | Ambiguous | 0.66 | Ambiguous | 0.83 | Ambiguous | 0.311 | Likely Benign | -1.86 | Neutral | 0.955 | Possibly Damaging | 0.985 | Probably Damaging | 3.52 | Benign | 0.12 | Tolerated | 0.0741 | 0.2461 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1955T>A | F652Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F652Y is not 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, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that agree on a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Three tools (FoldX, Foldetta, AlphaMissense‑Optimized) give uncertain results. High‑accuracy methods provide no definitive verdict: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie (2 pathogenic, 2 benign) and thus inconclusive; Foldetta is uncertain. Consequently, the overall prediction landscape is balanced, with an equal number of benign and pathogenic calls and several uncertain results. The variant is therefore most likely **inconclusive** in terms of pathogenicity, and this lack of consensus 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. | GAP | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -5.437 | Likely Benign | 0.890 | Likely Pathogenic | Ambiguous | 1.05 | Ambiguous | 0.2 | 0.27 | Likely Benign | 0.66 | Ambiguous | 1.24 | Destabilizing | 0.363 | Likely Benign | -2.92 | Deleterious | 0.957 | Probably Damaging | 0.390 | Benign | 3.13 | Benign | 0.00 | Affected | 0.1085 | 0.1584 | 7 | 3 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||
| c.745G>T | A249S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. Protein‑stability assessments are mixed: FoldX indicates a benign effect, while Rosetta and Foldetta are uncertain. High‑accuracy predictions show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the preponderance of evidence—including the high‑accuracy tools—suggests that A249S is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -5.707 | Likely Benign | 0.634 | Likely Pathogenic | Likely Benign | 0.48 | Likely Benign | 0.3 | 0.84 | Ambiguous | 0.66 | Ambiguous | 0.33 | Likely Benign | 0.465 | Likely Benign | -1.40 | Neutral | 0.990 | Probably Damaging | 0.681 | Possibly Damaging | 5.63 | Benign | 0.19 | Tolerated | 0.1962 | 0.3393 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.830A>T | K277M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K277M missense variant is not reported in ClinVar and has no entries in gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX and premPS, while the majority of tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label the change as pathogenic. High‑accuracy methods reinforce this trend: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.061840 | Structured | 0.321811 | Uncertain | 0.649 | 0.247 | 0.250 | -13.918 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.18 | Likely Benign | 0.0 | 1.14 | Ambiguous | 0.66 | Ambiguous | 0.15 | Likely Benign | 0.712 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.80 | Pathogenic | 0.00 | Affected | 0.0945 | 0.2584 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1064G>C | G355A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G355A missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. FoldX and Foldetta are uncertain and therefore not counted as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic) and Foldetta is uncertain. Consequently, the overall prediction leans toward a benign effect, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.155435 | Structured | 0.388832 | Uncertain | 0.810 | 0.354 | 0.125 | -5.431 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 0.88 | Ambiguous | 0.6 | 0.46 | Likely Benign | 0.67 | Ambiguous | 0.49 | Likely Benign | 0.286 | Likely Benign | -4.80 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.80 | Pathogenic | 0.03 | Affected | 0.4111 | 0.5045 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||
| c.1254A>C | K418N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K418N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM. 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, PROVEAN). Stability‑based methods (FoldX, Rosetta, premPS, Foldetta) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence indicates that K418N is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -13.310 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.57 | Ambiguous | 0.0 | 0.77 | Ambiguous | 0.67 | Ambiguous | 0.56 | Ambiguous | 0.132 | Likely Benign | -4.41 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.04 | Affected | 0.3483 | 0.0606 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1254A>T | K418N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K418N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions are provided by REVEL and FATHMM, whereas pathogenic predictions are given by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus score (Likely Pathogenic). Stability‑based methods FoldX, Rosetta, Foldetta, and premPS returned uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, and Foldetta’s stability analysis is inconclusive. Overall, the majority of reliable predictors classify K418N as pathogenic, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -13.310 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.57 | Ambiguous | 0.0 | 0.77 | Ambiguous | 0.67 | Ambiguous | 0.56 | Ambiguous | 0.132 | Likely Benign | -4.41 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.04 | Affected | 0.3483 | 0.0606 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1277A>G | N426S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N426S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The high‑accuracy AlphaMissense‑Optimized score is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and the Foldetta stability assessment is inconclusive. No evidence from FoldX or Rosetta is available. Overall, the majority of predictions support a benign impact, and this is consistent with the absence of a ClinVar assertion. Therefore, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -5.215 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.81 | Ambiguous | 0.0 | 0.52 | Ambiguous | 0.67 | Ambiguous | 0.03 | Likely Benign | 0.131 | Likely Benign | -2.37 | Neutral | 0.998 | Probably Damaging | 0.921 | Probably Damaging | 3.47 | Benign | 0.33 | Tolerated | 0.2224 | 0.3188 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.1283A>T | Y428F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y428F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b) predict a pathogenic impact. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as unavailable. Overall, the balance of evidence—five pathogenic versus three benign predictions, with a pathogenic SGM Consensus and a benign AlphaMissense‑Optimized—suggests that the variant is most likely pathogenic. 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. | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | -10.464 | Likely Pathogenic | 0.530 | Ambiguous | Likely Benign | 0.82 | Ambiguous | 0.1 | 0.52 | Ambiguous | 0.67 | Ambiguous | 0.89 | Ambiguous | 0.366 | Likely Benign | -3.82 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 3.41 | Benign | 0.04 | Affected | 0.2719 | 0.3146 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||
| c.1625A>C | N542T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N542T is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are SIFT and Rosetta. Tools that predict a pathogenic effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | -9.918 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 1.13 | Ambiguous | 0.1 | 0.20 | Likely Benign | 0.67 | Ambiguous | 0.75 | Ambiguous | 0.784 | Likely Pathogenic | -5.37 | Deleterious | 0.997 | Probably Damaging | 0.990 | Probably Damaging | -1.41 | Pathogenic | 0.12 | Tolerated | 0.1120 | 0.5872 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.1636T>C | C546R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C546R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include only SIFT, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta return uncertain results and are therefore not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | -15.237 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | -0.70 | Ambiguous | 0.3 | 2.04 | Destabilizing | 0.67 | Ambiguous | 1.70 | Destabilizing | 0.894 | Likely Pathogenic | -9.73 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.26 | Pathogenic | 0.06 | Tolerated | 0.1808 | 0.1685 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.1820T>G | L607R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L607R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FoldX, which scores the variant as benign. All other evaluated algorithms—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. Rosetta and Foldetta provide uncertain results and are therefore treated as unavailable evidence. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” while Foldetta remains uncertain. 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 annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | -14.234 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | -0.15 | Likely Benign | 0.1 | 1.48 | Ambiguous | 0.67 | Ambiguous | 1.24 | Destabilizing | 0.920 | Likely Pathogenic | -5.98 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | -1.51 | Pathogenic | 0.01 | Affected | 0.1490 | 0.0615 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2119G>T | A707S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A707S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign. In contrast, polyPhen‑2 HumDiv and HumVar classify the variant as pathogenic. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence supports a benign impact, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.203355 | Structured | 0.371229 | Uncertain | 0.927 | 0.365 | 0.000 | -4.432 | Likely Benign | 0.113 | Likely Benign | Likely Benign | 0.70 | Ambiguous | 0.1 | 0.63 | Ambiguous | 0.67 | Ambiguous | 0.28 | Likely Benign | 0.150 | Likely Benign | -1.07 | Neutral | 0.848 | Possibly Damaging | 0.945 | Probably Damaging | 3.43 | Benign | 0.08 | Tolerated | 0.1825 | 0.2924 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.2149C>T | L717F 2D AIThe SynGAP1 missense variant L717F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. No folding‑stability metrics (FoldX, Rosetta, premPS) provide decisive evidence. Overall, the majority of predictions lean toward pathogenicity, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.429342 | Uncertain | 0.969 | 0.397 | 0.000 | -10.917 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.74 | Ambiguous | 0.6 | 0.59 | Ambiguous | 0.67 | Ambiguous | 0.63 | Ambiguous | 0.157 | Likely Benign | -2.56 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.36 | Benign | 0.02 | Affected | 0.0444 | 0.2207 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2186A>T | N729I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729I is listed in gnomAD (ID 6‑33441651‑A‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicting benign, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a benign impact. 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 | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | 6-33441651-A-T | 1 | 6.20e-7 | -3.308 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.54 | Ambiguous | 0.6 | 0.79 | Ambiguous | 0.67 | Ambiguous | 0.29 | Likely Benign | 0.043 | Likely Benign | -2.96 | Deleterious | 0.506 | Possibly Damaging | 0.243 | Benign | 3.26 | Benign | 0.13 | Tolerated | 3.59 | 7 | 0.0625 | 0.4698 | -3 | -2 | 8.0 | -0.94 | |||||||||||||||||||||||||
| c.854G>A | C285Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and Rosetta. Those that agree on a pathogenic effect include SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for C285Y. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -7.210 | In-Between | 0.895 | Likely Pathogenic | Ambiguous | 3.66 | Destabilizing | 1.1 | -2.33 | Stabilizing | 0.67 | Ambiguous | 0.53 | Ambiguous | 0.484 | Likely Benign | -8.67 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.88 | Pathogenic | 0.18 | Tolerated | 0.1413 | 0.3689 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1064G>A | G355E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G355E is catalogued in gnomAD (6‑33437969‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining evaluated algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic impact. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is uncertain. Overall, the preponderance of evidence from standard pathogenicity predictors points to a deleterious effect, and this conclusion is not contradicted by any ClinVar classification (none is available). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.388832 | Uncertain | 0.810 | 0.354 | 0.125 | 6-33437969-G-A | 2 | 1.24e-6 | -9.395 | Likely Pathogenic | 0.891 | Likely Pathogenic | Ambiguous | 0.72 | Ambiguous | 0.6 | 0.63 | Ambiguous | 0.68 | Ambiguous | 0.54 | Ambiguous | 0.349 | Likely Benign | -6.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.80 | Pathogenic | 0.04 | Affected | 3.38 | 24 | 0.1590 | 0.4271 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||
| c.1469C>T | A490V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A490V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly favor a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate pathogenicity. No tool predicts a benign outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus remains likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the consensus of the majority of algorithms points to a pathogenic effect, and this conclusion does not conflict with the absence of ClinVar annotation. Thus, the variant is most likely pathogenic, with no contradiction from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.120615 | Structured | 0.322979 | Uncertain | 0.938 | 0.210 | 0.125 | -10.348 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.73 | Ambiguous | 0.3 | 0.62 | Ambiguous | 0.68 | Ambiguous | 0.69 | Ambiguous | 0.817 | Likely Pathogenic | -3.93 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | -1.26 | Pathogenic | 0.04 | Affected | 0.0983 | 0.4213 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.1522G>A | D508N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508N missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, premPS, FATHMM, AlphaMissense‑Optimized) and pathogenic predictions (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b). Three tools remain uncertain (Rosetta, Foldetta, AlphaMissense‑Default). High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized classifies the change as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—returns a pathogenic verdict; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an inconclusive result. Because the consensus of the high‑accuracy methods is split, the overall prediction is ambiguous, but the balance of evidence leans toward pathogenicity. This assessment does not contradict ClinVar, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -9.909 | Likely Pathogenic | 0.411 | Ambiguous | Likely Benign | 0.11 | Likely Benign | 0.1 | 1.24 | Ambiguous | 0.68 | Ambiguous | -0.12 | Likely Benign | 0.265 | Likely Benign | -4.62 | Deleterious | 0.870 | Possibly Damaging | 0.615 | Possibly Damaging | 3.32 | Benign | 0.04 | Affected | 0.1577 | 0.4599 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.1669T>G | S557A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S557A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Optimized and Rosetta, whereas a majority of tools (REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus) predict a pathogenic impact. Uncertain or inconclusive results come from AlphaMissense‑Default, FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.010261 | Uncertain | 0.924 | 0.215 | 0.000 | -11.044 | Likely Pathogenic | 0.421 | Ambiguous | Likely Benign | 1.26 | Ambiguous | 0.0 | 0.09 | Likely Benign | 0.68 | Ambiguous | 0.54 | Ambiguous | 0.801 | Likely Pathogenic | -2.70 | Deleterious | 0.944 | Possibly Damaging | 0.987 | Probably Damaging | -1.69 | Pathogenic | 0.05 | Affected | 0.4695 | 0.4836 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1736G>A | R579Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R579Q is listed in ClinVar with an uncertain significance (ClinVar ID 3964539) and is present in gnomAD (6‑33440788‑G‑A). Prediction tools that indicate a benign effect include SIFT and AlphaMissense‑Optimized, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX and Rosetta individually also return uncertain results. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. 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. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.022872 | Uncertain | 0.877 | 0.244 | 0.000 | Uncertain | 2 | 6-33440788-G-A | 18 | 1.12e-5 | -9.193 | Likely Pathogenic | 0.690 | Likely Pathogenic | Likely Benign | 0.65 | Ambiguous | 0.1 | 0.70 | Ambiguous | 0.68 | Ambiguous | 1.13 | Destabilizing | 0.673 | Likely Pathogenic | -3.31 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.34 | Pathogenic | 0.06 | Tolerated | 3.37 | 34 | 0.2677 | 0.1334 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||
| c.1808T>A | M603K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M603K is not reported in ClinVar and has no entries in gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, SGM Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while only FoldX reports a benign outcome. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No other tools provide a clear benign signal. Consequently, the variant is most likely pathogenic, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -15.561 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.17 | Likely Benign | 0.0 | 1.19 | Ambiguous | 0.68 | Ambiguous | 0.67 | Ambiguous | 0.933 | Likely Pathogenic | -5.64 | Deleterious | 0.923 | Possibly Damaging | 0.922 | Probably Damaging | -1.35 | Pathogenic | 0.00 | Affected | 0.1268 | 0.0488 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.1905C>A | N635K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N635K 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 and HumVar), SIFT, ESM1b, 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. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for N635K, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -13.144 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.60 | Ambiguous | 0.1 | 0.75 | Ambiguous | 0.68 | Ambiguous | 0.85 | Ambiguous | 0.332 | Likely Benign | -5.64 | Deleterious | 0.949 | Possibly Damaging | 0.550 | Possibly Damaging | 2.92 | Benign | 0.00 | Affected | 0.2125 | 0.2510 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1905C>G | N635K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N635K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM Consensus as Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. 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 existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -13.144 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.60 | Ambiguous | 0.1 | 0.75 | Ambiguous | 0.68 | Ambiguous | 0.85 | Ambiguous | 0.332 | Likely Benign | -5.64 | Deleterious | 0.949 | Possibly Damaging | 0.550 | Possibly Damaging | 2.92 | Benign | 0.00 | Affected | 0.2125 | 0.2510 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1907T>A | F636Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F636Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a pathogenic outcome (3/4 votes). High‑accuracy assessments further reveal AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as inconclusive. Stability‑based tools FoldX, Rosetta, and premPS are uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | -9.638 | Likely Pathogenic | 0.695 | Likely Pathogenic | Likely Benign | 0.84 | Ambiguous | 0.1 | 0.51 | Ambiguous | 0.68 | Ambiguous | 0.90 | Ambiguous | 0.394 | Likely Benign | -2.89 | Deleterious | 0.927 | Possibly Damaging | 0.836 | Possibly Damaging | 3.40 | Benign | 0.08 | Tolerated | 0.1297 | 0.1866 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1919C>T | T640I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T640I is not 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, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only PROVEAN predicts a pathogenic outcome. The remaining tools (FoldX, Rosetta, ESM1b, AlphaMissense‑Default, 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, and PROVEAN) is unavailable due to a tie, and Foldetta also yields an uncertain stability change. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.066181 | Structured | 0.137043 | Uncertain | 0.893 | 0.284 | 0.000 | -7.256 | In-Between | 0.358 | Ambiguous | Likely Benign | 0.70 | Ambiguous | 0.1 | 0.66 | Ambiguous | 0.68 | Ambiguous | 0.28 | Likely Benign | 0.193 | Likely Benign | -2.75 | Deleterious | 0.322 | Benign | 0.022 | Benign | 3.46 | Benign | 0.12 | Tolerated | 0.1030 | 0.4793 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||
| c.1963C>G | L655V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L655V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. No tools predict pathogenicity, and the uncertain stability assessment does not alter the overall benign inference. Therefore, based on the available predictions, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.015344 | Structured | 0.268808 | Uncertain | 0.961 | 0.274 | 0.000 | -6.743 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 0.78 | Ambiguous | 0.0 | 0.58 | Ambiguous | 0.68 | Ambiguous | 0.38 | Likely Benign | 0.058 | Likely Benign | -0.62 | Neutral | 0.008 | Benign | 0.003 | Benign | 3.45 | Benign | 0.44 | Tolerated | 0.1551 | 0.3190 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2035T>A | F679I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F679I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM. In contrast, a majority of predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently classify the substitution as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as Likely Pathogenic. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain, and the SGM Consensus remains pathogenic. Because the uncertain results are treated as unavailable, the clear majority of predictions support pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no entry for F679I. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -12.620 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.62 | Ambiguous | 0.4 | -0.27 | Likely Benign | 0.68 | Ambiguous | 0.88 | Ambiguous | 0.498 | Likely Benign | -5.91 | Deleterious | 0.993 | Probably Damaging | 0.977 | Probably Damaging | 3.59 | Benign | 0.01 | Affected | 0.1725 | 0.2322 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.2053T>A | L685M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from premPS, Foldetta, Rosetta, and AlphaMissense‑Optimized. High‑accuracy methods give inconclusive results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑to‑2 tie and therefore uncertain; Foldetta also reports an uncertain stability change. Consequently, the overall computational evidence is mixed, with a slight tilt toward pathogenicity. Thus, the variant is most likely pathogenic based on predictions, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -10.790 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.35 | Likely Benign | 0.1 | 1.01 | Ambiguous | 0.68 | Ambiguous | 0.83 | Ambiguous | 0.281 | Likely Benign | -2.00 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.29 | Benign | 0.01 | Affected | 0.0814 | 0.2758 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.2117A>T | E706V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E706V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Two tools, FoldX and Foldetta, give uncertain or inconclusive results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of predictions lean toward a benign impact, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.377033 | Uncertain | 0.929 | 0.363 | 0.000 | -9.306 | Likely Pathogenic | 0.667 | Likely Pathogenic | Likely Benign | 1.05 | Ambiguous | 0.0 | 0.30 | Likely Benign | 0.68 | Ambiguous | 0.05 | Likely Benign | 0.099 | Likely Benign | -2.63 | Deleterious | 0.555 | Possibly Damaging | 0.109 | Benign | 4.07 | Benign | 0.16 | Tolerated | 0.0528 | 0.4275 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2130G>C | K710N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K710N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain or unavailable results are reported for FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic impact for K710N, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.321458 | Structured | 0.370438 | Uncertain | 0.949 | 0.368 | 0.000 | -9.330 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 0.85 | Ambiguous | 0.0 | 0.50 | Ambiguous | 0.68 | Ambiguous | 0.33 | Likely Benign | 0.201 | Likely Benign | -4.39 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.04 | Affected | 0.2485 | 0.1124 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.2130G>T | K710N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K710N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM. In contrast, a majority of algorithms predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not conflict with the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.321458 | Structured | 0.370438 | Uncertain | 0.949 | 0.368 | 0.000 | -9.330 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 0.85 | Ambiguous | 0.0 | 0.50 | Ambiguous | 0.68 | Ambiguous | 0.33 | Likely Benign | 0.201 | Likely Benign | -4.39 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.04 | Affected | 0.2485 | 0.1124 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.628C>G | H210D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain, and Rosetta alone is also uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for H210D, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -16.440 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.13 | Likely Benign | 0.4 | 1.23 | Ambiguous | 0.68 | Ambiguous | 1.23 | Destabilizing | 0.489 | Likely Benign | -7.73 | Deleterious | 0.895 | Possibly Damaging | 0.533 | Possibly Damaging | 3.18 | Benign | 0.00 | Affected | 0.2025 | 0.1255 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.718G>T | D240Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240Y missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, premPS, and FATHMM; pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore not considered evidence. Taken together, the overwhelming majority of reliable predictors indicate a pathogenic effect for D240Y. This conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -16.890 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.29 | Likely Benign | 0.3 | 1.07 | Ambiguous | 0.68 | Ambiguous | -0.01 | Likely Benign | 0.899 | Likely Pathogenic | -7.90 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.77 | Benign | 0.00 | Affected | 0.0439 | 0.4932 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.794A>C | K265T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265T missense variant is reported in gnomAD (ID 6‑33437699‑A‑C) but has no ClinVar entry. Prediction tools that classify the variant as benign include REVEL, SIFT, and Rosetta. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Four tools give uncertain results: FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | 6-33437699-A-C | 1 | 6.20e-7 | -9.425 | Likely Pathogenic | 0.839 | Likely Pathogenic | Ambiguous | 0.99 | Ambiguous | 0.1 | 0.37 | Likely Benign | 0.68 | Ambiguous | 0.83 | Ambiguous | 0.441 | Likely Benign | -3.75 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.91 | Pathogenic | 0.07 | Tolerated | 3.38 | 18 | 0.2042 | 0.3178 | -1 | 0 | 3.2 | -27.07 | ||||||||||||||||||||||||
| c.869T>G | L290R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L290R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions are limited to FoldX, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all classify the variant as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. Overall, the consensus of the majority of evidence points to a pathogenic impact. This conclusion is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.127496 | Structured | 0.399723 | Uncertain | 0.904 | 0.255 | 0.000 | -13.938 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.48 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.68 | Ambiguous | 0.89 | Ambiguous | 0.705 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.03 | Pathogenic | 0.01 | Affected | 0.1215 | 0.1056 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1003C>T | R335C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R335C is listed in ClinVar with an uncertain significance (ClinVar ID 2835865.0) and is present in gnomAD (ID 6‑33437908‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL and premPS, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are AlphaMissense‑Optimized, FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion aligns with the ClinVar designation of uncertain significance, which does not contradict the prediction that the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.305330 | Structured | 0.331028 | Uncertain | 0.483 | 0.428 | 0.500 | Uncertain | 1 | 6-33437908-C-T | 1 | 6.20e-7 | -14.354 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 0.53 | Ambiguous | 0.1 | 0.85 | Ambiguous | 0.69 | Ambiguous | 0.46 | Likely Benign | 0.277 | Likely Benign | -5.69 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.67 | Pathogenic | 0.01 | Affected | 3.38 | 22 | 0.2882 | 0.3290 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||
| c.1057C>A | L353M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L353M has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. Uncertain results come from Rosetta, Foldetta, and premPS. 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. 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. | Likely Benign | C2 | 0.137348 | Structured | 0.373584 | Uncertain | 0.926 | 0.315 | 0.000 | -6.943 | Likely Benign | 0.206 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.0 | 1.28 | Ambiguous | 0.69 | Ambiguous | 0.60 | Ambiguous | 0.117 | Likely Benign | -0.47 | Neutral | 0.744 | Possibly Damaging | 0.289 | Benign | 1.33 | Pathogenic | 0.03 | Affected | 0.0847 | 0.4080 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| 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.1121C>A | S374Y 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant S374Y is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, whereas polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. Uncertain calls come from FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta likewise yields an uncertain stability change. Overall, the majority of available predictions favor a benign effect, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.642678 | Disordered | 0.428948 | Uncertain | 0.333 | 0.812 | 0.625 | Uncertain | 1 | -7.774 | In-Between | 0.344 | Ambiguous | Likely Benign | 0.71 | Ambiguous | 1.2 | 0.66 | Ambiguous | 0.69 | Ambiguous | -0.02 | Likely Benign | 0.310 | Likely Benign | -1.18 | Neutral | 0.875 | Possibly Damaging | 0.271 | Benign | 5.41 | Benign | 0.01 | Affected | 4.32 | 13 | 0.1175 | 0.6705 | -3 | -2 | -0.5 | 76.10 | 237.3 | -76.9 | 0.5 | 0.4 | 0.5 | 0.3 | Uncertain | Ser374 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus, large and relatively hydrophobic residues like tyrosine are rarely tolerated. Additionally, the hydroxyl group of Tyr374 frequently forms various hydrogen bonds with other loop residues in the variant simulations. Although no negative structural effects are observed in the variant simulations, Tyr374 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||||||
| c.1884G>C | K628N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K628N 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—premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—classify the variant as pathogenic or likely pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability predictions and are therefore treated as unavailable evidence. High‑accuracy assessments specifically show AlphaMissense‑Optimized predicting pathogenicity, the SGM‑Consensus indicating a likely pathogenic status, and Foldetta yielding an uncertain result. Based on the overwhelming agreement among the majority of prediction tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.035486 | Uncertain | 0.957 | 0.229 | 0.000 | -12.284 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.78 | Ambiguous | 0.1 | 0.59 | Ambiguous | 0.69 | Ambiguous | 1.11 | Destabilizing | 0.403 | Likely Benign | -4.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.37 | Pathogenic | 0.00 | Affected | 3.37 | 34 | 0.2740 | 0.1254 | 0 | 1 | 0.4 | -14.07 | |||||||||||||||||||||||||||
| c.1884G>T | K628N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K628N is catalogued in gnomAD (6‑33440936‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: a single benign prediction from REVEL, and a consensus of nine pathogenic predictions from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also labels the variant as Likely Pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus confirms a likely pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and therefore does not alter the overall interpretation. Consequently, the variant is most likely pathogenic according to the available computational evidence, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.035486 | Uncertain | 0.957 | 0.229 | 0.000 | 6-33440936-G-T | 1 | 6.20e-7 | -12.284 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.78 | Ambiguous | 0.1 | 0.59 | Ambiguous | 0.69 | Ambiguous | 1.11 | Destabilizing | 0.403 | Likely Benign | -4.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.37 | Pathogenic | 0.00 | Affected | 3.37 | 34 | 0.2740 | 0.1254 | 0 | 1 | 0.4 | -14.07 | ||||||||||||||||||||||||
| c.2049C>G | I683M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I683M variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of definitive predictions (five pathogenic vs. three benign) point to a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -9.010 | Likely Pathogenic | 0.424 | Ambiguous | Likely Benign | 0.69 | Ambiguous | 0.1 | 0.68 | Ambiguous | 0.69 | Ambiguous | 0.74 | Ambiguous | 0.296 | Likely Benign | -2.88 | Deleterious | 0.999 | Probably Damaging | 0.986 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 0.0933 | 0.2662 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||
| c.670A>G | T224A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T224A is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33435521‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and AlphaMissense‑Default. Predictions that are inconclusive are Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | Conflicting | 4 | 6-33435521-A-G | 2 | 1.24e-6 | -7.379 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | 0.33 | Likely Benign | 0.1 | 1.05 | Ambiguous | 0.69 | Ambiguous | 0.91 | Ambiguous | 0.464 | Likely Benign | -2.96 | Deleterious | 0.243 | Benign | 0.079 | Benign | 5.57 | Benign | 0.57 | Tolerated | 3.41 | 13 | 0.4253 | 0.5053 | 1 | 0 | 2.5 | -30.03 | 169.0 | 41.4 | -0.5 | 1.1 | -0.4 | 0.0 | X | X | Uncertain | The introduced residue Ala224 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the hydroxyl group of the Thr224 side chain in the WT model, the methyl side chain of Ala224 cannot form hydrogen bonds with nearby residues Ser204, Ser226, and Gly227. Without these hydrogen-bonding interactions at the β sheet surface, the secondary structure element becomes unstable and unfolds during the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||
| c.948C>A | N316K 2D AIThe SynGAP1 missense variant N316K is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL and SIFT, whereas the majority of tools predict a pathogenic outcome: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. No other high‑confidence predictions are available. Overall, the preponderance of evidence points to a pathogenic effect for N316K, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.385187 | Uncertain | 0.817 | 0.246 | 0.125 | -10.711 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.52 | Ambiguous | 0.7 | 0.86 | Ambiguous | 0.69 | Ambiguous | 0.67 | Ambiguous | 0.254 | Likely Benign | -3.87 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.77 | Pathogenic | 0.13 | Tolerated | 0.2220 | 0.6593 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.948C>G | N316K 2D AISynGAP1 missense variant N316K is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and SIFT, whereas a majority of tools predict pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of computational predictions indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.385187 | Uncertain | 0.817 | 0.246 | 0.125 | -10.711 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.52 | Ambiguous | 0.7 | 0.86 | Ambiguous | 0.69 | Ambiguous | 0.67 | Ambiguous | 0.254 | Likely Benign | -3.87 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.77 | Pathogenic | 0.13 | Tolerated | 0.2220 | 0.6593 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1003C>A | R335S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R335S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, premPS, and SIFT; pathogenic predictions from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No evidence from FoldX or Rosetta alone is available. Based on the preponderance of pathogenic predictions and the high‑accuracy tools, the variant is most likely pathogenic, which is consistent with the absence of ClinVar reporting and gnomAD data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.305330 | Structured | 0.331028 | Uncertain | 0.483 | 0.428 | 0.500 | -9.286 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.68 | Ambiguous | 0.1 | 0.72 | Ambiguous | 0.70 | Ambiguous | 0.14 | Likely Benign | 0.184 | Likely Benign | -3.30 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.89 | Pathogenic | 0.11 | Tolerated | 0.2598 | 0.4005 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||
| c.1281T>A | H427Q 2D  3DClick to see structure in 3D Viewer AISynGAP1 H427Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, 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 SIFT. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Default. 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 effect for H427Q. This conclusion is consistent with the absence of a 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 | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -5.858 | Likely Benign | 0.367 | Ambiguous | Likely Benign | 0.77 | Ambiguous | 0.1 | 0.62 | Ambiguous | 0.70 | Ambiguous | 0.73 | Ambiguous | 0.142 | Likely Benign | -2.41 | Neutral | 0.864 | Possibly Damaging | 0.088 | Benign | 3.52 | Benign | 0.02 | Affected | 0.1556 | 0.3382 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.1281T>G | H427Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 H427Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, 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 SIFT. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Default. 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 effect for H427Q. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -5.858 | Likely Benign | 0.367 | Ambiguous | Likely Benign | 0.77 | Ambiguous | 0.1 | 0.62 | Ambiguous | 0.70 | Ambiguous | 0.73 | Ambiguous | 0.142 | Likely Benign | -2.41 | Neutral | 0.864 | Possibly Damaging | 0.088 | Benign | 3.52 | Benign | 0.02 | Affected | 0.1556 | 0.3382 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.1480A>C | I494L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I494L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the balance of evidence (five pathogenic versus four benign predictions, with several uncertain calls) leans toward a pathogenic interpretation. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -10.175 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.28 | Likely Benign | 0.1 | 1.11 | Ambiguous | 0.70 | Ambiguous | 0.91 | Ambiguous | 0.513 | Likely Pathogenic | -1.69 | Neutral | 0.645 | Possibly Damaging | 0.718 | Possibly Damaging | -0.88 | Pathogenic | 0.11 | Tolerated | 0.0816 | 0.2851 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1480A>T | I494L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I494L variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta indicating uncertain stability change. Overall, the balance of evidence leans toward pathogenicity, with a majority of tools and the SGM Consensus supporting a deleterious effect. This conclusion does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -10.175 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.28 | Likely Benign | 0.1 | 1.11 | Ambiguous | 0.70 | Ambiguous | 0.91 | Ambiguous | 0.513 | Likely Pathogenic | -1.69 | Neutral | 0.645 | Possibly Damaging | 0.718 | Possibly Damaging | -0.88 | Pathogenic | 0.11 | Tolerated | 0.0816 | 0.2851 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1729G>A | A577T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A577T is listed in ClinVar as benign (ClinVar ID 2195056.0) and is present in gnomAD (ID 6‑33440781‑G‑A). 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. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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. No other high‑confidence stability predictions are available. Overall, the consensus of the available predictions indicates that the variant is most likely benign, which aligns with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | Benign | 1 | 6-33440781-G-A | 6 | 3.72e-6 | -5.311 | Likely Benign | 0.322 | Likely Benign | Likely Benign | 0.86 | Ambiguous | 0.1 | 0.54 | Ambiguous | 0.70 | Ambiguous | 0.54 | Ambiguous | 0.427 | Likely Benign | -1.47 | Neutral | 0.999 | Probably Damaging | 0.987 | Probably Damaging | -1.31 | Pathogenic | 0.47 | Tolerated | 3.37 | 34 | 0.1657 | 0.5875 | 1 | 0 | -2.5 | 30.03 | 191.9 | -43.4 | 0.0 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | Ala577 is located near the end and outer surface of an α-helix (res. Arg563-Glu578), where its methyl group does not form any particular interactions in the WT simulations. In the variant simulations, the hydroxyl group of the Thr577 side chain hydrogen bonds with the backbone atoms of Arg573 and Lys574 within the same helix, which has the potential to weaken the stability of the secondary structure element. Regardless, the residue swap seems to be well tolerated based on the variant simulations. | |||||||||||||
| c.2047A>C | I683L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683L 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), FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b. Remaining methods (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta remains uncertain. Overall, the balance of evidence favors a benign impact for I683L, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -9.988 | Likely Pathogenic | 0.488 | Ambiguous | Likely Benign | 0.63 | Ambiguous | 0.1 | 0.76 | Ambiguous | 0.70 | Ambiguous | 0.69 | Ambiguous | 0.286 | Likely Benign | -2.00 | Neutral | 0.011 | Benign | 0.056 | Benign | 3.43 | Benign | 0.04 | Affected | 0.0957 | 0.3185 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.2081C>A | A694D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A694D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, FATHMM, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, the variant’s functional impact remains ambiguous. The predictions do not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.127496 | Structured | 0.352199 | Uncertain | 0.938 | 0.269 | 0.000 | -9.542 | Likely Pathogenic | 0.841 | Likely Pathogenic | Ambiguous | 0.35 | Likely Benign | 0.1 | 1.04 | Ambiguous | 0.70 | Ambiguous | 1.01 | Destabilizing | 0.163 | Likely Benign | -2.47 | Neutral | 0.918 | Possibly Damaging | 0.375 | Benign | 3.48 | Benign | 0.05 | Affected | 0.2085 | 0.2216 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||
| c.757A>T | N253Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253Y is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX, FATHMM, and premPS, whereas a larger set—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Because the majority of evidence points to a deleterious impact, the variant is most likely pathogenic; this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -14.749 | Likely Pathogenic | 0.920 | Likely Pathogenic | Ambiguous | 0.27 | Likely Benign | 0.1 | 1.13 | Ambiguous | 0.70 | Ambiguous | 0.29 | Likely Benign | 0.896 | Likely Pathogenic | -7.01 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 5.55 | Benign | 0.01 | Affected | 0.0642 | 0.7055 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.788T>C | V263A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Rosetta, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), and SIFT. Predictions marked “Uncertain” include FoldX, Foldetta, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of evidence points to a benign effect. Thus, the variant is most likely benign based on current predictions, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.356141 | Uncertain | 0.918 | 0.257 | 0.000 | -6.877 | Likely Benign | 0.530 | Ambiguous | Likely Benign | 1.40 | Ambiguous | 0.1 | 0.00 | Likely Benign | 0.70 | Ambiguous | 1.26 | Destabilizing | 0.622 | Likely Pathogenic | -2.17 | Neutral | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 5.97 | Benign | 0.04 | Affected | 0.2565 | 0.1822 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.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.1510A>G | K504E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K504E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -9.890 | Likely Pathogenic | 0.587 | Likely Pathogenic | Likely Benign | 0.63 | Ambiguous | 0.4 | 0.78 | Ambiguous | 0.71 | Ambiguous | 1.06 | Destabilizing | 0.386 | Likely Benign | -3.40 | Deleterious | 0.924 | Possibly Damaging | 0.674 | Possibly Damaging | -1.25 | Pathogenic | 0.21 | Tolerated | 0.2583 | 0.0650 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1535A>C | E512A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E512A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results come from Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments show SGM‑Consensus as likely pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -10.979 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 0.45 | Likely Benign | 0.1 | 0.97 | Ambiguous | 0.71 | Ambiguous | 0.04 | Likely Benign | 0.309 | Likely Benign | -5.71 | Deleterious | 0.987 | Probably Damaging | 0.937 | Probably Damaging | 3.31 | Benign | 0.12 | Tolerated | 0.4293 | 0.5162 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.2006A>C | N669T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy methods give a split verdict: AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts it to be pathogenic; Foldetta remains inconclusive. Overall, the majority of tools favor a pathogenic interpretation, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.086615 | Uncertain | 0.872 | 0.380 | 0.000 | -9.875 | Likely Pathogenic | 0.565 | Likely Pathogenic | Likely Benign | 0.74 | Ambiguous | 0.1 | 0.68 | Ambiguous | 0.71 | Ambiguous | 0.49 | Likely Benign | 0.292 | Likely Benign | -5.25 | Deleterious | 0.991 | Probably Damaging | 0.962 | Probably Damaging | 3.50 | Benign | 0.17 | Tolerated | 0.1504 | 0.4803 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.2015C>A | T672K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T672K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from Foldetta, premPS, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the majority of tools lean toward a benign interpretation, but the high‑accuracy consensus is split, leaving the variant’s impact uncertain. Thus, the variant is most likely benign based on the bulk of predictions, and this does not contradict its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.102069 | Uncertain | 0.586 | 0.362 | 0.000 | Uncertain | 1 | -12.192 | Likely Pathogenic | 0.698 | Likely Pathogenic | Likely Benign | 0.20 | Likely Benign | 0.5 | 1.21 | Ambiguous | 0.71 | Ambiguous | 0.72 | Ambiguous | 0.065 | Likely Benign | -4.31 | Deleterious | 0.745 | Possibly Damaging | 0.051 | Benign | 3.40 | Benign | 0.07 | Tolerated | 3.40 | 25 | 0.1152 | 0.3250 | 0 | -1 | -3.2 | 27.07 | 195.1 | 7.0 | 0.4 | 0.7 | 0.4 | 0.1 | X | X | Potentially Pathogenic | The hydroxyl group of Thr672, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop itself, such as Lys566, Glu666, and Asn669. In the variant simulations, Lys672 can only form a hydrogen bond with the amino group of the Lys566 side chain via its backbone carbonyl group. Consequently, it cannot maintain the Lys566-Glu666 salt bridge through hydrogen bonding. However, the amino group of Lys periodically forms a salt bridge with the carboxylate group of Glu666, which prevents a drastic disruption of the hydrogen-bond network that keeps the loop close to the helices. | |||||||||||||||
| c.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.809A>C | E270A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E270A missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools cluster into three groups: benign predictions are made only by premPS; pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; and three tools (FoldX, Rosetta, Foldetta) give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points to a deleterious effect. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.382573 | Uncertain | 0.938 | 0.231 | 0.125 | -13.618 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.64 | Ambiguous | 0.2 | 0.77 | Ambiguous | 0.71 | Ambiguous | 0.41 | Likely Benign | 0.547 | Likely Pathogenic | -5.52 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.61 | Pathogenic | 0.01 | Affected | 0.4122 | 0.3951 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1052C>G | A351G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A351G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign vs two pathogenic), and Foldetta is uncertain. Taken together, the majority of available predictions lean toward a benign impact, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -4.983 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.0 | 1.04 | Ambiguous | 0.72 | Ambiguous | 0.55 | Ambiguous | 0.041 | Likely Benign | -2.53 | Deleterious | 0.688 | Possibly Damaging | 0.138 | Benign | 1.77 | Pathogenic | 0.04 | Affected | 0.2298 | 0.4737 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.1252A>G | K418E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K418E is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, and FATHMM. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Overall, the majority of evaluated tools (seven pathogenic vs four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for K418E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -12.443 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.63 | Ambiguous | 0.0 | 0.80 | Ambiguous | 0.72 | Ambiguous | 0.47 | Likely Benign | 0.367 | Likely Benign | -3.42 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.53 | Benign | 0.07 | Tolerated | 0.3578 | 0.0471 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1322T>G | V441G 2D  3DClick to see structure in 3D Viewer AISynGAP1 variant V441G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into three groups: benign predictions come from REVEL, FoldX, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; the remaining tools (Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized remains benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenic, and Foldetta is inconclusive. Taken together, the majority of evidence points to a benign effect, but the SGM Consensus and several individual pathogenic predictors introduce uncertainty. Therefore, the variant is most likely benign based on the overall prediction landscape, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | -12.380 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.18 | Likely Benign | 0.0 | 1.25 | Ambiguous | 0.72 | Ambiguous | 0.95 | Ambiguous | 0.273 | Likely Benign | -5.88 | Deleterious | 0.841 | Possibly Damaging | 0.997 | Probably Damaging | 3.41 | Benign | 0.24 | Tolerated | 0.1664 | 0.1715 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1583C>G | P528R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528R missense variant is not reported in ClinVar and is absent from gnomAD. No in silico predictor classifies it as benign; the following tools predict pathogenicity: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions that are uncertain or inconclusive (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -16.367 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.76 | Ambiguous | 0.4 | 0.67 | Ambiguous | 0.72 | Ambiguous | 0.73 | Ambiguous | 0.615 | Likely Pathogenic | -8.58 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.1261 | 0.2543 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1819C>T | L607F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L607F is catalogued in gnomAD (6‑33440871‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all report pathogenic or likely pathogenic. Only FoldX predicts a benign outcome, while Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show the SGM‑Consensus as likely pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for L607F, and this conclusion is not contradicted by ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | 6-33440871-C-T | 1 | 6.19e-7 | -13.654 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.23 | Likely Benign | 0.1 | 1.20 | Ambiguous | 0.72 | Ambiguous | 0.61 | Ambiguous | 0.758 | Likely Pathogenic | -3.98 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | -1.54 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.0872 | 0.2816 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||
| c.628C>A | H210N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 H210N missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and FATHMM, while pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus score (Likely Pathogenic). Two tools give uncertain results: Foldetta (combining FoldX‑MD and Rosetta outputs) and Rosetta alone. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points toward a pathogenic effect for H210N. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -13.699 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.19 | Likely Benign | 0.3 | 1.24 | Ambiguous | 0.72 | Ambiguous | 1.12 | Destabilizing | 0.375 | Likely Benign | -6.01 | Deleterious | 0.895 | Possibly Damaging | 0.533 | Possibly Damaging | 3.11 | Benign | 0.00 | Affected | 0.1166 | 0.1839 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| c.805A>G | I269V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I269V missense variant has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that are uncertain or inconclusive are FoldX, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools lean toward a benign interpretation, but the high‑accuracy consensus indicates a pathogenic signal, leaving the variant’s clinical significance uncertain. This assessment does not contradict any existing ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | -8.748 | Likely Pathogenic | 0.344 | Ambiguous | Likely Benign | 0.95 | Ambiguous | 0.0 | 0.49 | Likely Benign | 0.72 | Ambiguous | 0.71 | Ambiguous | 0.393 | Likely Benign | -0.72 | Neutral | 0.958 | Probably Damaging | 0.970 | Probably Damaging | 1.87 | Pathogenic | 0.10 | Tolerated | 0.0844 | 0.2859 | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||
| c.1003C>G | R335G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R335G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, and SIFT, whereas those that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, more tools predict pathogenicity than benignity, and the high‑accuracy consensus also leans pathogenic. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.305330 | Structured | 0.331028 | Uncertain | 0.483 | 0.428 | 0.500 | -11.860 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 1.01 | Ambiguous | 0.1 | 0.44 | Likely Benign | 0.73 | Ambiguous | 0.20 | Likely Benign | 0.194 | Likely Benign | -4.77 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.01 | Pathogenic | 0.10 | Tolerated | 0.3000 | 0.3554 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1204C>A | L402M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402M is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.243554 | Structured | 0.431978 | Uncertain | 0.961 | 0.383 | 0.000 | -6.991 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.0 | 1.33 | Ambiguous | 0.73 | Ambiguous | 0.80 | Ambiguous | 0.071 | Likely Benign | -0.99 | Neutral | 0.994 | Probably Damaging | 0.938 | Probably Damaging | 3.73 | Benign | 0.02 | Affected | 0.1064 | 0.4095 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1289T>G | M430R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430R is not 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, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and ESM1b. The remaining tools—FoldX, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of consensus tools lean toward a benign classification, while a subset of high‑accuracy methods suggest pathogenicity, leaving the variant’s impact ambiguous. Based on the aggregate predictions, the variant is most likely benign, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -10.636 | Likely Pathogenic | 0.558 | Ambiguous | Likely Benign | 0.98 | Ambiguous | 0.1 | 0.47 | Likely Benign | 0.73 | Ambiguous | 0.83 | Ambiguous | 0.153 | Likely Benign | -2.87 | Deleterious | 0.620 | Possibly Damaging | 0.046 | Benign | 3.48 | Benign | 0.38 | Tolerated | 0.1775 | 0.1652 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||
| c.1305G>C | L435F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote). High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain, providing no definitive evidence for either outcome. Given the preponderance of pathogenic predictions and the lack of any ClinVar annotation to contradict this assessment, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -11.871 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.51 | Ambiguous | 0.1 | 0.95 | Ambiguous | 0.73 | Ambiguous | 0.69 | Ambiguous | 0.222 | Likely Benign | -3.75 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.0587 | 0.2723 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1305G>T | L435F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (Likely Pathogenic). High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain, providing no definitive evidence for either outcome. Given the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -11.871 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.51 | Ambiguous | 0.1 | 0.95 | Ambiguous | 0.73 | Ambiguous | 0.69 | Ambiguous | 0.222 | Likely Benign | -3.75 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.0587 | 0.2723 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1336G>C | E446Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E446Q missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other folding‑stability predictions are available. Overall, the balance of evidence from the consensus of multiple in silico predictors points to a pathogenic classification for E446Q. This conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | -11.107 | Likely Pathogenic | 0.752 | Likely Pathogenic | Likely Benign | 0.92 | Ambiguous | 0.5 | 0.54 | Ambiguous | 0.73 | Ambiguous | 0.84 | Ambiguous | 0.337 | Likely Benign | -2.80 | Deleterious | 0.992 | Probably Damaging | 0.973 | Probably Damaging | 3.24 | Benign | 0.04 | Affected | 0.1049 | 0.6218 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1756G>T | D586Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D586Y missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that indicate a benign effect include FoldX, SIFT, and premPS, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome. Rosetta and Foldetta, which assess protein‑folding stability, return uncertain results and are therefore not considered evidence for either direction. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also as pathogenic, and Foldetta as uncertain. Overall, the preponderance of pathogenic predictions (13 vs. 3 benign) suggests that D586Y is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -12.916 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.37 | Likely Benign | 0.4 | 1.09 | Ambiguous | 0.73 | Ambiguous | -0.49 | Likely Benign | 0.712 | Likely Pathogenic | -5.38 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.16 | Pathogenic | 0.41 | Tolerated | 0.0623 | 0.5634 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.2101C>T | P701S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P701S (ClinVar ID 2995856.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (ID 6‑33441360‑C‑T). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). No tool in the dataset predicts a pathogenic outcome; all remaining predictions are either benign or uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.074921 | Structured | 0.404318 | Uncertain | 0.918 | 0.345 | 0.000 | Uncertain | 1 | 6-33441360-C-T | 3 | 1.86e-6 | -4.375 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 1.33 | Ambiguous | 0.0 | 0.12 | Likely Benign | 0.73 | Ambiguous | -0.36 | Likely Benign | 0.132 | Likely Benign | 0.78 | Neutral | 0.044 | Benign | 0.025 | Benign | 3.48 | Benign | 1.00 | Tolerated | 3.47 | 10 | 0.3149 | 0.3782 | -1 | 1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||
| c.2176A>G | R726G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R726G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, 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 AlphaMissense‑Default, FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain (treated as unavailable). Overall, the majority of evidence points to a benign impact for R726G, 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 | 0.521092 | Disordered | 0.449098 | Uncertain | 0.888 | 0.513 | 0.625 | -5.879 | Likely Benign | 0.528 | Ambiguous | Likely Benign | 0.80 | Ambiguous | 0.1 | 0.66 | Ambiguous | 0.73 | Ambiguous | 0.39 | Likely Benign | 0.159 | Likely Benign | -1.59 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.61 | Benign | 0.08 | Tolerated | 0.3343 | 0.3575 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||
| c.616A>G | I206V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I206V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive results are from FoldX (uncertain) and Foldetta (uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta remains uncertain. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -5.709 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 1.22 | Ambiguous | 0.1 | 0.24 | Likely Benign | 0.73 | Ambiguous | 0.40 | Likely Benign | 0.051 | Likely Benign | -0.51 | Neutral | 0.001 | Benign | 0.007 | Benign | 4.27 | Benign | 0.53 | Tolerated | 0.0833 | 0.2920 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.687A>C | K229N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K229N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. Four tools (FoldX, Rosetta, Foldetta, premPS) return uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. The variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -13.620 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.82 | Ambiguous | 0.1 | 0.64 | Ambiguous | 0.73 | Ambiguous | 0.61 | Ambiguous | 0.590 | Likely Pathogenic | -3.79 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.83 | Benign | 0.01 | Affected | 0.3682 | 0.1013 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.687A>T | K229N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K229N missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining nine tools—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is uncertain and therefore not considered evidence for or against pathogenicity. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -13.620 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.82 | Ambiguous | 0.1 | 0.64 | Ambiguous | 0.73 | Ambiguous | 0.61 | Ambiguous | 0.588 | Likely Pathogenic | -3.79 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.83 | Benign | 0.01 | Affected | 0.3682 | 0.1013 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.868C>A | L290M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L290M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, and PROVEAN, whereas pathogenic predictions are reported by polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Tools with uncertain outcomes include Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta. High‑accuracy analyses indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence leans toward a pathogenic effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.127496 | Structured | 0.399723 | Uncertain | 0.904 | 0.255 | 0.000 | -8.393 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | 0.48 | Likely Benign | 0.2 | 0.98 | Ambiguous | 0.73 | Ambiguous | 0.59 | Ambiguous | 0.438 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.92 | Pathogenic | 0.02 | Affected | 0.0823 | 0.4167 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1039A>T | T347S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictors indicate a benign effect, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | -3.342 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.65 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.74 | Ambiguous | -0.10 | Likely Benign | 0.104 | Likely Benign | 0.63 | Neutral | 0.002 | Benign | 0.001 | Benign | 1.75 | Pathogenic | 0.86 | Tolerated | 0.3205 | 0.4707 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1040C>G | T347S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictors indicate a benign effect, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | -3.342 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.65 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.74 | Ambiguous | -0.10 | Likely Benign | 0.054 | Likely Benign | 0.63 | Neutral | 0.002 | Benign | 0.001 | Benign | 1.75 | Pathogenic | 0.86 | Tolerated | 0.3205 | 0.4707 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.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.1348G>A | A450T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A450T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Because the majority of conventional tools lean toward benign and no ClinVar evidence contradicts this, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -9.149 | Likely Pathogenic | 0.380 | Ambiguous | Likely Benign | 0.50 | Ambiguous | 0.2 | 0.98 | Ambiguous | 0.74 | Ambiguous | 0.81 | Ambiguous | 0.233 | Likely Benign | -3.35 | Deleterious | 0.996 | Probably Damaging | 0.973 | Probably Damaging | 3.40 | Benign | 0.06 | Tolerated | 0.0943 | 0.5902 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.1438G>A | E480K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E480K is catalogued in gnomAD (ID 6‑33438470‑G‑A) but has no entry in ClinVar. Functional prediction tools cluster into two groups: benign predictions come from FoldX and SIFT, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results are reported by Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that E480K is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | 6-33438470-G-A | 1 | 6.20e-7 | -14.059 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 1.08 | Ambiguous | 0.74 | Ambiguous | 0.83 | Ambiguous | 0.768 | Likely Pathogenic | -3.45 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | -1.26 | Pathogenic | 0.11 | Tolerated | 3.37 | 34 | 0.1828 | 0.6813 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.1453C>A | R485S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FoldX, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that return uncertain results are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for R485S, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | Uncertain | 1 | -15.603 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 1.07 | Ambiguous | 0.74 | Ambiguous | 0.82 | Ambiguous | 0.609 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0.2968 | 0.3266 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||
| c.1862G>T | R621L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R621L has no ClinVar entry and is absent from gnomAD. Prediction tools that classify it as benign include Rosetta, premPS, and FATHMM, whereas the majority—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—label it pathogenic or likely pathogenic. FoldX and Foldetta return uncertain results and are not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, and Foldetta remains inconclusive. Overall, the consensus of the available predictions points to a pathogenic effect for R621L, 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 | 0.222385 | Structured | 0.084420 | Uncertain | 0.945 | 0.216 | 0.000 | -16.055 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 1.70 | Ambiguous | 0.3 | -0.22 | Likely Benign | 0.74 | Ambiguous | 0.34 | Likely Benign | 0.718 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.83 | Benign | 0.00 | Affected | 0.1424 | 0.3568 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1873C>A | L625I 2D AIThe SynGAP1 missense variant L625I is not 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 (premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Tools with uncertain or inconclusive results—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, the overall evidence leans toward pathogenicity, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | -11.713 | Likely Pathogenic | 0.866 | Likely Pathogenic | Ambiguous | 0.75 | Ambiguous | 0.6 | 0.72 | Ambiguous | 0.74 | Ambiguous | 1.09 | Destabilizing | 0.412 | Likely Benign | -1.96 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.06 | Benign | 0.01 | Affected | 0.0864 | 0.3588 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1904A>G | N635S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N635S is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6-33440956-A-G). Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and ESM1b. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, the majority of available predictions lean toward a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | Conflicting | 4 | 6-33440956-A-G | 10 | 6.20e-6 | -9.002 | Likely Pathogenic | 0.101 | Likely Benign | Likely Benign | 0.80 | Ambiguous | 0.1 | 0.67 | Ambiguous | 0.74 | Ambiguous | 0.95 | Ambiguous | 0.104 | Likely Benign | -4.45 | Deleterious | 0.261 | Benign | 0.044 | Benign | 3.06 | Benign | 0.05 | Affected | 3.37 | 34 | 0.2816 | 0.4279 | 1 | 1 | 2.7 | -27.03 | 196.0 | 30.9 | 0.1 | 0.0 | -0.3 | 0.2 | X | Uncertain | In the WT simulations, the carboxamide side chain of Asn635, located on the outer surface of an α helix (res. Glu617-Asn635), forms hydrogen bonds with Gln631 on the same α helix and with the hydroxyl side chain of Ser590 on an opposing α helix (res. Glu582-Met603).In the variant simulations, the side chain of Ser635 is shorter than asparagine and thus prefers to hydrogen bond with the carbonyl group of Gln631 on the same helix and, to a lesser extent, with Ser590 compared to Asn635 in the WT. Ser635 forms hydrogen bonds with the backbone atoms of the same helix, which may destabilize the helix, although this is not clearly evident in the simulations. The weakening of the hydrogen bond between Ser635 and Ser590 in the variant may also weaken the tertiary structure assembly between the helices.Additionally, Asn635 is at the GTPase interface. However, the implication of the residue swap on the complex formation with the GTPase cannot be investigated using solvent-only simulations. | ||||||||||||||
| c.2060G>T | R687L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R687L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign include REVEL, SIFT, ESM1b, and FATHMM, while those that agree on pathogenic are AlphaMissense‑Default, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The remaining tools—AlphaMissense‑Optimized, FoldX, Foldetta, and premPS—return uncertain or inconclusive results. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. Consequently, the evidence does not strongly support either benign or pathogenic classification. The variant is therefore most likely inconclusive, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.054297 | Structured | 0.191060 | Uncertain | 0.914 | 0.259 | 0.000 | -6.925 | Likely Benign | 0.901 | Likely Pathogenic | Ambiguous | 1.43 | Ambiguous | 0.3 | 0.05 | Likely Benign | 0.74 | Ambiguous | 0.83 | Ambiguous | 0.448 | Likely Benign | -5.76 | Deleterious | 1.000 | Probably Damaging | 0.987 | Probably Damaging | 3.90 | Benign | 0.10 | Tolerated | 0.1252 | 0.3376 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||
| c.2173C>A | L725M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L725M is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Uncertain or inconclusive predictions come from Foldetta, premPS, AlphaMissense‑Default, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic (2 pathogenic vs. 1 benign). Foldetta remains uncertain and is not used as evidence. Overall, the majority of tools, including the high‑accuracy consensus, predict a pathogenic impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.557691 | Disordered | 0.455613 | Uncertain | 0.911 | 0.491 | 0.625 | -9.531 | Likely Pathogenic | 0.436 | Ambiguous | Likely Benign | 0.42 | Likely Benign | 0.1 | 1.05 | Ambiguous | 0.74 | Ambiguous | 0.80 | Ambiguous | 0.172 | Likely Benign | -1.81 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.32 | Pathogenic | 0.04 | Affected | 0.0854 | 0.4156 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||
| c.2186A>G | N729S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Across the available in‑silico predictors, the majority (REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as benign, while Rosetta and Foldetta return uncertain results. No tool predicts pathogenicity. High‑accuracy assessments reinforce this benign trend: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta’s stability prediction is inconclusive. Overall, the computational evidence strongly supports a benign effect, and this does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | Conflicting | 2 | -1.578 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.14 | Likely Benign | 0.1 | 1.34 | Ambiguous | 0.74 | Ambiguous | -0.36 | Likely Benign | 0.063 | Likely Benign | -0.42 | Neutral | 0.221 | Benign | 0.027 | Benign | 3.38 | Benign | 0.93 | Tolerated | 3.59 | 7 | 0.3411 | 0.4854 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||
| c.625G>A | V209M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V209M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Five tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -8.112 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.70 | Ambiguous | 0.4 | 0.77 | Ambiguous | 0.74 | Ambiguous | 0.78 | Ambiguous | 0.115 | Likely Benign | -1.48 | Neutral | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 3.68 | Benign | 0.02 | Affected | 0.0669 | 0.3982 | 2 | 1 | -2.3 | 32.06 | ||||||||||||||||||||||||||||||
| c.674C>T | S225L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S225L is reported in gnomAD (6‑33435525‑C‑T) but has no ClinVar entry. In silico predictors that agree on a benign effect include REVEL, FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only PROVEAN predicts a pathogenic outcome. Predictions that are inconclusive are Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign effect for S225L, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.150080 | Structured | 0.344191 | Uncertain | 0.817 | 0.319 | 0.250 | 6-33435525-C-T | 1 | 6.20e-7 | -6.644 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.29 | Likely Benign | 0.4 | 1.18 | Ambiguous | 0.74 | Ambiguous | 0.18 | Likely Benign | 0.320 | Likely Benign | -3.76 | Deleterious | 0.000 | Benign | 0.001 | Benign | 5.70 | Benign | 0.28 | Tolerated | 3.41 | 13 | 0.1039 | 0.6554 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||||||
| c.786T>A | N262K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262K has no ClinVar entry and is not present in gnomAD. Prediction tools that indicate a benign effect include FoldX, premPS, and FATHMM. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic impact for N262K. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.284882 | Structured | 0.399879 | Uncertain | 0.912 | 0.240 | 0.000 | -12.512 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.47 | Likely Benign | 0.2 | 1.00 | Ambiguous | 0.74 | Ambiguous | 0.33 | Likely Benign | 0.531 | Likely Pathogenic | -5.13 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 5.84 | Benign | 0.02 | Affected | 0.1799 | 0.3413 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.786T>G | N262K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262K has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely disagree: benign predictions come from FoldX, premPS, and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and Foldetta. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Taken together, the majority of evidence points to a pathogenic effect for N262K. This conclusion is consistent with the absence of a ClinVar classification, as there is no existing report to contradict the prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.284882 | Structured | 0.399879 | Uncertain | 0.912 | 0.240 | 0.000 | -12.512 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.47 | Likely Benign | 0.2 | 1.00 | Ambiguous | 0.74 | Ambiguous | 0.33 | Likely Benign | 0.532 | Likely Pathogenic | -5.13 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 5.84 | Benign | 0.02 | Affected | 0.1799 | 0.3413 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.853T>A | C285S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285S has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas a majority of the remaining predictors (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default) indicate a pathogenic impact. The remaining tools (FoldX, Rosetta, Foldetta, ESM1b, AlphaMissense‑Optimized) return uncertain results, which are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -7.149 | In-Between | 0.868 | Likely Pathogenic | Ambiguous | 0.73 | Ambiguous | 0.1 | 0.75 | Ambiguous | 0.74 | Ambiguous | 1.20 | Destabilizing | 0.507 | Likely Pathogenic | -8.09 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.90 | Pathogenic | 0.08 | Tolerated | 0.5210 | 0.2038 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||
| c.854G>C | C285S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and SIFT, whereas premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. Predictions from FoldX, Rosetta, ESM1b, AlphaMissense‑Optimized, and Foldetta are inconclusive. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic classification; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for C285S, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -7.149 | In-Between | 0.868 | Likely Pathogenic | Ambiguous | 0.73 | Ambiguous | 0.1 | 0.75 | Ambiguous | 0.74 | Ambiguous | 1.20 | Destabilizing | 0.499 | Likely Benign | -8.09 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.90 | Pathogenic | 0.08 | Tolerated | 0.5210 | 0.2038 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||
| c.1033C>G | L345V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L345V missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, Rosetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans toward benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.260850 | Structured | 0.354989 | Uncertain | 0.936 | 0.478 | 0.125 | -6.594 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 1.31 | Ambiguous | 0.0 | 0.18 | Likely Benign | 0.75 | Ambiguous | 0.92 | Ambiguous | 0.126 | Likely Benign | -1.96 | Neutral | 0.802 | Possibly Damaging | 0.277 | Benign | 1.77 | Pathogenic | 0.06 | Tolerated | 0.1411 | 0.3455 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1256A>C | E419A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E419A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -10.951 | Likely Pathogenic | 0.944 | Likely Pathogenic | Ambiguous | 0.56 | Ambiguous | 0.1 | 0.94 | Ambiguous | 0.75 | Ambiguous | 0.28 | Likely Benign | 0.398 | Likely Benign | -5.60 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.32 | Benign | 0.03 | Affected | 0.4051 | 0.6705 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1501A>G | I501V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions from FoldX, Rosetta, and Foldetta are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for I501V, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -2.326 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.94 | Ambiguous | 0.0 | 0.56 | Ambiguous | 0.75 | Ambiguous | 0.06 | Likely Benign | 0.200 | Likely Benign | 0.20 | Neutral | 0.951 | Possibly Damaging | 0.960 | Probably Damaging | 3.52 | Benign | 1.00 | Tolerated | 0.0985 | 0.2491 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.1645T>G | L549V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L549V is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include Rosetta, PROVEAN, and SIFT, whereas a majority of tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default) predict a pathogenic impact. Four tools (FoldX, Foldetta, premPS, and AlphaMissense‑Optimized) give uncertain or inconclusive results. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic interpretation. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.007921 | Uncertain | 0.955 | 0.281 | 0.000 | -9.379 | Likely Pathogenic | 0.847 | Likely Pathogenic | Ambiguous | 1.22 | Ambiguous | 0.3 | 0.27 | Likely Benign | 0.75 | Ambiguous | 0.88 | Ambiguous | 0.544 | Likely Pathogenic | -2.32 | Neutral | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.23 | Pathogenic | 0.21 | Tolerated | 0.1400 | 0.1860 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1697A>C | K566T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K566T missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only Rosetta, which scores the variant as benign. All other evaluated predictors—REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized—classify the variant as pathogenic. FoldX, Foldetta, and premPS are inconclusive, giving uncertain results. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for K566T, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.047887 | Uncertain | 0.924 | 0.219 | 0.000 | -12.866 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 1.70 | Ambiguous | 0.2 | -0.21 | Likely Benign | 0.75 | Ambiguous | 0.99 | Ambiguous | 0.788 | Likely Pathogenic | -5.37 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.43 | Pathogenic | 0.04 | Affected | 0.1804 | 0.3847 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.2047A>G | I683V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683V is listed in ClinVar with an uncertain significance and is present in gnomAD (6‑33441306‑A‑G). Across a panel of in silico predictors, the majority indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (derived from a majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only polyPhen‑2 HumDiv classifies the change as pathogenic. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote) is benign, and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is inconclusive and therefore not considered evidence. No other tool provides a pathogenic signal. Consequently, the variant is most likely benign, and this assessment does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | Uncertain | 1 | 6-33441306-A-G | 2 | 1.24e-6 | -7.588 | In-Between | 0.138 | Likely Benign | Likely Benign | 0.90 | Ambiguous | 0.0 | 0.60 | Ambiguous | 0.75 | Ambiguous | 0.76 | Ambiguous | 0.112 | Likely Benign | -0.78 | Neutral | 0.538 | Possibly Damaging | 0.080 | Benign | 3.35 | Benign | 0.14 | Tolerated | 3.42 | 17 | 0.1021 | 0.2898 | 4 | 3 | -0.3 | -14.03 | 215.6 | 29.1 | 0.0 | 0.0 | -0.7 | 0.1 | X | Potentially Benign | The sec-butyl side chain of Ile683, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is sterically packed against His453 and Glu688. In the variant simulations, the iso-propyl side chain of Val683 has similar size and physicochemical properties as Ile630 in the WT, and thus, it is able to maintain similar interactions in the inter-helix space. Consequently, no negative structural effects are observed during the simulations due to the residue swap. | |||||||||||||
| c.2128A>G | K710E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K710E missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.321458 | Structured | 0.370438 | Uncertain | 0.949 | 0.368 | 0.000 | -11.405 | Likely Pathogenic | 0.885 | Likely Pathogenic | Ambiguous | 0.56 | Ambiguous | 0.0 | 0.94 | Ambiguous | 0.75 | Ambiguous | 0.39 | Likely Benign | 0.178 | Likely Benign | -3.53 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 3.45 | Benign | 0.08 | Tolerated | 0.2655 | 0.0789 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.2131C>A | L711M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L711M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta reports an uncertain stability change, which is treated as unavailable evidence. Overall, the majority of individual predictors (six pathogenic vs. five benign) and the available high‑accuracy results lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.308712 | Structured | 0.377436 | Uncertain | 0.950 | 0.364 | 0.000 | -9.368 | Likely Pathogenic | 0.679 | Likely Pathogenic | Likely Benign | 0.39 | Likely Benign | 0.0 | 1.11 | Ambiguous | 0.75 | Ambiguous | 1.40 | Destabilizing | 0.216 | Likely Benign | -1.86 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.34 | Benign | 0.00 | Affected | 0.0755 | 0.2758 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.2144C>T | P715L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P715L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX and premPS give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Because the majority of consensus and individual predictors indicate pathogenicity, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, which contains no entry for P715L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | -12.207 | Likely Pathogenic | 0.764 | Likely Pathogenic | Likely Benign | 1.43 | Ambiguous | 0.1 | 0.06 | Likely Benign | 0.75 | Ambiguous | 0.58 | Ambiguous | 0.318 | Likely Benign | -9.10 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.1944 | 0.5105 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.911A>T | D304V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304V missense variant is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include Rosetta and premPS, while the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for D304V. This conclusion is not contradicted by ClinVar, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -8.280 | Likely Pathogenic | 0.803 | Likely Pathogenic | Ambiguous | 1.35 | Ambiguous | 0.3 | 0.14 | Likely Benign | 0.75 | Ambiguous | 0.35 | Likely Benign | 0.541 | Likely Pathogenic | -6.22 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.81 | Pathogenic | 0.00 | Affected | 0.0971 | 0.6999 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1746G>C | E582D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E582D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: a benign group comprising REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, and a pathogenic group containing polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Remaining tools (FoldX, Rosetta, ESM1b, AlphaMissense‑Default) yield uncertain results and are treated as unavailable. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans toward benign, and Foldetta indicates no significant destabilization. Consequently, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.102787 | Structured | 0.033838 | Uncertain | 0.845 | 0.235 | 0.000 | -7.974 | In-Between | 0.520 | Ambiguous | Likely Benign | 0.57 | Ambiguous | 0.2 | 0.95 | Ambiguous | 0.76 | Ambiguous | 0.40 | Likely Benign | 0.093 | Likely Benign | -1.63 | Neutral | 0.986 | Probably Damaging | 0.989 | Probably Damaging | 3.22 | Benign | 0.27 | Tolerated | 0.1481 | 0.2236 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1746G>T | E582D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E582D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: a benign group comprising REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, and a pathogenic group consisting of polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Remaining tools (FoldX, Rosetta, ESM1b, AlphaMissense‑Default) yield uncertain results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because two of the four inputs are uncertain; Foldetta, which integrates FoldX‑MD and Rosetta outputs, also reports an uncertain stability change. Consequently, the preponderance of evidence points to a benign effect. This conclusion aligns with the absence of a ClinVar assertion, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.102787 | Structured | 0.033838 | Uncertain | 0.845 | 0.235 | 0.000 | -7.974 | In-Between | 0.520 | Ambiguous | Likely Benign | 0.57 | Ambiguous | 0.2 | 0.95 | Ambiguous | 0.76 | Ambiguous | 0.40 | Likely Benign | 0.093 | Likely Benign | -1.63 | Neutral | 0.986 | Probably Damaging | 0.989 | Probably Damaging | 3.22 | Benign | 0.27 | Tolerated | 0.1481 | 0.2236 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1850A>T | E617V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617V has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into benign (premPS, SIFT) and pathogenic (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default). Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments reinforce the pathogenic signal: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic, while AlphaMissense‑Optimized remains uncertain and Foldetta is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E617V. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | -10.826 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 0.60 | Ambiguous | 0.1 | 0.92 | Ambiguous | 0.76 | Ambiguous | 0.28 | Likely Benign | 0.816 | Likely Pathogenic | -5.71 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | -1.47 | Pathogenic | 0.13 | Tolerated | 0.0587 | 0.6503 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.601G>A | D201N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The remaining tools—Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default—return uncertain results and are treated as unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is unavailable because two of the four inputs are uncertain. Foldetta also yields an uncertain result and is unavailable. Overall, the preponderance of evidence points to a benign impact for D201N, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -7.686 | In-Between | 0.525 | Ambiguous | Likely Benign | 0.31 | Likely Benign | 0.0 | 1.21 | Ambiguous | 0.76 | Ambiguous | -0.10 | Likely Benign | 0.160 | Likely Benign | -2.36 | Neutral | 0.996 | Probably Damaging | 0.877 | Possibly Damaging | 4.08 | Benign | 0.13 | Tolerated | 0.0911 | 0.5413 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.868C>G | L290V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L290V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and Rosetta, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, premPS, ESM1b, AlphaMissense‑Optimized, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence from multiple pathogenic‑predicting tools and the SGM Consensus suggests that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.127496 | Structured | 0.399723 | Uncertain | 0.904 | 0.255 | 0.000 | -7.392 | In-Between | 0.834 | Likely Pathogenic | Ambiguous | 1.17 | Ambiguous | 0.1 | 0.35 | Likely Benign | 0.76 | Ambiguous | 0.62 | Ambiguous | 0.366 | Likely Benign | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.98 | Pathogenic | 0.05 | Affected | 0.1574 | 0.4177 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.916G>A | V306I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant V306I is listed in ClinVar with an uncertain significance (ClinVar ID 4708871) and is present in gnomAD (ID 6‑33437821‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and Rosetta. Tools that predict a pathogenic outcome 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 indicates a likely benign effect; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports an uncertain result and is therefore not considered evidence for or against pathogenicity. Overall, the majority of predictions support a benign classification, 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 | 0.363090 | Structured | 0.315026 | Uncertain | 0.896 | 0.287 | 0.125 | Conflicting | 2 | 6-33437821-G-A | 11 | 6.82e-6 | -5.989 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 1.13 | Ambiguous | 0.2 | 0.38 | Likely Benign | 0.76 | Ambiguous | 0.19 | Likely Benign | 0.154 | Likely Benign | -0.17 | Neutral | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 1.75 | Pathogenic | 0.36 | Tolerated | 3.38 | 19 | 0.0603 | 0.3461 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||||
| c.995A>C | D332A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and Rosetta, while the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -12.290 | Likely Pathogenic | 0.876 | Likely Pathogenic | Ambiguous | 1.19 | Ambiguous | 0.2 | 0.32 | Likely Benign | 0.76 | Ambiguous | 0.54 | Ambiguous | 0.458 | Likely Benign | -6.45 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.24 | Pathogenic | 0.02 | Affected | 0.2998 | 0.4176 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1465C>A | L489I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into three groups: benign predictions come from REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; the remaining methods (FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default) yield uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is indeterminate due to a tie between pathogenic and benign signals, and Foldetta reports an uncertain stability change. Overall, the preponderance of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | -7.333 | In-Between | 0.342 | Ambiguous | Likely Benign | 1.01 | Ambiguous | 0.0 | 0.52 | Ambiguous | 0.77 | Ambiguous | 0.90 | Ambiguous | 0.490 | Likely Benign | -1.55 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.42 | Pathogenic | 0.21 | Tolerated | 0.1069 | 0.4080 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1618C>G | Q540E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q540E is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated tools—REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus majority vote—predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX and Rosetta individually also returned uncertain results. Based on the overall consensus of the majority of prediction algorithms, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.029522 | Uncertain | 0.958 | 0.371 | 0.000 | -14.417 | Likely Pathogenic | 0.622 | Likely Pathogenic | Likely Benign | 0.69 | Ambiguous | 0.1 | 0.85 | Ambiguous | 0.77 | Ambiguous | 0.80 | Ambiguous | 0.747 | Likely Pathogenic | -2.98 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | -1.32 | Pathogenic | 0.04 | Affected | 0.1171 | 0.1337 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1658A>C | K553T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K553T is listed in ClinVar with an uncertain significance (ClinVar ID 2007142.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include Rosetta and SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, both polyPhen‑2 HumDiv and HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the consensus of the available predictions indicates that K553T is most likely pathogenic, which does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.012270 | Structured | 0.006539 | Uncertain | 0.949 | 0.246 | 0.000 | Uncertain | 1 | -15.328 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.06 | Ambiguous | 0.2 | 0.48 | Likely Benign | 0.77 | Ambiguous | 0.79 | Ambiguous | 0.761 | Likely Pathogenic | -5.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.34 | Pathogenic | 0.14 | Tolerated | 3.37 | 35 | 0.1733 | 0.2619 | 0 | -1 | 3.2 | -27.07 | 218.2 | -10.7 | 0.0 | 0.0 | -0.2 | 0.5 | X | Potentially Pathogenic | Lys533 is located on an α-helix (res. Ala533-Val560). In the WT simulations, Lys533 packs against Phe513, and its amino side chain occasionally forms an ionic interaction with the carboxylate group of Glu512 from an opposing α-helix (res. Gln503-Tyr518). In the variant simulations, Thr533 is unable to reproduce these interactions, potentially weakening the integrity of the tertiary structure. Additionally, Thr533 forms a hydrogen bond with the backbone carbonyl group of Leu549 in the same helix, which could potentially weaken the secondary structure. Regardless, the residue swap does not cause significant structural effects based on the simulations. | ||||||||||||||||
| c.1699G>C | E567Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E567Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that agree on a pathogenic effect are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results come from AlphaMissense‑Optimized, Foldetta, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta’s stability prediction is also uncertain. Overall, more tools (7) predict pathogenicity than benign (5), with three inconclusive. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.021816 | Structured | 0.051008 | Uncertain | 0.916 | 0.234 | 0.000 | -11.302 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 0.03 | Likely Benign | 0.1 | 1.50 | Ambiguous | 0.77 | Ambiguous | 0.33 | Likely Benign | 0.345 | Likely Benign | -2.82 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 3.47 | Benign | 0.14 | Tolerated | 0.1029 | 0.5391 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1783C>G | L595V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L595V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, and FATHMM, while pathogenic calls are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions marked uncertain include FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy consensus methods give a clearer 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) is also inconclusive. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.015344 | Structured | 0.128444 | Uncertain | 0.920 | 0.150 | 0.000 | -13.490 | Likely Pathogenic | 0.905 | Likely Pathogenic | Ambiguous | 1.29 | Ambiguous | 0.1 | 0.24 | Likely Benign | 0.77 | Ambiguous | 1.01 | Destabilizing | 0.398 | Likely Benign | -2.99 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 2.78 | Benign | 0.01 | Affected | 0.1441 | 0.3406 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1834C>G | Q612E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q612E is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). In silico predictors that agree on a benign effect include REVEL, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictors that agree on a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. FoldX, Rosetta, and Foldetta are inconclusive, with Foldetta specifically yielding an uncertain stability change. High‑accuracy tools give a mixed picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of consensus‑based and high‑accuracy predictions lean toward pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.203988 | Uncertain | 0.822 | 0.263 | 0.000 | -12.179 | Likely Pathogenic | 0.338 | Likely Benign | Likely Benign | 0.52 | Ambiguous | 0.4 | 1.01 | Ambiguous | 0.77 | Ambiguous | 1.03 | Destabilizing | 0.423 | Likely Benign | -2.89 | Deleterious | 0.995 | Probably Damaging | 0.981 | Probably Damaging | -1.17 | Pathogenic | 0.26 | Tolerated | 0.1393 | 0.2099 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| 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.911A>C | D304A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304A variant has no ClinVar entry and is not listed in gnomAD. Prediction tools that classify it as benign include premPS, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact. This prediction does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -6.258 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 1.00 | Ambiguous | 0.1 | 0.54 | Ambiguous | 0.77 | Ambiguous | 0.39 | Likely Benign | 0.523 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.80 | Pathogenic | 0.02 | Affected | 0.4457 | 0.6642 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1033C>A | L345M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L345M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a benign outcome; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is uncertain. Overall, the majority of evidence points to a benign impact for the L345M variant, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.260850 | Structured | 0.354989 | Uncertain | 0.936 | 0.478 | 0.125 | -3.918 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.75 | Ambiguous | 0.1 | 0.80 | Ambiguous | 0.78 | Ambiguous | 0.54 | Ambiguous | 0.101 | Likely Benign | -0.97 | Neutral | 0.802 | Possibly Damaging | 0.122 | Benign | 1.73 | Pathogenic | 0.07 | Tolerated | 0.0677 | 0.3246 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1231A>G | I411V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411V is reported in ClinVar as benign (ClinVar ID 1654508.0) and is not found in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Two tools predict a pathogenic outcome: PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. Predictions that are inconclusive or unavailable are AlphaMissense‑Default, FoldX, Rosetta, premPS, and Foldetta. 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) is uncertain. Overall, the preponderance of evidence points to a benign effect for I411V, which is consistent with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | Likely Benign | 1 | -6.290 | Likely Benign | 0.385 | Ambiguous | Likely Benign | 0.74 | Ambiguous | 0.0 | 0.82 | Ambiguous | 0.78 | Ambiguous | 0.99 | Ambiguous | 0.212 | Likely Benign | -0.86 | Neutral | 0.935 | Possibly Damaging | 0.858 | Possibly Damaging | 3.90 | Benign | 0.27 | Tolerated | 3.38 | 28 | 0.1112 | 0.3526 | 4 | 3 | -0.3 | -14.03 | 233.3 | 28.2 | -0.2 | 0.0 | -0.2 | 0.0 | X | Potentially Benign | The sec-butyl side chain of Ile411, located in the hydrophobic space between an anti-parallel β sheet strand (res. Pro398-Ile411) and an α helix (res. Asp684-Gln702), packs against multiple residues (e.g., Met409, Arg259). In the variant simulations, the side chain of Val411 is able to favorably fill the same hydrophobic niche despite its slightly smaller size. In short, the residue swap has no apparent negative effect on the structure based on the simulations. | ||||||||||||||||
| c.1525G>A | A509T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain and therefore unavailable for interpretation. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -8.961 | Likely Pathogenic | 0.171 | Likely Benign | Likely Benign | 0.95 | Ambiguous | 0.4 | 0.61 | Ambiguous | 0.78 | Ambiguous | 0.04 | Likely Benign | 0.360 | Likely Benign | -2.15 | Neutral | 0.031 | Benign | 0.058 | Benign | -1.25 | Pathogenic | 0.32 | Tolerated | 0.1344 | 0.5593 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.1580A>T | D527V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D527V missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that are uncertain (FoldX, Rosetta, Foldetta, premPS) provide no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, while Foldetta remains uncertain. Overall, the majority of reliable predictors classify the variant as pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Thus, based on current computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -16.844 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.71 | Ambiguous | 0.7 | 0.84 | Ambiguous | 0.78 | Ambiguous | -0.55 | Ambiguous | 0.938 | Likely Pathogenic | -8.78 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | -2.40 | Pathogenic | 0.00 | Affected | 0.0659 | 0.3984 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1606T>A | L536M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L536M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | -10.124 | Likely Pathogenic | 0.462 | Ambiguous | Likely Benign | 0.37 | Likely Benign | 0.1 | 1.18 | Ambiguous | 0.78 | Ambiguous | 0.93 | Ambiguous | 0.571 | Likely Pathogenic | -1.94 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 0.0937 | 0.3299 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1849G>A | E617K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617K is not reported in ClinVar but is present in gnomAD (6‑33440901‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from FoldX, premPS, and SIFT, while pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. A third set of methods (Foldetta, AlphaMissense‑Optimized, Rosetta) yield uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect for E617K, 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 | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | 6-33440901-G-A | 1 | 6.20e-7 | -10.702 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.37 | Likely Benign | 0.1 | 1.19 | Ambiguous | 0.78 | Ambiguous | 0.17 | Likely Benign | 0.534 | Likely Pathogenic | -3.32 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | -1.34 | Pathogenic | 0.48 | Tolerated | 3.37 | 35 | 0.1981 | 0.6282 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.1882A>G | K628E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K628E 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 pathogenic effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that are inconclusive or uncertain are FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Overall, the majority of evidence points to a deleterious effect. The variant is most likely pathogenic based on these predictions, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.035486 | Uncertain | 0.957 | 0.229 | 0.000 | -14.658 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.04 | Ambiguous | 0.2 | 0.52 | Ambiguous | 0.78 | Ambiguous | 1.06 | Destabilizing | 0.652 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.37 | Pathogenic | 0.00 | Affected | 0.2909 | 0.0810 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.854G>T | C285F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome; Foldetta is uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence (12 pathogenic vs. 3 benign predictions) indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -9.397 | Likely Pathogenic | 0.716 | Likely Pathogenic | Likely Benign | 3.27 | Destabilizing | 1.1 | -1.72 | Ambiguous | 0.78 | Ambiguous | 0.35 | Likely Benign | 0.500 | Likely Pathogenic | -8.84 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.81 | Pathogenic | 0.12 | Tolerated | 0.1626 | 0.4007 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.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.1294T>A | C432S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C432S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools (SGM Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show SGM Consensus as likely pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification for C432S, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -8.229 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.61 | Ambiguous | 0.1 | 0.96 | Ambiguous | 0.79 | Ambiguous | 1.52 | Destabilizing | 0.496 | Likely Benign | -9.55 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.53 | Benign | 0.12 | Tolerated | 0.4262 | 0.1415 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1295G>C | C432S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C432S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools (SGM Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show SGM Consensus as likely pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification for C432S, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -8.229 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.61 | Ambiguous | 0.1 | 0.96 | Ambiguous | 0.79 | Ambiguous | 1.52 | Destabilizing | 0.417 | Likely Benign | -9.55 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.53 | Benign | 0.12 | Tolerated | 0.4262 | 0.1415 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1366C>G | Q456E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remaining uncertain. Overall, the predictions are split, but the high‑accuracy consensus leans toward pathogenicity. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -12.982 | Likely Pathogenic | 0.503 | Ambiguous | Likely Benign | 0.71 | Ambiguous | 0.1 | 0.87 | Ambiguous | 0.79 | Ambiguous | 0.65 | Ambiguous | 0.233 | Likely Benign | -2.76 | Deleterious | 0.998 | Probably Damaging | 0.964 | Probably Damaging | 3.41 | Benign | 0.15 | Tolerated | 0.1191 | 0.1276 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.1378A>C | K460Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K460Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, SIFT, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive include FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments give a pathogenic consensus from the SGM method (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and an uncertain result from AlphaMissense‑Optimized; Foldetta likewise reports no definitive stability change. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -9.404 | Likely Pathogenic | 0.793 | Likely Pathogenic | Ambiguous | 0.71 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.79 | Ambiguous | 0.86 | Ambiguous | 0.312 | Likely Benign | -3.15 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 3.35 | Benign | 0.14 | Tolerated | 0.4523 | 0.1454 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1408A>C | M470L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M470L is listed in ClinVar as benign (ClinVar ID 536996.0) and is present in gnomAD (variant ID 6‑33438440‑A‑C). Functional prediction tools cluster into two groups: benign predictions come from SIFT and AlphaMissense‑Optimized, while pathogenic predictions are made by REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No definitive folding‑stability change is reported by FoldX or Rosetta individually. Overall, the majority of predictive algorithms favor a pathogenic effect, directly contradicting the benign classification in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | Likely Benign | 1 | 6-33438440-A-C | 1 | 6.20e-7 | -8.993 | Likely Pathogenic | 0.406 | Ambiguous | Likely Benign | 0.73 | Ambiguous | 0.1 | 0.84 | Ambiguous | 0.79 | Ambiguous | 1.04 | Destabilizing | 0.678 | Likely Pathogenic | -2.72 | Deleterious | 0.484 | Possibly Damaging | 0.654 | Possibly Damaging | -1.22 | Pathogenic | 0.16 | Tolerated | 3.37 | 34 | 0.1192 | 0.4071 | 4 | 2 | 1.9 | -18.03 | 225.3 | 17.9 | 0.0 | 0.0 | -0.8 | 0.5 | X | Potentially Benign | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, Met470 also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the iso-butyl side chain of Leu470 packs similarly with the hydrophobic residues as methionine, resulting in no negative effects on the protein structure during the simulation. | |||||||||||||
| c.1408A>T | M470L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M470L is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on benign effect include SIFT and AlphaMissense‑Optimized. Tools that agree on pathogenic effect include SGM Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. AlphaMissense‑Default, FoldX, Rosetta, and Foldetta are inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, whereas the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -8.993 | Likely Pathogenic | 0.406 | Ambiguous | Likely Benign | 0.73 | Ambiguous | 0.1 | 0.84 | Ambiguous | 0.79 | Ambiguous | 1.04 | Destabilizing | 0.678 | Likely Pathogenic | -2.72 | Deleterious | 0.484 | Possibly Damaging | 0.654 | Possibly Damaging | -1.22 | Pathogenic | 0.16 | Tolerated | 3.37 | 34 | 0.1192 | 0.4071 | 4 | 2 | 1.9 | -18.03 | 225.3 | 17.9 | 0.0 | 0.0 | -0.8 | 0.5 | X | Potentially Benign | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, Met470 also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the iso-butyl side chain of Leu470 packs similarly with the hydrophobic residues as methionine, resulting in no negative effects on the protein structure during the simulation. | ||||||||||||||||||
| c.1444C>T | L482F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX and premPS, while pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further reveal AlphaMissense‑Optimized as Uncertain, SGM Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for L482F. This conclusion is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -11.257 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.48 | Likely Benign | 0.0 | 1.09 | Ambiguous | 0.79 | Ambiguous | 0.43 | Likely Benign | 0.724 | Likely Pathogenic | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | -1.22 | Pathogenic | 0.01 | Affected | 0.0457 | 0.1814 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1856C>A | T619N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T619N has no ClinVar entry and is not reported in gnomAD. Prediction tools that assess pathogenicity all lean toward a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.219301 | Structured | 0.119723 | Uncertain | 0.929 | 0.237 | 0.000 | -11.796 | Likely Pathogenic | 0.900 | Likely Pathogenic | Ambiguous | 0.61 | Ambiguous | 0.1 | 0.96 | Ambiguous | 0.79 | Ambiguous | 1.23 | Destabilizing | 0.715 | Likely Pathogenic | -4.61 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.38 | Pathogenic | 0.05 | Affected | 0.0998 | 0.2690 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.1906T>C | F636L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F636L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus confirms Likely Pathogenic, and the Foldetta stability analysis is inconclusive. Other stability tools (FoldX, Rosetta, premPS) are uncertain. Based on the preponderance of pathogenic predictions and the consensus from high‑accuracy methods, 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 | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | -11.871 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.88 | Ambiguous | 0.1 | 0.69 | Ambiguous | 0.79 | Ambiguous | 0.71 | Ambiguous | 0.478 | Likely Benign | -5.78 | Deleterious | 0.994 | Probably Damaging | 0.952 | Probably Damaging | 3.60 | Benign | 0.22 | Tolerated | 0.1853 | 0.3024 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1908T>A | F636L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F636L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus confirms Likely Pathogenic, and the Foldetta stability analysis is inconclusive. Other stability tools (FoldX, Rosetta, premPS) are uncertain. Based on the preponderance of pathogenic predictions and the consensus from high‑accuracy methods, 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 | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | -11.871 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.88 | Ambiguous | 0.1 | 0.69 | Ambiguous | 0.79 | Ambiguous | 0.71 | Ambiguous | 0.268 | Likely Benign | -5.78 | Deleterious | 0.994 | Probably Damaging | 0.952 | Probably Damaging | 3.60 | Benign | 0.22 | Tolerated | 0.1853 | 0.3024 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1908T>G | F636L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F636L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, SIFT, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus confirms a Likely Pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from FoldX‑MD, Rosetta, or premPS is available to alter this view. Overall, the majority of reliable predictors indicate a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | -11.871 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.88 | Ambiguous | 0.1 | 0.69 | Ambiguous | 0.79 | Ambiguous | 0.71 | Ambiguous | 0.268 | Likely Benign | -5.78 | Deleterious | 0.994 | Probably Damaging | 0.952 | Probably Damaging | 3.60 | Benign | 0.22 | Tolerated | 0.1853 | 0.3024 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1912A>G | K638E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K638E is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are uncertain or unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.098064 | Uncertain | 0.937 | 0.260 | 0.000 | -13.390 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 0.57 | Ambiguous | 0.0 | 1.00 | Ambiguous | 0.79 | Ambiguous | 0.32 | Likely Benign | 0.363 | Likely Benign | -3.70 | Deleterious | 0.995 | Probably Damaging | 0.947 | Probably Damaging | 3.50 | Benign | 0.12 | Tolerated | 0.3036 | 0.0790 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.2101C>G | P701A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P701A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; all of these classify the substitution as benign. No tool predicts a pathogenic outcome. Predictions that are inconclusive are FoldX (uncertain) and Foldetta (uncertain). High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta remains uncertain. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.074921 | Structured | 0.404318 | Uncertain | 0.918 | 0.345 | 0.000 | -6.836 | Likely Benign | 0.217 | Likely Benign | Likely Benign | 1.35 | Ambiguous | 0.0 | 0.23 | Likely Benign | 0.79 | Ambiguous | -0.16 | Likely Benign | 0.058 | Likely Benign | -0.55 | Neutral | 0.002 | Benign | 0.011 | Benign | 3.50 | Benign | 0.82 | Tolerated | 0.3143 | 0.3765 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.2182C>G | P728A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P728A is 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, whereas the majority of tools predict a pathogenic effect: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta is uncertain. Overall, the preponderance of evidence from multiple in silico tools 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 | 0.632174 | Disordered | 0.434760 | Uncertain | 0.725 | 0.567 | 0.625 | -9.350 | Likely Pathogenic | 0.800 | Likely Pathogenic | Ambiguous | 0.78 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.79 | Ambiguous | 0.69 | Ambiguous | 0.277 | Likely Benign | -6.59 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 0.68 | Pathogenic | 0.00 | Affected | 0.3568 | 0.3148 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||
| c.688T>G | C230G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reached a consensus fall into two groups: benign predictions come from polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain or inconclusive results from FoldX, Rosetta, Foldetta, and premPS are treated as unavailable and do not influence the overall assessment. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also Likely Pathogenic; Foldetta remains uncertain. Based on the aggregate predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -10.888 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.1 | 0.86 | Ambiguous | 0.79 | Ambiguous | 0.81 | Ambiguous | 0.775 | Likely Pathogenic | -9.95 | Deleterious | 0.001 | Benign | 0.004 | Benign | 5.85 | Benign | 0.03 | Affected | 0.3313 | 0.2574 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.1334A>G | E445G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E445G missense variant 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 (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. Predictions that are inconclusive or uncertain are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E445G, 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 | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -12.294 | Likely Pathogenic | 0.823 | Likely Pathogenic | Ambiguous | 0.80 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.80 | Ambiguous | 0.69 | Ambiguous | 0.523 | Likely Pathogenic | -6.68 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.2446 | 0.4202 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1391T>A | F464Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464Y is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, while AlphaMissense‑Optimized and Foldetta provide uncertain results and are treated as unavailable evidence. Overall, the balance of evidence points to a pathogenic effect for F464Y, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -10.056 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 1.35 | Ambiguous | 0.1 | 0.24 | Likely Benign | 0.80 | Ambiguous | 1.31 | Destabilizing | 0.387 | Likely Benign | -2.98 | Deleterious | 0.979 | Probably Damaging | 0.953 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.1081 | 0.1523 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1549C>A | L517M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. Benign predictions are provided by FoldX and PROVEAN. High‑accuracy assessments are mixed: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenic, whereas AlphaMissense‑Optimized and Foldetta yield uncertain results and are treated as unavailable. No evidence from ClinVar contradicts these findings. Overall, the preponderance of evidence supports a pathogenic classification for L517M, with no conflict from existing database annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -11.613 | Likely Pathogenic | 0.799 | Likely Pathogenic | Ambiguous | 0.38 | Likely Benign | 0.2 | 1.22 | Ambiguous | 0.80 | Ambiguous | 0.93 | Ambiguous | 0.665 | Likely Pathogenic | -1.74 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.47 | Pathogenic | 0.01 | Affected | 0.0775 | 0.2558 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1692G>C | E564D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E564D is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX, premPS, and SIFT, whereas a majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default) classify the change as pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic; this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023534 | Structured | 0.038418 | Uncertain | 0.891 | 0.208 | 0.000 | -10.184 | Likely Pathogenic | 0.915 | Likely Pathogenic | Ambiguous | 0.47 | Likely Benign | 0.1 | 1.13 | Ambiguous | 0.80 | Ambiguous | 0.26 | Likely Benign | 0.637 | Likely Pathogenic | -2.75 | Deleterious | 0.994 | Probably Damaging | 0.979 | Probably Damaging | -1.37 | Pathogenic | 0.07 | Tolerated | 0.1431 | 0.3354 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1692G>T | E564D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E564D is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX, premPS, and SIFT, whereas a majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default) classify the change as pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic; this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023534 | Structured | 0.038418 | Uncertain | 0.891 | 0.208 | 0.000 | -10.184 | Likely Pathogenic | 0.915 | Likely Pathogenic | Ambiguous | 0.47 | Likely Benign | 0.1 | 1.13 | Ambiguous | 0.80 | Ambiguous | 0.26 | Likely Benign | 0.637 | Likely Pathogenic | -2.75 | Deleterious | 0.994 | Probably Damaging | 0.979 | Probably Damaging | -1.37 | Pathogenic | 0.07 | Tolerated | 0.1431 | 0.3354 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1846G>A | D616N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D616N missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into benign (REVEL, premPS, SIFT, FATHMM, AlphaMissense‑Optimized) and pathogenic (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b). Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenic, and Foldetta remains uncertain. Overall, the majority of conventional predictors lean toward a benign effect, whereas the SGM Consensus suggests pathogenicity, leaving the variant’s clinical significance ambiguous. Based on the prevailing evidence, the variant is most likely benign, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | -8.292 | Likely Pathogenic | 0.349 | Ambiguous | Likely Benign | 0.54 | Ambiguous | 0.2 | 1.05 | Ambiguous | 0.80 | Ambiguous | 0.03 | Likely Benign | 0.149 | Likely Benign | -3.74 | Deleterious | 0.875 | Possibly Damaging | 0.581 | Possibly Damaging | 3.41 | Benign | 0.11 | Tolerated | 0.1053 | 0.3976 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.1891C>G | Q631E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q631E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifying it as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain result. Overall, the majority of evidence (eight pathogenic predictions versus three benign) points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which is currently unavailable. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.038963 | Uncertain | 0.948 | 0.230 | 0.000 | -15.628 | Likely Pathogenic | 0.782 | Likely Pathogenic | Likely Benign | 0.04 | Likely Benign | 0.1 | 1.55 | Ambiguous | 0.80 | Ambiguous | 0.95 | Ambiguous | 0.532 | Likely Pathogenic | -2.99 | Deleterious | 0.997 | Probably Damaging | 0.981 | Probably Damaging | 2.78 | Benign | 0.01 | Affected | 0.1068 | 0.1264 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1895A>G | N632S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N632S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions (six benign vs. three pathogenic) support a benign classification, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.042364 | Structured | 0.041437 | Uncertain | 0.938 | 0.254 | 0.000 | -7.677 | In-Between | 0.291 | Likely Benign | Likely Benign | 0.81 | Ambiguous | 0.1 | 0.78 | Ambiguous | 0.80 | Ambiguous | 0.41 | Likely Benign | 0.469 | Likely Benign | -3.85 | Deleterious | 0.718 | Possibly Damaging | 0.086 | Benign | -1.37 | Pathogenic | 0.12 | Tolerated | 0.3302 | 0.6486 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||
| c.2086C>A | L696I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L696I missense change is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and premPS give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is unavailable. Overall, the majority of conventional tools lean toward pathogenicity, and the high‑accuracy prediction that is available (AlphaMissense‑Optimized) indicates benign, leaving the evidence mixed. Thus, the variant is most likely pathogenic based on the preponderance of predictions, and this does not contradict the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | -10.652 | Likely Pathogenic | 0.698 | Likely Pathogenic | Likely Benign | 1.01 | Ambiguous | 0.1 | 0.58 | Ambiguous | 0.80 | Ambiguous | 0.85 | Ambiguous | 0.250 | Likely Benign | -1.86 | Neutral | 0.996 | Probably Damaging | 0.989 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 0.0921 | 0.2542 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.719A>T | D240V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, FATHMM, and premPS, whereas the majority of algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score—classify the change as pathogenic or likely pathogenic. FoldX and Foldetta return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for D240V. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -15.095 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 1.32 | Ambiguous | 0.1 | 0.28 | Likely Benign | 0.80 | Ambiguous | 0.11 | Likely Benign | 0.894 | Likely Pathogenic | -7.94 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 5.82 | Benign | 0.00 | Affected | 0.0610 | 0.4949 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.722A>T | K241I 2D 3DClick to see structure in 3D Viewer AISynGAP1 K241I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta, premPS, and FATHMM. Those that predict a damaging effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX and Foldetta return uncertain results. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized reports pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta remains inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -14.370 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.31 | Ambiguous | 0.5 | 0.28 | Likely Benign | 0.80 | Ambiguous | 0.41 | Likely Benign | 0.852 | Likely Pathogenic | -6.96 | Deleterious | 0.985 | Probably Damaging | 0.704 | Possibly Damaging | 5.71 | Benign | 0.01 | Affected | 0.1176 | 0.3868 | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||
| c.830A>C | K277T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K277T missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect are Rosetta and premPS, while the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict pathogenicity. FoldX and Foldetta return uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that K277T is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.061840 | Structured | 0.321811 | Uncertain | 0.649 | 0.247 | 0.250 | -11.688 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 1.46 | Ambiguous | 0.1 | 0.14 | Likely Benign | 0.80 | Ambiguous | 0.17 | Likely Benign | 0.573 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.02 | Pathogenic | 0.01 | Affected | 0.1837 | 0.2220 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.953C>T | P318L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P318L is listed in ClinVar with an uncertain significance (ClinVar ID 956570.0) and is present in gnomAD (6‑33437858‑C‑T). Functional prediction tools that agree on a benign effect are Rosetta and premPS. The remaining tools—REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Taken together, the preponderance of evidence points to a pathogenic effect for P318L, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.111485 | Structured | 0.400936 | Uncertain | 0.858 | 0.234 | 0.000 | Uncertain | 3 | 6-33437858-C-T | 3 | 1.86e-6 | -10.090 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 1.33 | Ambiguous | 0.1 | 0.26 | Likely Benign | 0.80 | Ambiguous | 0.43 | Likely Benign | 0.624 | Likely Pathogenic | -8.96 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.82 | Pathogenic | 0.03 | Affected | 3.38 | 23 | 0.2166 | 0.6941 | -3 | -3 | 5.4 | 16.04 | 228.6 | -68.9 | -0.7 | 0.7 | -0.4 | 0.1 | X | Potentially Benign | The cyclic five-membered pyrrolidine ring of Pro318, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Asp330-Ala322, res. Thr305-Asn315), packs against the hydrophobic side chain of Ile205 at the end of the anti-parallel β sheet in the PH domain. In the variant simulations, the iso-butyl side chain of Leu318 is unable to do the same, potentially weakening the PH and C2 domain association. Importantly, the residue swap could also affect loop formation during folding, as proline can make tighter turns than leucine. Because the residue swap could affect the C2 domain stability, it could also negatively impact the SynGAP-membrane association. | |||||||||||||
| c.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.1270G>T | V424F 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant V424F is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) yield uncertain or unavailable results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -10.947 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 1.99 | Ambiguous | 0.3 | -0.37 | Likely Benign | 0.81 | Ambiguous | 0.55 | Ambiguous | 0.275 | Likely Benign | -3.66 | Deleterious | 0.995 | Probably Damaging | 0.775 | Possibly Damaging | 3.40 | Benign | 0.01 | Affected | 0.0816 | 0.2094 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||
| c.1400A>C | D467A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D467A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS and SIFT, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results—FoldX, Rosetta, and Foldetta—do not provide decisive evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -12.499 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.83 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.81 | Ambiguous | 0.23 | Likely Benign | 0.790 | Likely Pathogenic | -7.71 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.19 | Pathogenic | 0.07 | Tolerated | 0.3134 | 0.5117 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1622C>G | A541G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A541G is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438865‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, and ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, the balance of evidence leans toward a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | Uncertain | 1 | 6-33438865-C-G | 2 | 1.24e-6 | -7.233 | In-Between | 0.341 | Ambiguous | Likely Benign | 0.67 | Ambiguous | 0.0 | 0.94 | Ambiguous | 0.81 | Ambiguous | 0.76 | Ambiguous | 0.421 | Likely Benign | -1.48 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.31 | Pathogenic | 0.57 | Tolerated | 3.37 | 35 | 0.1787 | 0.2428 | 1 | 0 | -2.2 | -14.03 | 170.1 | 23.6 | 0.0 | 0.0 | 0.0 | 0.0 | X | Potentially Pathogenic | Ala541 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala541 is on the surface and does not form any interactions. Glycine, known as an “α-helix breaker,” weakens the integrity of the helix. Indeed, in the variant simulations, the hydrogen bond formation between Gly541 and the backbone carbonyl of Ala537 is disrupted. | ||||||||||||||
| c.1733A>G | E578G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E578G missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Four tools give uncertain or inconclusive results (FoldX, Rosetta, Foldetta, ESM1b). High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenic. Foldetta, a protein‑folding stability method, yields an uncertain result. Overall, the majority of high‑confidence predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.059222 | Structured | 0.020971 | Uncertain | 0.902 | 0.240 | 0.000 | -7.680 | In-Between | 0.601 | Likely Pathogenic | Likely Benign | 0.98 | Ambiguous | 0.1 | 0.63 | Ambiguous | 0.81 | Ambiguous | 0.08 | Likely Benign | 0.589 | Likely Pathogenic | -2.40 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.49 | Pathogenic | 0.19 | Tolerated | 0.2608 | 0.4843 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||
| c.2107C>T | L703F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703F is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized, while those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta remains unavailable. Overall, the majority of reliable predictions lean toward pathogenicity, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -10.929 | Likely Pathogenic | 0.768 | Likely Pathogenic | Likely Benign | 1.03 | Ambiguous | 0.1 | 0.59 | Ambiguous | 0.81 | Ambiguous | 0.50 | Likely Benign | 0.247 | Likely Benign | -3.25 | Deleterious | 0.994 | Probably Damaging | 0.806 | Possibly Damaging | 3.12 | Benign | 0.00 | Affected | 0.0600 | 0.2555 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2137C>A | P713T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P713T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further clarify the picture: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic, whereas AlphaMissense‑Optimized and Foldetta provide inconclusive results and are treated as unavailable. Taken together, the preponderance of evidence points to a pathogenic effect for P713T, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.393235 | Uncertain | 0.961 | 0.371 | 0.000 | -9.915 | Likely Pathogenic | 0.819 | Likely Pathogenic | Ambiguous | 1.15 | Ambiguous | 0.0 | 0.46 | Likely Benign | 0.81 | Ambiguous | 0.65 | Ambiguous | 0.225 | Likely Benign | -6.72 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.34 | Benign | 0.00 | Affected | 0.1417 | 0.3818 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.655T>A | C219S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from FoldX, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. With the majority of evidence pointing to a damaging effect and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -12.962 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.09 | Likely Benign | 0.4 | 1.53 | Ambiguous | 0.81 | Ambiguous | 1.56 | Destabilizing | 0.892 | Likely Pathogenic | -8.35 | Deleterious | 0.900 | Possibly Damaging | 0.380 | Benign | 5.95 | Benign | 0.04 | Affected | 0.3568 | 0.1454 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.656G>C | C219S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219S is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, polyPhen‑2 HumVar, and FATHMM, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta’s stability analysis is inconclusive (treated as unavailable). Taken together, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic impact for C219S. This conclusion is not contradicted by ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -12.962 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.09 | Likely Benign | 0.4 | 1.53 | Ambiguous | 0.81 | Ambiguous | 1.56 | Destabilizing | 0.817 | Likely Pathogenic | -8.35 | Deleterious | 0.900 | Possibly Damaging | 0.380 | Benign | 5.95 | Benign | 0.04 | Affected | 0.3568 | 0.1454 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.863A>C | D288A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288A missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, and SIFT. Those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized, Foldetta, and Rosetta give uncertain results and are treated as unavailable for pathogenicity inference. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain. Overall, seven tools predict pathogenicity while four predict benign, with no conflicting ClinVar evidence. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -13.470 | Likely Pathogenic | 0.908 | Likely Pathogenic | Ambiguous | 0.34 | Likely Benign | 0.1 | 1.27 | Ambiguous | 0.81 | Ambiguous | 0.10 | Likely Benign | 0.451 | Likely Benign | -6.09 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.71 | Pathogenic | 0.07 | Tolerated | 0.4060 | 0.5788 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.941T>A | F314Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and Rosetta, whereas a majority of tools (SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive—AlphaMissense‑Optimized, FoldX, and Foldetta—are treated as unavailable. High‑accuracy assessments further support pathogenicity: the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, while Foldetta’s combined stability analysis is uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -13.297 | Likely Pathogenic | 0.918 | Likely Pathogenic | Ambiguous | 1.33 | Ambiguous | 0.1 | 0.29 | Likely Benign | 0.81 | Ambiguous | 1.28 | Destabilizing | 0.374 | Likely Benign | -2.62 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 1.20 | Pathogenic | 0.02 | Affected | 0.1427 | 0.2173 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1080G>C | E360D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and SIFT. In contrast, a majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are therefore not considered evidence for either side. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus remains Likely Pathogenic, while Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E360D. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.421183 | Uncertain | 0.955 | 0.498 | 0.250 | -9.383 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.0 | 0.63 | Ambiguous | 0.82 | Ambiguous | 0.11 | Likely Benign | 0.290 | Likely Benign | -2.76 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.77 | Pathogenic | 0.07 | Tolerated | 0.2339 | 0.5735 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1080G>T | E360D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, premPS, and SIFT, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.421183 | Uncertain | 0.955 | 0.498 | 0.250 | -9.383 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.0 | 0.63 | Ambiguous | 0.82 | Ambiguous | 0.11 | Likely Benign | 0.290 | Likely Benign | -2.76 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.77 | Pathogenic | 0.07 | Tolerated | 0.2339 | 0.5735 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1385A>C | K462T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K462T missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect. This conclusion is not contradicted by ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | -11.586 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.55 | Ambiguous | 0.0 | 1.08 | Ambiguous | 0.82 | Ambiguous | 0.30 | Likely Benign | 0.414 | Likely Benign | -5.82 | Deleterious | 0.999 | Probably Damaging | 1.000 | Probably Damaging | 3.47 | Benign | 0.08 | Tolerated | 0.2095 | 0.3257 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1399G>C | D467H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D467H is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only premPS, whereas the remaining evaluated algorithms uniformly predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta yield uncertain results and are treated as unavailable. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; Foldetta remains uncertain. Overall, the variant is most likely pathogenic based on the consensus of the available predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -13.348 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.05 | Ambiguous | 0.1 | 0.59 | Ambiguous | 0.82 | Ambiguous | 0.32 | Likely Benign | 0.851 | Likely Pathogenic | -6.71 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.31 | Pathogenic | 0.02 | Affected | 0.1074 | 0.5564 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1648G>A | A550T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A550T missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SIFT, Rosetta, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Foldetta, and premPS are inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta’s stability analysis is uncertain. Overall, the majority of reliable predictors (8/11) indicate a pathogenic impact, whereas only three suggest benign. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | -10.555 | Likely Pathogenic | 0.621 | Likely Pathogenic | Likely Benign | 1.68 | Ambiguous | 0.3 | -0.05 | Likely Benign | 0.82 | Ambiguous | 0.73 | Ambiguous | 0.627 | Likely Pathogenic | -3.19 | Deleterious | 0.991 | Probably Damaging | 0.872 | Possibly Damaging | -1.25 | Pathogenic | 0.10 | Tolerated | 0.0931 | 0.4465 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1914G>C | K638N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K638N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.098064 | Uncertain | 0.937 | 0.260 | 0.000 | -9.420 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 0.74 | Ambiguous | 0.1 | 0.90 | Ambiguous | 0.82 | Ambiguous | 0.40 | Likely Benign | 0.256 | Likely Benign | -4.59 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 3.40 | Benign | 0.02 | Affected | 0.2875 | 0.1126 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1914G>T | K638N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K638N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.098064 | Uncertain | 0.937 | 0.260 | 0.000 | -9.420 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 0.74 | Ambiguous | 0.1 | 0.90 | Ambiguous | 0.82 | Ambiguous | 0.40 | Likely Benign | 0.256 | Likely Benign | -4.59 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 3.40 | Benign | 0.02 | Affected | 0.2875 | 0.1126 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.618C>G | I206M 2D AIThe SynGAP1 I206M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and FATHMM, whereas tools that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With six pathogenic predictions versus four benign and three uncertain, the overall evidence leans toward pathogenicity. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -10.008 | Likely Pathogenic | 0.878 | Likely Pathogenic | Ambiguous | 0.42 | Likely Benign | 0.6 | 1.21 | Ambiguous | 0.82 | Ambiguous | 1.08 | Destabilizing | 0.085 | Likely Benign | -2.42 | Neutral | 0.838 | Possibly Damaging | 0.467 | Possibly Damaging | 3.64 | Benign | 0.01 | Affected | 0.0576 | 0.2716 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||
| c.706G>T | A236S 2D AIThe SynGAP1 A236S variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Predictions that are inconclusive or uncertain are Rosetta, Foldetta, premPS, and ESM1b. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for A236S, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -7.845 | In-Between | 0.106 | Likely Benign | Likely Benign | 0.40 | Likely Benign | 0.5 | 1.24 | Ambiguous | 0.82 | Ambiguous | 0.65 | Ambiguous | 0.648 | Likely Pathogenic | -2.30 | Neutral | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.83 | Benign | 0.13 | Tolerated | 0.2641 | 0.5547 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.713A>T | E238V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E238V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E238V. This conclusion is not contradicted by ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -14.329 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.88 | Ambiguous | 0.4 | 0.75 | Ambiguous | 0.82 | Ambiguous | 0.45 | Likely Benign | 0.890 | Likely Pathogenic | -6.35 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.42 | Benign | 0.00 | Affected | 0.0848 | 0.6093 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.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.944A>G | N315S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -4.847 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.85 | Ambiguous | 0.2 | 0.78 | Ambiguous | 0.82 | Ambiguous | 0.68 | Ambiguous | 0.250 | Likely Benign | -1.84 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.03 | Pathogenic | 0.60 | Tolerated | 0.4022 | 0.7395 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.946A>G | N316D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316D is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, Rosetta, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain and therefore not considered evidence. Overall, seven of the evaluated tools predict pathogenicity versus four predicting benignity, indicating that the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.385187 | Uncertain | 0.817 | 0.246 | 0.125 | -11.672 | Likely Pathogenic | 0.777 | Likely Pathogenic | Likely Benign | 1.18 | Ambiguous | 0.1 | 0.46 | Likely Benign | 0.82 | Ambiguous | 0.69 | Ambiguous | 0.293 | Likely Benign | -3.20 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.76 | Pathogenic | 0.25 | Tolerated | 0.1978 | 0.4596 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1061C>G | A354G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A354G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. Predictions marked uncertain (Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a benign impact for A354G, 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 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | -4.285 | Likely Benign | 0.113 | Likely Benign | Likely Benign | 0.41 | Likely Benign | 0.0 | 1.24 | Ambiguous | 0.83 | Ambiguous | 0.65 | Ambiguous | 0.037 | Likely Benign | -1.87 | Neutral | 0.146 | Benign | 0.038 | Benign | 1.75 | Pathogenic | 0.05 | Affected | 0.2563 | 0.4777 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| 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.1177G>A | G393S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G393S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, polyPhen‑2 HumDiv, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. No other tools provide decisive evidence. Overall, the majority of reliable predictors lean toward a benign effect, and this consensus does not conflict with the absence of ClinVar annotation. Therefore, G393S is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.538167 | Disordered | 0.402365 | Uncertain | 0.333 | 0.670 | 0.625 | -5.207 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 2.43 | Destabilizing | 0.7 | -0.78 | Ambiguous | 0.83 | Ambiguous | 0.24 | Likely Benign | 0.466 | Likely Benign | -1.76 | Neutral | 0.889 | Possibly Damaging | 0.444 | Benign | 1.33 | Pathogenic | 0.07 | Tolerated | 0.3011 | 0.5232 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.1523A>C | D508A 2D 3DClick to see structure in 3D Viewer AISynGAP1 D508A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy methods give a split result: AlphaMissense‑Optimized predicts benign, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is uncertain. No prediction or stability result is missing; all available outputs are considered. Overall, the predictions are evenly divided between benign and pathogenic, with no clear consensus. Therefore, the variant is inconclusive; it is not contradictory to the ClinVar status, which has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -11.434 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | -0.18 | Likely Benign | 0.2 | 1.84 | Ambiguous | 0.83 | Ambiguous | 0.09 | Likely Benign | 0.339 | Likely Benign | -7.37 | Deleterious | 0.988 | Probably Damaging | 0.762 | Possibly Damaging | 3.37 | Benign | 0.06 | Tolerated | 0.3758 | 0.4241 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1579G>C | D527H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D527H is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX and premPS, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. Uncertain results come from Rosetta and Foldetta. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as pathogenic, and Foldetta as inconclusive. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -13.334 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 1.2 | 1.26 | Ambiguous | 0.83 | Ambiguous | 0.49 | Likely Benign | 0.901 | Likely Pathogenic | -6.80 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -2.39 | Pathogenic | 0.00 | Affected | 0.1092 | 0.4346 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1748A>G | D583G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D583G missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and ESM1b, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default—classify it as pathogenic. Uncertain results come from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessment shows the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and AlphaMissense‑Optimized remains inconclusive; Foldetta also reports no definitive stability change. Overall, the preponderance of evidence points to a pathogenic effect for D583G, and this conclusion does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.038478 | Uncertain | 0.805 | 0.247 | 0.000 | -6.765 | Likely Benign | 0.953 | Likely Pathogenic | Ambiguous | 1.10 | Ambiguous | 0.2 | 0.56 | Ambiguous | 0.83 | Ambiguous | 0.10 | Likely Benign | 0.850 | Likely Pathogenic | -6.77 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.43 | Pathogenic | 0.03 | Affected | 0.3072 | 0.4284 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1910C>A | S637Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S637Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of individual predictors (seven versus five) lean toward pathogenicity, and the consensus‑based SGM‑Consensus also supports a likely pathogenic classification. Therefore, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -12.633 | Likely Pathogenic | 0.770 | Likely Pathogenic | Likely Benign | 0.13 | Likely Benign | 0.1 | 1.52 | Ambiguous | 0.83 | Ambiguous | 0.50 | Likely Benign | 0.209 | Likely Benign | -3.78 | Deleterious | 0.985 | Probably Damaging | 0.681 | Possibly Damaging | 3.35 | Benign | 0.00 | Affected | 0.0968 | 0.4071 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.1999A>C | I667L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I667L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, indicating no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.142424 | Structured | 0.083597 | Uncertain | 0.927 | 0.379 | 0.000 | -10.452 | Likely Pathogenic | 0.459 | Ambiguous | Likely Benign | 0.93 | Ambiguous | 0.2 | 0.72 | Ambiguous | 0.83 | Ambiguous | 0.75 | Ambiguous | 0.300 | Likely Benign | -1.97 | Neutral | 0.457 | Possibly Damaging | 0.392 | Benign | 3.36 | Benign | 0.13 | Tolerated | 0.0980 | 0.3145 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.2014A>G | T672A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T672A is listed in ClinVar as Benign (ClinVar ID 2154412.0) and is present in gnomAD (variant ID 6‑33441273‑A‑G). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only PROVEAN predicts a pathogenic outcome. Uncertain results are reported for FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a benign effect, and this conclusion is consistent with the ClinVar designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.116183 | Structured | 0.102069 | Uncertain | 0.586 | 0.362 | 0.000 | Benign | 1 | 6-33441273-A-G | 3 | 1.86e-6 | -6.524 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.51 | Ambiguous | 0.3 | 1.15 | Ambiguous | 0.83 | Ambiguous | 0.65 | Ambiguous | 0.046 | Likely Benign | -3.20 | Deleterious | 0.006 | Benign | 0.002 | Benign | 3.44 | Benign | 0.12 | Tolerated | 3.40 | 25 | 0.3687 | 0.4380 | 1 | 0 | 2.5 | -30.03 | 188.5 | 42.5 | -0.1 | 0.3 | 0.2 | 0.0 | X | Potentially Pathogenic | The hydroxyl group of Thr672, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop itself, such as Lys566, Glu666, and Asn669. In the variant simulations, Ala672 can only form a hydrogen bond with Lys566 via its backbone carbonyl group. Consequently, it cannot maintain the Lys566-Glu666 salt bridge through hydrogen bonding, leading to a significant disruption of the intricate and stable hydrogen-bond network between the loop and the helices. | |||||||||||||
| c.664G>A | V222I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V222I missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy consensus methods give a benign signal: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, while Foldetta’s stability assessment is uncertain. Overall, the majority of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -6.347 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 0.21 | Likely Benign | 0.2 | 1.45 | Ambiguous | 0.83 | Ambiguous | 0.09 | Likely Benign | 0.612 | Likely Pathogenic | -0.87 | Neutral | 0.984 | Probably Damaging | 0.956 | Probably Damaging | 5.77 | Benign | 0.08 | Tolerated | 0.0637 | 0.3574 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||
| c.700C>T | R234W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234W missense variant is listed in ClinVar (ID 856396.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33435551‑C‑T). Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) indicate a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain”; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is “Uncertain.” Overall, the preponderance of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertainty rather than a benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | Uncertain | 1 | 6-33435551-C-T | 3 | 1.86e-6 | -12.625 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 0.96 | Ambiguous | 0.3 | 0.69 | Ambiguous | 0.83 | Ambiguous | 0.13 | Likely Benign | 0.805 | Likely Pathogenic | -5.52 | Deleterious | 0.997 | Probably Damaging | 0.803 | Possibly Damaging | 5.76 | Benign | 0.01 | Affected | 3.40 | 14 | 0.1302 | 0.4035 | 2 | -3 | 3.6 | 30.03 | 262.8 | 39.6 | -0.1 | 0.0 | -0.2 | 0.2 | X | Potentially Pathogenic | The guanidinium group of Arg234, located in a β-α loop between an anti-parallel β sheet strand (residues Gly227-Phe231) and an α helix (res. Ala236-Val250), forms a salt bridge with the carboxylate group of Glu238 in the α helix. Occasionally, it also bonds with the GAP domain residues Ser678 and Glu680. Thus, the positively charged Arg234 could contribute to the tertiary structure assembly between the PH and GAP domains. In contrast, the indole side chain of Trp234 in the variant is located on the protein surface in the variant simulations and is unable to form any interactions. | |||||||||||||
| c.811G>T | A271S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A271S is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are Foldetta and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for A271S, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.413873 | Uncertain | 0.939 | 0.220 | 0.125 | Uncertain | 1 | -9.552 | Likely Pathogenic | 0.629 | Likely Pathogenic | Likely Benign | 0.19 | Likely Benign | 0.1 | 1.47 | Ambiguous | 0.83 | Ambiguous | 1.14 | Destabilizing | 0.453 | Likely Benign | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 0.64 | Pathogenic | 0.03 | Affected | 0.2260 | 0.3312 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||
| c.913A>T | T305S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are provided by Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -2.899 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.4 | 1.21 | Ambiguous | 0.83 | Ambiguous | 0.55 | Ambiguous | 0.135 | Likely Benign | -0.60 | Neutral | 0.760 | Possibly Damaging | 0.484 | Possibly Damaging | 1.86 | Pathogenic | 0.54 | Tolerated | 0.3579 | 0.4496 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.914C>G | T305S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are provided by Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -2.899 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.4 | 1.21 | Ambiguous | 0.83 | Ambiguous | 0.55 | Ambiguous | 0.104 | Likely Benign | -0.60 | Neutral | 0.760 | Possibly Damaging | 0.484 | Possibly Damaging | 1.86 | Pathogenic | 0.54 | Tolerated | 0.3579 | 0.4496 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1247T>G | L416R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L416R missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans toward benign, while Foldetta remains uncertain. Overall, the majority of reliable predictors classify the variant as benign, 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 | 0.104810 | Structured | 0.336105 | Uncertain | 0.935 | 0.227 | 0.000 | -8.600 | Likely Pathogenic | 0.511 | Ambiguous | Likely Benign | 0.71 | Ambiguous | 0.0 | 0.97 | Ambiguous | 0.84 | Ambiguous | 0.84 | Ambiguous | 0.238 | Likely Benign | -2.05 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.35 | Benign | 0.43 | Tolerated | 0.1445 | 0.0702 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||
| c.1439A>T | E480V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E480V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only premPS. All other evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—classify the variant as pathogenic or likely pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the overwhelming majority of predictions support a pathogenic effect for E480V. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -12.347 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.94 | Ambiguous | 0.1 | 0.74 | Ambiguous | 0.84 | Ambiguous | 0.31 | Likely Benign | 0.797 | Likely Pathogenic | -6.07 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | -1.24 | Pathogenic | 0.02 | Affected | 0.0496 | 0.7192 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1828C>A | L610I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L610I is listed in gnomAD (ID 6‑33440880‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM. Four tools are uncertain (FoldX, Foldetta, premPS, AlphaMissense‑Default). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores benign, the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, whereas Foldetta’s stability estimate is unavailable. Overall, the balance of evidence points to a benign effect for L610I, 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. | GAP | 0.271506 | Structured | 0.209504 | Uncertain | 0.888 | 0.253 | 0.000 | 6-33440880-C-A | 1 | 6.19e-7 | -6.362 | Likely Benign | 0.389 | Ambiguous | Likely Benign | 1.50 | Ambiguous | 0.2 | 0.18 | Likely Benign | 0.84 | Ambiguous | 0.76 | Ambiguous | 0.544 | Likely Pathogenic | -1.86 | Neutral | 0.992 | Probably Damaging | 0.997 | Probably Damaging | -1.34 | Pathogenic | 0.15 | Tolerated | 3.37 | 35 | 0.0999 | 0.3219 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||
| c.1943T>A | F648Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F648Y is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33441202‑T‑A). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence favors a pathogenic classification for F648Y. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.346782 | Uncertain | 0.943 | 0.339 | 0.000 | 6-33441202-T-A | 4 | 2.48e-6 | -8.632 | Likely Pathogenic | 0.889 | Likely Pathogenic | Ambiguous | 0.74 | Ambiguous | 0.1 | 0.94 | Ambiguous | 0.84 | Ambiguous | 1.11 | Destabilizing | 0.407 | Likely Benign | -2.99 | Deleterious | 0.984 | Probably Damaging | 0.913 | Probably Damaging | 3.41 | Benign | 0.11 | Tolerated | 3.37 | 30 | 0.1307 | 0.1396 | 3 | 7 | -4.1 | 16.00 | ||||||||||||||||||||||||
| c.2116G>A | E706K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E706K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM all classify the change as benign. In contrast, ESM1b and AlphaMissense‑Default predict a pathogenic impact. Tools that return uncertain results—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—do not provide decisive evidence. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic versus two benign calls). High‑accuracy assessments are likewise ambiguous: AlphaMissense‑Optimized is uncertain, Foldetta is uncertain, and the SGM Consensus remains inconclusive. Overall, the preponderance of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.200174 | Structured | 0.377033 | Uncertain | 0.929 | 0.363 | 0.000 | Uncertain | 1 | -10.519 | Likely Pathogenic | 0.833 | Likely Pathogenic | Ambiguous | 1.17 | Ambiguous | 0.1 | 0.51 | Ambiguous | 0.84 | Ambiguous | 0.08 | Likely Benign | 0.080 | Likely Benign | -1.51 | Neutral | 0.345 | Benign | 0.028 | Benign | 4.15 | Benign | 0.52 | Tolerated | 3.47 | 10 | 0.2065 | 0.4511 | 0 | 1 | -0.4 | -0.94 | 187.1 | 49.2 | 0.0 | 0.0 | 0.4 | 0.1 | X | Uncertain | The carboxylate side chain of Glu706, located at the end and outer surface of an α-helix (res. Thr704-Gly712), forms a salt bridge with Lys710 and a hydrogen bond with its own backbone amino group at the helix end in the WT simulations. Although Lys706 is unable to make these transient interactions in the variant simulations, there is no apparent negative effect on the protein structure due to the residue swap. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | |||||||||||||||||
| c.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.1242G>A | M414I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 M414I missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is also inconclusive. Overall, more tools (five) predict pathogenicity than benign (four), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -6.203 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.83 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.85 | Ambiguous | 0.84 | Ambiguous | 0.265 | Likely Benign | -3.00 | Deleterious | 0.870 | Possibly Damaging | 0.801 | Possibly Damaging | 3.44 | Benign | 0.36 | Tolerated | 0.1168 | 0.3161 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1242G>C | M414I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414I is not 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. Those 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 is uncertain, so these results are treated as unavailable. Overall, the majority of evaluated tools (5 pathogenic vs 4 benign) and the single high‑accuracy pathogenic prediction support a likely pathogenic classification. 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. | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -6.203 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.83 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.85 | Ambiguous | 0.84 | Ambiguous | 0.265 | Likely Benign | -3.00 | Deleterious | 0.870 | Possibly Damaging | 0.801 | Possibly Damaging | 3.44 | Benign | 0.36 | Tolerated | 0.1168 | 0.3161 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1242G>T | M414I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414I is not 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. Those 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 is uncertain, so these results are treated as unavailable. Overall, the majority of evaluated tools (5 pathogenic vs 4 benign) and the single high‑accuracy pathogenic prediction support a likely pathogenic classification. 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. | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -6.203 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.83 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.85 | Ambiguous | 0.84 | Ambiguous | 0.265 | Likely Benign | -3.00 | Deleterious | 0.870 | Possibly Damaging | 0.801 | Possibly Damaging | 3.44 | Benign | 0.36 | Tolerated | 0.1168 | 0.3161 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1547C>A | A516D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A516D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, which scores the substitution as tolerated. In contrast, the majority of algorithms predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, while Foldetta remains uncertain. Overall, the preponderance of evidence indicates that A516D is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -14.621 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.65 | Ambiguous | 0.2 | 1.04 | Ambiguous | 0.85 | Ambiguous | 0.62 | Ambiguous | 0.725 | Likely Pathogenic | -5.17 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.23 | Pathogenic | 0.15 | Tolerated | 0.1890 | 0.1679 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1777C>T | L593F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L593F is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive—FoldX, Foldetta, premPS, and AlphaMissense‑Optimized—are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009728 | Structured | 0.110534 | Uncertain | 0.941 | 0.151 | 0.000 | -12.723 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 1.46 | Ambiguous | 0.4 | 0.24 | Likely Benign | 0.85 | Ambiguous | 0.62 | Ambiguous | 0.304 | Likely Benign | -3.78 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.95 | Benign | 0.01 | Affected | 0.0884 | 0.2631 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2079T>A | H693Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL and FATHMM, while the remaining evaluated algorithms (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all predict pathogenicity. FoldX and Rosetta give uncertain stability changes, and Foldetta likewise reports no definitive effect. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains inconclusive. Overall, the preponderance of evidence from multiple pathogenic‑oriented predictors and the high‑accuracy consensus indicates that H693Q is most likely pathogenic, a conclusion that aligns with the lack of ClinVar annotation and gnomAD data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -11.425 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 0.78 | Ambiguous | 0.85 | Ambiguous | 1.27 | Destabilizing | 0.386 | Likely Benign | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.921 | Probably Damaging | 3.14 | Benign | 0.01 | Affected | 0.1274 | 0.2955 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.2079T>G | H693Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL and FATHMM, while the remaining evaluated algorithms (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all predict pathogenicity. FoldX and Rosetta give uncertain stability changes, and Foldetta likewise reports no definitive effect. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains inconclusive. Overall, the preponderance of evidence from multiple pathogenic‑oriented predictors and the high‑accuracy consensus indicates that H693Q is most likely pathogenic, a conclusion that aligns with the lack of ClinVar annotation and gnomAD data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -11.425 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 0.78 | Ambiguous | 0.85 | Ambiguous | 1.27 | Destabilizing | 0.386 | Likely Benign | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.921 | Probably Damaging | 3.14 | Benign | 0.01 | Affected | 0.1274 | 0.2955 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.695C>A | A232D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232D is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus. Uncertain or inconclusive results are reported for Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as pathogenic, while Foldetta remains uncertain. Overall, the majority of available predictions support a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -13.956 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.14 | Likely Benign | 0.2 | 1.55 | Ambiguous | 0.85 | Ambiguous | 0.77 | Ambiguous | 0.725 | Likely Pathogenic | -2.50 | Deleterious | 0.845 | Possibly Damaging | 0.348 | Benign | 5.78 | Benign | 0.02 | Affected | 0.2066 | 0.2896 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.707C>T | A236V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A236V is listed in ClinVar as Benign (ID 469162.0) and is present in gnomAD (6‑33435558‑C‑T). Prediction tools that report benign include polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, and ESM1b. Four tools give uncertain or inconclusive results: FoldX, Rosetta, Foldetta, and premPS. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because the votes are evenly split. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as uncertain, and the SGM Consensus as unavailable. Consequently, the overall prediction profile is mixed, but the most reliable high‑accuracy evidence points toward a benign effect. Therefore, the variant is most likely benign, which aligns with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | Benign/Likely benign | 2 | 6-33435558-C-T | 6 | 3.72e-6 | -8.752 | Likely Pathogenic | 0.267 | Likely Benign | Likely Benign | 0.61 | Ambiguous | 0.2 | 1.08 | Ambiguous | 0.85 | Ambiguous | 0.64 | Ambiguous | 0.777 | Likely Pathogenic | -3.55 | Deleterious | 0.981 | Probably Damaging | 0.446 | Benign | 5.79 | Benign | 0.03 | Affected | 3.40 | 14 | 0.0913 | 0.5859 | 0 | 0 | 2.4 | 28.05 | 213.8 | -44.7 | 0.0 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | The methyl side chain of Ala236, located on an α helix (residues Ala236-Val250) facing an anti-parallel β sheet strand (residues Ile205-Val209), interacts hydrophobically with nearby residues such as Arg239 and Phe218. In the variant simulations, the isopropyl branched hydrocarbon side chain of Val236 maintains similar hydrophobic interactions as alanine in the WT, with an overall arrangement remarkably similar to Ala236. The residue swap does not affect the protein structure based on the simulations. | ||||||||||||||
| c.765C>A | D255E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change D255E is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include premPS, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, the majority of available predictions (seven pathogenic vs. four benign) point to a likely pathogenic impact. This conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -6.876 | Likely Benign | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.3 | 0.90 | Ambiguous | 0.85 | Ambiguous | 0.15 | Likely Benign | 0.508 | Likely Pathogenic | -2.98 | Deleterious | 0.994 | Probably Damaging | 0.978 | Probably Damaging | 5.89 | Benign | 0.08 | Tolerated | 0.1365 | 0.5067 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||
| c.765C>G | D255E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255E is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include premPS, SIFT, ESM1b, and FATHMM, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The remaining tools (FoldX, Rosetta, Foldetta) provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta is also inconclusive. Overall, the majority of available predictions (7 pathogenic vs. 4 benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -6.876 | Likely Benign | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.3 | 0.90 | Ambiguous | 0.85 | Ambiguous | 0.15 | Likely Benign | 0.509 | Likely Pathogenic | -2.98 | Deleterious | 0.994 | Probably Damaging | 0.978 | Probably Damaging | 5.89 | Benign | 0.08 | Tolerated | 0.1365 | 0.5067 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||
| c.940T>C | F314L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that F314L is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -6.004 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.87 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.85 | Ambiguous | 1.21 | Destabilizing | 0.476 | Likely Benign | -4.85 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.30 | Pathogenic | 0.05 | Affected | 0.2204 | 0.3089 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.942T>A | F314L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that F314L is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -6.004 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.87 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.85 | Ambiguous | 1.21 | Destabilizing | 0.336 | Likely Benign | -4.85 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.30 | Pathogenic | 0.05 | Affected | 0.2204 | 0.3089 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.942T>G | F314L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that F314L is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -6.004 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.87 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.85 | Ambiguous | 1.21 | Destabilizing | 0.336 | Likely Benign | -4.85 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.30 | Pathogenic | 0.05 | Affected | 0.2204 | 0.3089 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1247T>A | L416Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L416Q 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, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict benign. Only two tools, polyPhen‑2 (HumDiv and HumVar), predict a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM‑Consensus is benign, and Foldetta remains uncertain. Overall, the evidence strongly supports a benign classification for this variant, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.104810 | Structured | 0.336105 | Uncertain | 0.935 | 0.227 | 0.000 | -6.445 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 1.17 | Ambiguous | 0.1 | 0.54 | Ambiguous | 0.86 | Ambiguous | 0.88 | Ambiguous | 0.187 | Likely Benign | -1.07 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.39 | Benign | 0.46 | Tolerated | 0.1281 | 0.0860 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1381G>A | A461T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A461T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta is also inconclusive. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -10.885 | Likely Pathogenic | 0.323 | Likely Benign | Likely Benign | 1.21 | Ambiguous | 0.2 | 0.51 | Ambiguous | 0.86 | Ambiguous | 0.65 | Ambiguous | 0.214 | Likely Benign | -3.27 | Deleterious | 0.508 | Possibly Damaging | 0.042 | Benign | 3.40 | Benign | 0.13 | Tolerated | 0.1083 | 0.5930 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.1535A>T | E512V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E512V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -14.011 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 0.72 | Ambiguous | 0.1 | 1.00 | Ambiguous | 0.86 | Ambiguous | 0.14 | Likely Benign | 0.439 | Likely Benign | -6.71 | Deleterious | 0.989 | Probably Damaging | 0.854 | Possibly Damaging | 3.23 | Benign | 0.01 | Affected | 0.0994 | 0.4884 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1608G>C | L536F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L536F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only Rosetta. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus. Predictions that are uncertain or inconclusive are FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of reliable tools predict a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | -10.316 | Likely Pathogenic | 0.851 | Likely Pathogenic | Ambiguous | 1.31 | Ambiguous | 0.5 | 0.40 | Likely Benign | 0.86 | Ambiguous | 0.70 | Ambiguous | 0.724 | Likely Pathogenic | -3.90 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 0.0874 | 0.2804 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1608G>T | L536F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L536F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only Rosetta. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus. Predictions that are uncertain or inconclusive are FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of reliable tools predict a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | -10.316 | Likely Pathogenic | 0.851 | Likely Pathogenic | Ambiguous | 1.31 | Ambiguous | 0.5 | 0.40 | Likely Benign | 0.86 | Ambiguous | 0.70 | Ambiguous | 0.722 | Likely Pathogenic | -3.90 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 0.0874 | 0.2804 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1634T>C | M545T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) uniformly predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta’s protein‑folding stability analysis is inconclusive. Taken together, the preponderance of evidence points to a pathogenic effect for M545T. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | -8.070 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.94 | Ambiguous | 0.2 | 0.78 | Ambiguous | 0.86 | Ambiguous | 0.97 | Ambiguous | 0.722 | Likely Pathogenic | -5.03 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.24 | Pathogenic | 0.36 | Tolerated | 0.1727 | 0.1847 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||
| c.1781T>A | F594Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F594Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to Rosetta, which scores the substitution as benign. In contrast, the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, SGM‑Consensus, and premPS all classify the variant as pathogenic. FoldX and Foldetta are uncertain, and AlphaMissense‑Optimized is also uncertain, so these results are treated as unavailable. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, while AlphaMissense‑Optimized and Foldetta remain inconclusive. Overall, the preponderance of evidence indicates that F594Y is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009187 | Structured | 0.120166 | Uncertain | 0.946 | 0.147 | 0.000 | -13.692 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.30 | Ambiguous | 0.2 | 0.41 | Likely Benign | 0.86 | Ambiguous | 1.21 | Destabilizing | 0.929 | Likely Pathogenic | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.976 | Probably Damaging | -1.98 | Pathogenic | 0.01 | Affected | 0.1264 | 0.0731 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.2101C>A | P701T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P701T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a tolerated change. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive, and FoldX alone is uncertain, so these results are treated as unavailable. Overall, the evidence strongly supports a benign effect for P701T, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.074921 | Structured | 0.404318 | Uncertain | 0.918 | 0.345 | 0.000 | -6.920 | Likely Benign | 0.272 | Likely Benign | Likely Benign | 1.61 | Ambiguous | 0.0 | 0.11 | Likely Benign | 0.86 | Ambiguous | -0.18 | Likely Benign | 0.144 | Likely Benign | -0.43 | Neutral | 0.084 | Benign | 0.050 | Benign | 3.44 | Benign | 0.70 | Tolerated | 0.1398 | 0.4160 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.2122C>G | L708V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results are from FoldX (uncertain) and Foldetta (uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta remains uncertain. Overall, the evidence strongly indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.365875 | Uncertain | 0.931 | 0.378 | 0.000 | -4.361 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 1.59 | Ambiguous | 0.0 | 0.12 | Likely Benign | 0.86 | Ambiguous | -0.02 | Likely Benign | 0.122 | Likely Benign | -0.23 | Neutral | 0.158 | Benign | 0.035 | Benign | 3.35 | Benign | 0.94 | Tolerated | 0.1094 | 0.2460 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| 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.850C>A | L284I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L284I missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Overall, the majority of predictions, including the high‑accuracy methods, support a benign classification. This consensus does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.094817 | Structured | 0.371601 | Uncertain | 0.950 | 0.255 | 0.000 | -5.853 | Likely Benign | 0.293 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.0 | 1.22 | Ambiguous | 0.86 | Ambiguous | 0.49 | Likely Benign | 0.364 | Likely Benign | -1.51 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.88 | Pathogenic | 0.13 | Tolerated | 0.0738 | 0.3006 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.1369A>G | S457G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S457G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for S457G. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -9.154 | Likely Pathogenic | 0.811 | Likely Pathogenic | Ambiguous | 0.86 | Ambiguous | 0.0 | 0.87 | Ambiguous | 0.87 | Ambiguous | 0.65 | Ambiguous | 0.382 | Likely Benign | -3.82 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 3.35 | Benign | 0.13 | Tolerated | 0.2735 | 0.4074 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.2005A>T | N669Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669Y is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include FoldX, FATHMM, and premPS. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With eight pathogenic predictions versus three benign, the overall evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.086615 | Uncertain | 0.872 | 0.380 | 0.000 | -13.548 | Likely Pathogenic | 0.802 | Likely Pathogenic | Ambiguous | 0.45 | Likely Benign | 0.4 | 1.29 | Ambiguous | 0.87 | Ambiguous | 0.21 | Likely Benign | 0.546 | Likely Pathogenic | -7.01 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.34 | Benign | 0.00 | Affected | 0.0666 | 0.4151 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.2110A>C | S704R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704R is not reported in gnomAD and has no ClinVar entry. Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. FoldX, Rosetta, and Foldetta provide uncertain stability results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the evidence points to the variant being most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | -9.417 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.1 | 0.92 | Ambiguous | 0.87 | Ambiguous | 0.31 | Likely Benign | 0.178 | Likely Benign | -2.65 | Deleterious | 0.997 | Probably Damaging | 0.822 | Possibly Damaging | 3.53 | Benign | 0.05 | Affected | 0.0714 | 0.3038 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2112C>A | S704R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus confirms Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result, providing no additional evidence. Overall, the preponderance of evidence from multiple independent predictors indicates that S704R is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | -9.417 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.1 | 0.92 | Ambiguous | 0.87 | Ambiguous | 0.31 | Likely Benign | 0.200 | Likely Benign | -2.65 | Deleterious | 0.997 | Probably Damaging | 0.822 | Possibly Damaging | 3.53 | Benign | 0.05 | Affected | 0.0714 | 0.3038 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2112C>G | S704R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). FoldX and Rosetta give uncertain results, and Foldetta (a combined FoldX‑MD/Rosetta stability assessment) is also uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as unavailable. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic; this conclusion does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | -9.417 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.1 | 0.92 | Ambiguous | 0.87 | Ambiguous | 0.31 | Likely Benign | 0.200 | Likely Benign | -2.65 | Deleterious | 0.997 | Probably Damaging | 0.822 | Possibly Damaging | 3.53 | Benign | 0.05 | Affected | 0.0714 | 0.3038 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.719A>C | D240A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are premPS and FATHMM, while the remaining pathogenic‑predicting tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently flag the variant as deleterious. Tools with uncertain outcomes (FoldX, Rosetta, Foldetta) provide no definitive guidance. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -12.935 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.75 | Ambiguous | 0.1 | 0.99 | Ambiguous | 0.87 | Ambiguous | 0.22 | Likely Benign | 0.872 | Likely Pathogenic | -7.03 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.80 | Benign | 0.05 | Affected | 0.3317 | 0.4992 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1477G>T | A493S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A493S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are uncertain or inconclusive (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as unavailable. Based on the consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -6.271 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.66 | Ambiguous | 0.1 | 1.10 | Ambiguous | 0.88 | Ambiguous | 0.53 | Ambiguous | 0.507 | Likely Pathogenic | -2.12 | Neutral | 0.983 | Probably Damaging | 0.993 | Probably Damaging | -1.27 | Pathogenic | 0.44 | Tolerated | 0.1821 | 0.2763 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1765A>G | I589V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I589V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta is uncertain. Taken together, the majority of evidence, including the high‑accuracy predictions, points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.018415 | Structured | 0.084536 | Uncertain | 0.927 | 0.214 | 0.000 | -6.966 | Likely Benign | 0.464 | Ambiguous | Likely Benign | 0.98 | Ambiguous | 0.0 | 0.78 | Ambiguous | 0.88 | Ambiguous | 0.96 | Ambiguous | 0.535 | Likely Pathogenic | -1.00 | Neutral | 0.969 | Probably Damaging | 0.960 | Probably Damaging | -1.50 | Pathogenic | 0.31 | Tolerated | 0.1356 | 0.3568 | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||
| c.1948A>G | N650D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Stability‑based methods (FoldX, Rosetta, premPS, Foldetta) yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the majority of available predictions support a pathogenic impact. The variant is most likely pathogenic based on the consensus of predictive tools, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -14.267 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 1.14 | Ambiguous | 0.3 | 0.61 | Ambiguous | 0.88 | Ambiguous | 0.91 | Ambiguous | 0.389 | Likely Benign | -4.98 | Deleterious | 0.591 | Possibly Damaging | 0.185 | Benign | 2.99 | Benign | 0.03 | Affected | 0.2320 | 0.2973 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.718G>C | D240H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240H missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy methods give a pathogenic verdict: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the consensus of the available predictions indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -14.551 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.14 | Ambiguous | 0.0 | 0.61 | Ambiguous | 0.88 | Ambiguous | 0.19 | Likely Benign | 0.865 | Likely Pathogenic | -6.12 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.78 | Benign | 0.00 | Affected | 0.1223 | 0.5398 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.785A>T | N262I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262I is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include premPS and FATHMM, whereas the majority of tools predict a pathogenic outcome: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are uncertain and therefore treated as unavailable. High‑accuracy methods give an uncertain result for AlphaMissense‑Optimized, a pathogenic consensus from SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain result for Foldetta. Overall, the evidence points to a pathogenic effect for the variant, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.284882 | Structured | 0.399879 | Uncertain | 0.912 | 0.240 | 0.000 | -15.203 | Likely Pathogenic | 0.868 | Likely Pathogenic | Ambiguous | 1.21 | Ambiguous | 0.4 | 0.54 | Ambiguous | 0.88 | Ambiguous | 0.09 | Likely Benign | 0.777 | Likely Pathogenic | -7.79 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 5.88 | Benign | 0.01 | Affected | 0.0449 | 0.4638 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.899C>G | S300C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300C is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437804‑C‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Rosetta and Foldetta give uncertain results and are therefore not considered evidence for either side. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of reliable predictions indicate a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | 6-33437804-C-G | -6.749 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.2 | 1.45 | Ambiguous | 0.88 | Ambiguous | 0.34 | Likely Benign | 0.129 | Likely Benign | -2.45 | Neutral | 0.975 | Probably Damaging | 0.815 | Possibly Damaging | 1.55 | Pathogenic | 0.01 | Affected | 3.47 | 19 | 0.1005 | 0.6493 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||
| c.1010A>C | K337T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K337T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, FoldX, and premPS, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Three tools report uncertainty: Rosetta, Foldetta, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Pathogenic. In the high‑accuracy subset, AlphaMissense‑Optimized remains uncertain, SGM‑Consensus is Likely Pathogenic, and Foldetta is uncertain. Taken together, the majority of evidence points toward a deleterious effect. Therefore, K337T is most likely pathogenic, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.348540 | Uncertain | 0.449 | 0.438 | 0.500 | -10.896 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 0.45 | Likely Benign | 0.2 | 1.33 | Ambiguous | 0.89 | Ambiguous | 0.25 | Likely Benign | 0.338 | Likely Benign | -5.32 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.70 | Pathogenic | 0.01 | Affected | 0.1741 | 0.3354 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| 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.1261G>T | A421S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A421S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from PROVEAN, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as Likely Pathogenic. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus predicts pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Stability calculations from FoldX and Rosetta are uncertain, and premPS is unavailable. Overall, the majority of tools lean toward a pathogenic interpretation, and this aligns with the SGM‑Consensus result; there is no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.404927 | Uncertain | 0.965 | 0.257 | 0.000 | -9.220 | Likely Pathogenic | 0.715 | Likely Pathogenic | Likely Benign | 0.66 | Ambiguous | 0.1 | 1.12 | Ambiguous | 0.89 | Ambiguous | 0.70 | Ambiguous | 0.155 | Likely Benign | -2.50 | Deleterious | 0.058 | Benign | 0.072 | Benign | 3.46 | Benign | 0.08 | Tolerated | 0.2247 | 0.3621 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1430T>C | M477T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477T has no ClinVar entry and is present in gnomAD (ID 6‑33438462‑T‑C). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Default) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign (2 benign vs. 1 pathogenic votes); Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | 6-33438462-T-C | 2 | 1.24e-6 | -2.509 | Likely Benign | 0.373 | Ambiguous | Likely Benign | 1.62 | Ambiguous | 0.2 | 0.16 | Likely Benign | 0.89 | Ambiguous | 0.51 | Ambiguous | 0.273 | Likely Benign | -1.33 | Neutral | 0.765 | Possibly Damaging | 0.363 | Benign | -1.10 | Pathogenic | 0.40 | Tolerated | 3.37 | 34 | 0.2177 | 0.1950 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||
| c.1589A>T | K530M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS. Tools that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Based on the predominance of pathogenic predictions and the SGM Consensus result, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | -12.235 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 0.51 | Ambiguous | 0.0 | 1.26 | Ambiguous | 0.89 | Ambiguous | 0.24 | Likely Benign | 0.671 | Likely Pathogenic | -5.17 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | -1.69 | Pathogenic | 0.00 | Affected | 0.0745 | 0.3123 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1760G>A | R587K 2D 3DClick to see structure in 3D Viewer AISynGAP1 R587K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from SIFT and AlphaMissense‑Optimized, and pathogenic predictions from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, which is consistent with the SGM‑Consensus prediction but contradicts the benign calls from SIFT and AlphaMissense‑Optimized. Thus, the variant is most likely pathogenic, and this conclusion aligns with the lack of ClinVar annotation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.077330 | Uncertain | 0.862 | 0.216 | 0.000 | -10.220 | Likely Pathogenic | 0.433 | Ambiguous | Likely Benign | 0.63 | Ambiguous | 0.1 | 1.14 | Ambiguous | 0.89 | Ambiguous | 0.88 | Ambiguous | 0.539 | Likely Pathogenic | -2.55 | Deleterious | 0.967 | Probably Damaging | 0.955 | Probably Damaging | -1.16 | Pathogenic | 0.07 | Tolerated | 0.5313 | 0.3897 | Weaken | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||
| c.1790T>A | F597Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F597Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include ESM1b and Rosetta, whereas a majority of tools (REVEL, SIFT, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, PROVEAN, premPS, and AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive or unavailable are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, AlphaMissense‑Optimized as Uncertain, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for F597Y. This conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.142961 | Uncertain | 0.944 | 0.151 | 0.000 | -5.869 | Likely Benign | 0.796 | Likely Pathogenic | Ambiguous | 1.41 | Ambiguous | 0.1 | 0.37 | Likely Benign | 0.89 | Ambiguous | 1.11 | Destabilizing | 0.877 | Likely Pathogenic | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.976 | Probably Damaging | -1.99 | Pathogenic | 0.02 | Affected | 0.1471 | 0.1494 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.2123T>G | L708R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as Likely Pathogenic. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of tools (six pathogenic vs. four benign) and the SGM Consensus support a pathogenic classification, whereas AlphaMissense‑Optimized suggests benign. The variant is most likely pathogenic based on the collective predictions, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.250310 | Structured | 0.365875 | Uncertain | 0.931 | 0.378 | 0.000 | -9.154 | Likely Pathogenic | 0.638 | Likely Pathogenic | Likely Benign | 0.87 | Ambiguous | 0.0 | 0.90 | Ambiguous | 0.89 | Ambiguous | 1.24 | Destabilizing | 0.249 | Likely Benign | -4.18 | Deleterious | 0.988 | Probably Damaging | 0.598 | Possibly Damaging | 3.27 | Benign | 0.19 | Tolerated | 0.1091 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.947A>G | N316S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316S is catalogued in gnomAD (ID 6‑33437852‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Stability‑related methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates Likely Benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.118441 | Structured | 0.385187 | Uncertain | 0.817 | 0.246 | 0.125 | 6-33437852-A-G | 1 | 6.20e-7 | -4.512 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 1.19 | Ambiguous | 0.1 | 0.59 | Ambiguous | 0.89 | Ambiguous | 0.68 | Ambiguous | 0.151 | Likely Benign | -2.22 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 1.77 | Pathogenic | 0.38 | Tolerated | 3.38 | 23 | 0.4333 | 0.7751 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||
| c.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.1066C>A | R356S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R356S is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL and SIFT, whereas the remaining tools—premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized—predict it to be pathogenic. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is inconclusive. Taken together, the preponderance of evidence points to a pathogenic effect for R356S, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.219301 | Structured | 0.395028 | Uncertain | 0.802 | 0.373 | 0.250 | -13.059 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.90 | Ambiguous | 1.04 | Destabilizing | 0.292 | Likely Benign | -5.28 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 1.84 | Pathogenic | 0.07 | Tolerated | 0.2891 | 0.4491 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||
| c.1072T>C | F358L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F358L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results are reported for Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta’s stability prediction is unavailable due to inconclusiveness. Overall, the majority of available evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -7.865 | In-Between | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.18 | Likely Benign | 0.1 | 1.62 | Ambiguous | 0.90 | Ambiguous | 0.97 | Ambiguous | 0.290 | Likely Benign | -4.21 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 4.12 | Benign | 0.22 | Tolerated | 0.2555 | 0.3602 | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||
| c.1074C>A | F358L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F358L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results are reported for Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta’s stability prediction is unavailable due to inconclusiveness. Overall, the majority of available evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -7.865 | In-Between | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.18 | Likely Benign | 0.1 | 1.62 | Ambiguous | 0.90 | Ambiguous | 0.97 | Ambiguous | 0.215 | Likely Benign | -4.21 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 4.12 | Benign | 0.22 | Tolerated | 0.2555 | 0.3602 | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||
| c.1074C>G | F358L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F358L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta’s stability prediction is unavailable. Overall, the majority of reliable tools predict a pathogenic impact for F358L. This conclusion does not contradict ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -7.865 | In-Between | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.18 | Likely Benign | 0.1 | 1.62 | Ambiguous | 0.90 | Ambiguous | 0.97 | Ambiguous | 0.215 | Likely Benign | -4.21 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 4.12 | Benign | 0.22 | Tolerated | 0.2555 | 0.3602 | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||
| c.1207A>G | K403E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K403E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for K403E, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -15.279 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.01 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.90 | Ambiguous | 0.70 | Ambiguous | 0.445 | Likely Benign | -3.62 | Deleterious | 0.998 | Probably Damaging | 0.981 | Probably Damaging | 3.79 | Benign | 0.04 | Affected | 0.3650 | 0.1715 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1298C>G | A433G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A433G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach a consensus all indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. The protein‑folding stability method Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is therefore treated as unavailable evidence. Overall, the collective predictions strongly suggest that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.098513 | Structured | 0.352258 | Uncertain | 0.938 | 0.302 | 0.000 | -5.044 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.59 | Ambiguous | 0.0 | 1.21 | Ambiguous | 0.90 | Ambiguous | 0.70 | Ambiguous | 0.038 | Likely Benign | -1.54 | Neutral | 0.035 | Benign | 0.014 | Benign | 3.38 | Benign | 0.15 | Tolerated | 0.1629 | 0.2919 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1771G>T | A591S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A591S 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect, and the Foldetta stability analysis is inconclusive (unavailable). Consequently, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.018787 | Structured | 0.093848 | Uncertain | 0.882 | 0.185 | 0.000 | -7.535 | In-Between | 0.126 | Likely Benign | Likely Benign | 0.58 | Ambiguous | 0.1 | 1.21 | Ambiguous | 0.90 | Ambiguous | 0.49 | Likely Benign | 0.083 | Likely Benign | -2.11 | Neutral | 0.034 | Benign | 0.082 | Benign | 3.52 | Benign | 0.19 | Tolerated | 0.2405 | 0.3304 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1921T>C | S641P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S641P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and SIFT. The remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward 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 based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.125101 | Structured | 0.157322 | Uncertain | 0.786 | 0.270 | 0.000 | -6.907 | Likely Benign | 0.378 | Ambiguous | Likely Benign | 1.73 | Ambiguous | 1.3 | 0.07 | Likely Benign | 0.90 | Ambiguous | 0.59 | Ambiguous | 0.205 | Likely Benign | -3.05 | Deleterious | 0.000 | Benign | 0.000 | Benign | 3.34 | Benign | 0.04 | Affected | 0.2289 | 0.5791 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.2183C>A | P728H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P728H is 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, which scores the variant as benign. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default, all of which predict a deleterious impact. Predictions that are inconclusive or uncertain are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic effect for P728H, and this conclusion does not contradict any ClinVar status because the variant is not yet classified in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.632174 | Disordered | 0.434760 | Uncertain | 0.725 | 0.567 | 0.625 | -8.897 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 0.94 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.90 | Ambiguous | 0.64 | Ambiguous | 0.402 | Likely Benign | -7.23 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 0.65 | Pathogenic | 0.00 | Affected | 0.1993 | 0.3016 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||
| c.758A>G | N253S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253S is listed in ClinVar with no submitted interpretation and is present in gnomAD (ID 6‑33435609‑A‑G). Prediction tools that agree on a benign effect include premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the evidence is mixed, but the single high‑accuracy tool that is available points to a benign effect. Therefore, the variant is most likely benign based on current predictions, and this assessment does not contradict the ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | 6-33435609-A-G | -7.197 | In-Between | 0.541 | Ambiguous | Likely Benign | 0.60 | Ambiguous | 0.1 | 1.19 | Ambiguous | 0.90 | Ambiguous | -0.03 | Likely Benign | 0.716 | Likely Pathogenic | -4.26 | Deleterious | 0.993 | Probably Damaging | 0.956 | Probably Damaging | 5.56 | Benign | 0.09 | Tolerated | 3.39 | 15 | 0.3960 | 0.7764 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||
| c.1509G>C | Q503H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, SIFT, and FATHMM. FoldX, Rosetta, and Foldetta report uncertain or inconclusive stability changes and are therefore considered unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus inconclusive, and Foldetta remains uncertain. Overall, the majority of evaluated predictors (7 benign vs. 3 pathogenic) lean toward a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -5.335 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.94 | Ambiguous | 0.2 | 0.88 | Ambiguous | 0.91 | Ambiguous | 0.48 | Likely Benign | 0.331 | Likely Benign | -3.40 | Deleterious | 0.002 | Benign | 0.004 | Benign | -1.52 | Pathogenic | 0.01 | Affected | 0.1091 | 0.2125 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1509G>T | Q503H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, SIFT, and FATHMM. FoldX, Rosetta, and Foldetta report uncertain or inconclusive stability changes and are therefore considered unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus inconclusive, and Foldetta remains uncertain. Overall, the majority of evaluated predictors (7 benign vs. 3 pathogenic) lean toward a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -5.335 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.94 | Ambiguous | 0.2 | 0.88 | Ambiguous | 0.91 | Ambiguous | 0.48 | Likely Benign | 0.331 | Likely Benign | -3.40 | Deleterious | 0.002 | Benign | 0.004 | Benign | -1.52 | Pathogenic | 0.01 | Affected | 0.1091 | 0.2125 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1544G>A | R515H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R515H is listed in ClinVar with an uncertain significance (ClinVar ID 638438.0) and is present in gnomAD (variant ID 6‑33438787‑G‑A). Prediction tools that agree on a benign effect include AlphaMissense‑Default and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Overall, the balance of evidence favors a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | Uncertain | 1 | 6-33438787-G-A | 3 | 1.86e-6 | -10.774 | Likely Pathogenic | 0.337 | Likely Benign | Likely Benign | 1.07 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.91 | Ambiguous | 1.09 | Destabilizing | 0.730 | Likely Pathogenic | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2343 | 0.0746 | 2 | 0 | 1.3 | -19.05 | 239.2 | 77.8 | 0.0 | 0.0 | 0.4 | 0.2 | X | Potentially Benign | The guanidinium group of Arg515, located in the middle of an α-helix at the GAP domain (res. Gly502-Tyr518), forms salt bridges with the carboxylate groups of Glu512 on the same helix and Glu217 on a loop in the PH domain. Additionally, the positively charged Arg515 side chain forms hydrogen bonds with Leu610 and Gln612 in an opposing loop (res. Gly609-Asp616). In contrast, in the variant simulations, the imidazole ring of His515 cannot form salt bridges with either of the acidic residues, and its side chain is too short to form hydrogen bonds with the loop residues. Accordingly, the residue swap could weaken the tertiary structure assembly of the protein. Due to the missing N-terminal part of the SynGAP model, the effect could be largely underestimated or missing. Notably, the doubly protonated and positively charged form of histidine was not simulated here. | |||||||||||||
| c.1609G>C | A537P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FATHMM and Rosetta; FoldX and Foldetta are inconclusive. The high‑accuracy consensus (SGM‑Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN indicates a likely benign outcome, while AlphaMissense‑Optimized also predicts benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the majority of evidence points to a benign impact for A537P, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | 0.404 | Likely Benign | 0.102 | Likely Benign | Likely Benign | -0.61 | Ambiguous | 0.6 | 2.43 | Destabilizing | 0.91 | Ambiguous | -0.18 | Likely Benign | 0.218 | Likely Benign | 0.67 | Neutral | 0.020 | Benign | 0.022 | Benign | -1.29 | Pathogenic | 0.35 | Tolerated | 0.2152 | 0.3807 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1664T>C | V555A 2D 3DClick to see structure in 3D Viewer AISynGAP1 V555A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess sequence conservation and structural impact uniformly indicate a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all classify the variant as pathogenic. No tool predicts a benign outcome. Predictions that are inconclusive—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—are listed as uncertain and do not alter the overall assessment. High‑accuracy methods give a pathogenic consensus from SGM and an uncertain result from AlphaMissense‑Optimized and Foldetta. Consequently, the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.008218 | Uncertain | 0.943 | 0.225 | 0.000 | -8.781 | Likely Pathogenic | 0.857 | Likely Pathogenic | Ambiguous | 0.91 | Ambiguous | 0.0 | 0.90 | Ambiguous | 0.91 | Ambiguous | 1.04 | Destabilizing | 0.633 | Likely Pathogenic | -3.48 | Deleterious | 0.979 | Probably Damaging | 0.956 | Probably Damaging | -1.34 | Pathogenic | 0.01 | Affected | 0.2602 | 0.1761 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.2093A>G | E698G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E698G 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, premPS, and FATHMM. In contrast, a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all indicate deleteriousness. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E698G. This prediction aligns with the absence of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.120615 | Structured | 0.417514 | Uncertain | 0.922 | 0.315 | 0.000 | -10.617 | Likely Pathogenic | 0.786 | Likely Pathogenic | Ambiguous | 0.57 | Ambiguous | 0.0 | 1.25 | Ambiguous | 0.91 | Ambiguous | 0.29 | Likely Benign | 0.439 | Likely Benign | -6.37 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | 0.2529 | 0.3286 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| 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.614T>A | I205N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I205N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. No evidence from these tools contradicts the lack of ClinVar annotation. Overall, the majority of predictions (five pathogenic vs. four benign) and the pathogenic SGM Consensus suggest the variant is most likely pathogenic, with no ClinVar status to conflict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -10.928 | Likely Pathogenic | 0.552 | Ambiguous | Likely Benign | 0.66 | Ambiguous | 0.1 | 1.16 | Ambiguous | 0.91 | Ambiguous | 1.57 | Destabilizing | 0.138 | Likely Benign | -3.56 | Deleterious | 0.940 | Possibly Damaging | 0.641 | Possibly Damaging | 4.06 | Benign | 0.07 | Tolerated | 0.0802 | 0.0212 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||
| c.785A>G | N262S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N262S is not listed in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools cluster into two groups: benign predictions come from SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is uncertain. Consequently, the overall evidence is mixed, with a slight tilt toward pathogenicity because five tools predict pathogenic while four predict benign. The variant is most likely pathogenic based on the current predictions, and this assessment does not contradict ClinVar status, as the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.284882 | Structured | 0.399879 | Uncertain | 0.912 | 0.240 | 0.000 | -8.841 | Likely Pathogenic | 0.182 | Likely Benign | Likely Benign | 0.91 | Ambiguous | 0.2 | 0.90 | Ambiguous | 0.91 | Ambiguous | 0.69 | Ambiguous | 0.638 | Likely Pathogenic | -4.31 | Deleterious | 0.997 | Probably Damaging | 0.970 | Probably Damaging | 5.84 | Benign | 0.16 | Tolerated | 0.3101 | 0.5158 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||
| c.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.1214G>T | R405L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R405L missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are Rosetta and FATHMM, while the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) indicate a pathogenic or likely pathogenic impact. Uncertain results come from FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta providing an inconclusive stability prediction. Overall, the preponderance of evidence points to a pathogenic effect for R405L, 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 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | -11.576 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 1.43 | Ambiguous | 0.7 | 0.40 | Likely Benign | 0.92 | Ambiguous | 0.72 | Ambiguous | 0.512 | Likely Pathogenic | -6.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.64 | Benign | 0.01 | Affected | 0.2126 | 0.5555 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1460A>T | N487I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N487I has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely disagree, but the majority indicate a deleterious effect. Benign predictions come from Rosetta, premPS, and FATHMM, whereas pathogenic predictions are reported by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are provided by FoldX and Foldetta. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenic; Foldetta remains inconclusive. Overall, the preponderance of evidence supports a pathogenic classification for N487I, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -16.592 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.71 | Ambiguous | 0.1 | 0.13 | Likely Benign | 0.92 | Ambiguous | 0.33 | Likely Benign | 0.591 | Likely Pathogenic | -8.95 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.67 | Benign | 0.00 | Affected | 0.0633 | 0.3531 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.1540A>G | I514V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514V is catalogued in gnomAD (variant ID 6‑33438783‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are limited to polyPhen‑2 HumDiv and HumVar. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence indicates that I514V is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | 6-33438783-A-G | 7 | 4.34e-6 | -5.187 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 1.39 | Ambiguous | 0.0 | 0.44 | Likely Benign | 0.92 | Ambiguous | 0.89 | Ambiguous | 0.173 | Likely Benign | -0.79 | Neutral | 0.914 | Possibly Damaging | 0.960 | Probably Damaging | 3.15 | Benign | 0.13 | Tolerated | 3.37 | 35 | 0.0939 | 0.2130 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||
| c.1636T>A | C546S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C546S is reported in gnomAD (ID 6‑33438879‑T‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from FoldX and SIFT; pathogenic predictions from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give uncertain results: Rosetta and Foldetta. High‑accuracy assessments reinforce a pathogenic signal: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains inconclusive. Overall, the preponderance of evidence, including the high‑accuracy tools, indicates that C546S is most likely pathogenic, and this assessment does not conflict with any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | 6-33438879-T-A | 1 | 6.20e-7 | -8.079 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.44 | Likely Benign | 0.1 | 1.39 | Ambiguous | 0.92 | Ambiguous | 1.65 | Destabilizing | 0.836 | Likely Pathogenic | -8.04 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.21 | Pathogenic | 0.17 | Tolerated | 3.37 | 35 | 0.4343 | 0.1950 | -1 | 0 | -3.3 | -16.06 | ||||||||||||||||||||||||
| c.1637G>C | C546S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C546S is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX and SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta and Foldetta are uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for C546S, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | -8.079 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.44 | Likely Benign | 0.1 | 1.39 | Ambiguous | 0.92 | Ambiguous | 1.65 | Destabilizing | 0.788 | Likely Pathogenic | -8.04 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.21 | Pathogenic | 0.17 | Tolerated | 3.37 | 35 | 0.4343 | 0.1950 | -1 | 0 | -3.3 | -16.06 | |||||||||||||||||||||||||||
| c.1927G>A | E643K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic calls arise from SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Four tools (Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta) give uncertain results. High‑accuracy assessments focus on AlphaMissense‑Optimized (Uncertain), SGM‑Consensus (Likely Pathogenic), and Foldetta (Uncertain). Because the consensus of the most reliable predictors leans toward pathogenicity, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -14.318 | Likely Pathogenic | 0.868 | Likely Pathogenic | Ambiguous | 0.39 | Likely Benign | 0.2 | 1.44 | Ambiguous | 0.92 | Ambiguous | 0.82 | Ambiguous | 0.449 | Likely Benign | -3.79 | Deleterious | 0.042 | Benign | 0.004 | Benign | 2.95 | Benign | 0.04 | Affected | 0.2961 | 0.6269 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1990T>A | L664M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also uncertain due to a 2‑vs‑2 split; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of conventional tools predict a pathogenic impact, whereas the high‑accuracy methods do not provide a definitive verdict. Consequently, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | -11.819 | Likely Pathogenic | 0.807 | Likely Pathogenic | Ambiguous | 0.49 | Likely Benign | 0.1 | 1.35 | Ambiguous | 0.92 | Ambiguous | 0.96 | Ambiguous | 0.429 | Likely Benign | -2.00 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.92 | Benign | 0.01 | Affected | 0.0620 | 0.2541 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.2015C>T | T672M 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant T672M is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33441274‑C‑T). Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Rosetta and Foldetta report uncertain results, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta remain unavailable. Overall, the balance of evidence favors a benign effect, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.116183 | Structured | 0.102069 | Uncertain | 0.586 | 0.362 | 0.000 | Conflicting | 3 | 6-33441274-C-T | 19 | 1.18e-5 | -9.472 | Likely Pathogenic | 0.174 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.4 | 1.52 | Ambiguous | 0.92 | Ambiguous | 0.41 | Likely Benign | 0.127 | Likely Benign | -4.34 | Deleterious | 0.993 | Probably Damaging | 0.520 | Possibly Damaging | 3.39 | Benign | 0.00 | Affected | 3.40 | 25 | 0.1332 | 0.6677 | -1 | -1 | 2.6 | 30.09 | 231.9 | -52.9 | 1.1 | 0.1 | 0.5 | 0.0 | X | X | Potentially Pathogenic | The hydroxyl group of Thr672, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop itself, such as Lys566, Glu666, and Asn669. Met672 can only form a hydrogen bond with the amino group of the Lys566 side chain via its backbone carbonyl group. Nevertheless, the Lys566-Glu666 salt bridge forms intermittently. This is possible because Asn669 keeps the carboxylate group of Glu666 in the vicinity through hydrogen bonding, and the hydrophobic side chain of Met stays mostly rotated away from the salt bridge. Consequently, no drastic disruption of the hydrogen-bond network that keeps the loop close to the helices occurs in the variant simulations. | |||||||||||||
| c.710C>T | A237V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237V is not reported in ClinVar and is absent from gnomAD. Standard in‑silico predictors are divided: benign calls come from premPS, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 HumDiv, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) are uncertain. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a pathogenic outcome from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain result from Foldetta. Because the majority of conventional predictors and the optimized AlphaMissense model favor benign, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -8.927 | Likely Pathogenic | 0.397 | Ambiguous | Likely Benign | 0.87 | Ambiguous | 0.4 | 0.97 | Ambiguous | 0.92 | Ambiguous | 0.18 | Likely Benign | 0.565 | Likely Pathogenic | -3.26 | Deleterious | 0.900 | Possibly Damaging | 0.430 | Benign | 5.87 | Benign | 0.10 | Tolerated | 0.0771 | 0.4853 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.939G>C | E313D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and SIFT, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating a likely pathogenic effect, and Foldetta yielding an uncertain stability change. Overall, the balance of evidence points to a pathogenic interpretation; this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | -8.309 | Likely Pathogenic | 0.636 | Likely Pathogenic | Likely Benign | 0.87 | Ambiguous | 0.0 | 0.96 | Ambiguous | 0.92 | Ambiguous | 0.60 | Ambiguous | 0.346 | Likely Benign | -1.66 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.88 | Pathogenic | 0.14 | Tolerated | 0.1970 | 0.4640 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.939G>T | E313D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and SIFT, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating a likely pathogenic outcome, and Foldetta yielding an uncertain stability change. Overall, the balance of evidence points to a pathogenic effect for E313D, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | -8.309 | Likely Pathogenic | 0.636 | Likely Pathogenic | Likely Benign | 0.87 | Ambiguous | 0.0 | 0.96 | Ambiguous | 0.92 | Ambiguous | 0.60 | Ambiguous | 0.346 | Likely Benign | -1.66 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.88 | Pathogenic | 0.14 | Tolerated | 0.1970 | 0.4640 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1126G>A | G376S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G376S is reported in gnomAD (ID 6‑33438031‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Pathogenic predictions arise from FoldX, polyPhen‑2 (HumDiv and HumVar), and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates benign, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of evidence points to a benign effect; this conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.680603 | Disordered | 0.428979 | Uncertain | 0.326 | 0.869 | 0.625 | 6-33438031-G-A | 1 | 6.21e-7 | -4.913 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 2.30 | Destabilizing | 0.5 | -0.45 | Likely Benign | 0.93 | Ambiguous | 0.32 | Likely Benign | 0.471 | Likely Benign | -0.73 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.33 | Pathogenic | 0.22 | Tolerated | 4.32 | 12 | 0.2831 | 0.4801 | 0 | 1 | -0.4 | 30.03 | ||||||||||||||||||||||||
| c.1256A>T | E419V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E419V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, FATHMM, and premPS, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies 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 outputs, yields an uncertain result. No evidence from the high‑accuracy tools contradicts the pathogenic prediction. Overall, the majority of computational evidence points to a pathogenic effect, which is consistent with the lack of ClinVar reporting and gnomAD absence, suggesting the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -12.290 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.45 | Likely Benign | 0.0 | 1.41 | Ambiguous | 0.93 | Ambiguous | 0.27 | Likely Benign | 0.494 | Likely Benign | -6.55 | Deleterious | 0.998 | Probably Damaging | 0.983 | Probably Damaging | 3.35 | Benign | 0.01 | Affected | 0.0953 | 0.6834 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1730C>G | A577G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A577G is listed in ClinVar as Benign (ClinVar ID 1010280.0) and is present in gnomAD (ID 6‑33440782‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy methods give a benign verdict: AlphaMissense‑Optimized is benign, the SGM‑Consensus is Likely Benign, and Foldetta is uncertain. Overall, the majority of reliable predictions support a benign impact, which is consistent with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | Benign/Likely benign | 2 | 6-33440782-C-G | 1 | 6.20e-7 | -5.717 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.83 | Ambiguous | 0.0 | 1.02 | Ambiguous | 0.93 | Ambiguous | 0.86 | Ambiguous | 0.443 | Likely Benign | -1.84 | Neutral | 0.997 | Probably Damaging | 0.990 | Probably Damaging | -1.31 | Pathogenic | 0.31 | Tolerated | 3.37 | 34 | 0.2120 | 0.3780 | 1 | 0 | -2.2 | -14.03 | 158.7 | 23.6 | 0.0 | 0.0 | 0.0 | 0.0 | X | Potentially Benign | Ala577 is located near the end and outer surface of an α-helix (res. Arg563-Glu578), where its methyl group does not form any particular interactions in the WT simulations. The introduced residue, glycine, is known as an “α-helix breaker.” However, the residue swap caused only minor helix shortening in one of the replica simulations for the variant system. Regardless, the residue swap seems to be well tolerated based on the variant simulations. | |||||||||||||
| c.1804A>T | I602F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I602F missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign outcome. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Taken together, the overwhelming majority of evidence points to a pathogenic effect. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -13.974 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 2.47 | Destabilizing | 1.1 | -0.61 | Ambiguous | 0.93 | Ambiguous | 0.87 | Ambiguous | 0.822 | Likely Pathogenic | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.937 | Probably Damaging | -1.82 | Pathogenic | 0.00 | Affected | 0.0708 | 0.2343 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1816A>G | S606G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S606G is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by SGM‑Consensus, PROVEAN, 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 (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result and is treated as unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -12.281 | Likely Pathogenic | 0.603 | Likely Pathogenic | Likely Benign | 0.43 | Likely Benign | 0.1 | 1.42 | Ambiguous | 0.93 | Ambiguous | 0.84 | Ambiguous | 0.229 | Likely Benign | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.35 | Benign | 0.04 | Affected | 0.2286 | 0.3279 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.1980G>A | M660I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M660I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and the protein‑folding stability method Foldetta returns an uncertain result. Stability predictions from FoldX, Rosetta, and premPS are also inconclusive. Overall, the majority of evidence points to a pathogenic effect for M660I. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.134270 | Uncertain | 0.944 | 0.289 | 0.000 | -11.150 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.15 | Ambiguous | 0.1 | 0.71 | Ambiguous | 0.93 | Ambiguous | 0.95 | Ambiguous | 0.464 | Likely Benign | -3.99 | Deleterious | 0.887 | Possibly Damaging | 0.289 | Benign | 3.52 | Benign | 0.04 | Affected | 0.1170 | 0.2878 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1980G>C | M660I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M660I (GAP domain) is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, polyPhen‑2 HumVar, and FATHMM. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No other stability predictions are available. Overall, the preponderance of evidence points to a pathogenic effect for M660I. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.134270 | Uncertain | 0.944 | 0.289 | 0.000 | -11.150 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.15 | Ambiguous | 0.1 | 0.71 | Ambiguous | 0.93 | Ambiguous | 0.95 | Ambiguous | 0.464 | Likely Benign | -3.99 | Deleterious | 0.887 | Possibly Damaging | 0.289 | Benign | 3.52 | Benign | 0.04 | Affected | 0.1170 | 0.2878 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1980G>T | M660I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M660I (GAP domain) is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, polyPhen‑2 HumVar, and FATHMM. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No other stability predictions are available. Overall, the preponderance of evidence points to a pathogenic effect for M660I. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.134270 | Uncertain | 0.944 | 0.289 | 0.000 | -11.150 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.15 | Ambiguous | 0.1 | 0.71 | Ambiguous | 0.93 | Ambiguous | 0.95 | Ambiguous | 0.464 | Likely Benign | -3.99 | Deleterious | 0.887 | Possibly Damaging | 0.289 | Benign | 3.52 | Benign | 0.04 | Affected | 0.1170 | 0.2878 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.649G>C | E217Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E217Q is reported in gnomAD (ID 6‑33435291‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With six benign versus three pathogenic calls and a benign consensus from the high‑accuracy panel, the variant is most likely benign. This conclusion does not contradict ClinVar, which contains no classification for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | 6-33435291-G-C | 1 | 6.20e-7 | -6.810 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.25 | Likely Benign | 0.2 | 1.61 | Ambiguous | 0.93 | Ambiguous | 0.67 | Ambiguous | 0.459 | Likely Benign | -1.89 | Neutral | 0.900 | Possibly Damaging | 0.461 | Possibly Damaging | 5.83 | Benign | 0.14 | Tolerated | 3.41 | 13 | 0.1474 | 0.8473 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||
| c.695C>G | A232G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A232G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the change as benign include REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Those that predict pathogenicity are polyPhen‑2 HumDiv and AlphaMissense‑Default. Uncertain or inconclusive results come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a benign effect; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -4.924 | Likely Benign | 0.835 | Likely Pathogenic | Ambiguous | 0.43 | Likely Benign | 0.1 | 1.43 | Ambiguous | 0.93 | Ambiguous | 0.53 | Ambiguous | 0.453 | Likely Benign | -1.39 | Neutral | 0.608 | Possibly Damaging | 0.172 | Benign | 5.81 | Benign | 0.11 | Tolerated | 0.2012 | 0.4724 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.697T>A | C233S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors pathogenicity (3 pathogenic vs 1 benign). Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -10.862 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.61 | Ambiguous | 0.1 | 1.25 | Ambiguous | 0.93 | Ambiguous | 1.50 | Destabilizing | 0.764 | Likely Pathogenic | -8.89 | Deleterious | 0.421 | Benign | 0.080 | Benign | 5.79 | Benign | 0.03 | Affected | 0.4528 | 0.2833 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.698G>C | C233S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of evidence points to a pathogenic impact for C233S, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -10.862 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.61 | Ambiguous | 0.1 | 1.25 | Ambiguous | 0.93 | Ambiguous | 1.50 | Destabilizing | 0.830 | Likely Pathogenic | -8.89 | Deleterious | 0.421 | Benign | 0.080 | Benign | 5.79 | Benign | 0.03 | Affected | 0.4528 | 0.2833 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1046C>T | P349L 2D AIThe SynGAP1 missense variant P349L is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and AlphaMissense‑Optimized, whereas the majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy methods give conflicting results: AlphaMissense‑Optimized reports a benign outcome, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Other stability‑based predictors (FoldX, Rosetta, premPS) are also inconclusive. Overall, the preponderance of evidence from the consensus of multiple in‑silico tools points to a pathogenic effect for P349L. This prediction does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -11.734 | Likely Pathogenic | 0.650 | Likely Pathogenic | Likely Benign | 0.70 | Ambiguous | 0.6 | 1.17 | Ambiguous | 0.94 | Ambiguous | 0.57 | Ambiguous | 0.326 | Likely Benign | -8.04 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | 0.2222 | 0.6867 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.1181A>T | K394I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K394I missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include premPS, polyPhen‑2 HumVar, and FATHMM, while a majority (seven) predict pathogenicity: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) remains Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No evidence from these tools contradicts the ClinVar status, which is absent. Overall, the preponderance of pathogenic predictions suggests the variant is most likely pathogenic, with no conflict from ClinVar data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | -9.244 | Likely Pathogenic | 0.876 | Likely Pathogenic | Ambiguous | 0.78 | Ambiguous | 0.2 | 1.10 | Ambiguous | 0.94 | Ambiguous | 0.19 | Likely Benign | 0.519 | Likely Pathogenic | -3.96 | Deleterious | 0.700 | Possibly Damaging | 0.403 | Benign | 4.59 | Benign | 0.00 | Affected | 0.1728 | 0.4123 | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||
| c.1480A>G | I494V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant I494V is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438512‑A‑G). Functional prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Pathogenic predictions come from premPS and FATHMM. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign; Foldetta remains uncertain. Overall, the majority of evidence supports a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | Conflicting | 2 | 6-33438512-A-G | 36 | 2.23e-5 | -7.102 | In-Between | 0.112 | Likely Benign | Likely Benign | 1.16 | Ambiguous | 0.0 | 0.71 | Ambiguous | 0.94 | Ambiguous | 1.02 | Destabilizing | 0.439 | Likely Benign | -0.83 | Neutral | 0.278 | Benign | 0.179 | Benign | -1.30 | Pathogenic | 0.07 | Tolerated | 3.37 | 35 | 0.0965 | 0.2491 | 4 | 3 | -0.3 | -14.03 | 248.6 | 29.3 | 0.0 | 0.0 | -1.1 | 0.5 | X | Potentially Benign | The sec-butyl side chain of Ile494, located in an α-helix (res. Leu489-Glu519), packs against hydrophobic residues (e.g., Phe484, Leu465, Trp572, Ala493, Met468) in an inter-helix space (res. Leu489-Glu519 and res. Ala461-Phe476). In the variant simulations, the hydrophobic iso-propyl side chain of Val494, which is of a similar size and has similar physicochemical properties to Ile494 in the WT, resides similarly in the inter-helix hydrophobic space. Thus, no negative effects on the protein structure are observed. | ||||||||||||||
| c.1679T>C | V560A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V560A is not reported in ClinVar (ClinVar status: none) and has no entry in gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta remains uncertain. Overall, the majority of predictions (eight pathogenic vs. three benign) indicate 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 | GAP | 0.021381 | Structured | 0.013872 | Uncertain | 0.853 | 0.204 | 0.000 | -8.260 | Likely Pathogenic | 0.701 | Likely Pathogenic | Likely Benign | 0.54 | Ambiguous | 0.1 | 1.33 | Ambiguous | 0.94 | Ambiguous | 1.19 | Destabilizing | 0.447 | Likely Benign | -3.15 | Deleterious | 0.911 | Possibly Damaging | 0.657 | Possibly Damaging | -1.20 | Pathogenic | 0.31 | Tolerated | 0.2549 | 0.2212 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1760G>C | R587T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R587T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT and AlphaMissense‑Optimized, whereas a majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic outcome. Uncertain predictions from FoldX, Rosetta, Foldetta, and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R587T, which does not contradict the ClinVar “Uncertain” classification but suggests that the variant is more likely pathogenic rather than benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.077330 | Uncertain | 0.862 | 0.216 | 0.000 | Uncertain | 1 | -9.697 | Likely Pathogenic | 0.784 | Likely Pathogenic | Likely Benign | 1.14 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.94 | Ambiguous | 0.98 | Ambiguous | 0.603 | Likely Pathogenic | -4.71 | Deleterious | 0.998 | Probably Damaging | 0.847 | Possibly Damaging | -1.19 | Pathogenic | 0.08 | Tolerated | 3.37 | 35 | 0.1958 | 0.4578 | -1 | -1 | 3.8 | -55.08 | 227.2 | 87.4 | 0.0 | 0.0 | 0.5 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg587, located on an α helix (res. Glu582-Met603), is constantly rotating and breaking/forming multiple hydrogen bonds and/or salt bridges at the surface intersection of α helices in the WT simulations. The positively charged Arg587 side chain can form a salt bridge with either the carboxylate group of Asp583 or Asp586 in the same helix, or with Glu480 on the opposing short helical loop structure (res. Glu480-Leu482).Importantly, the Arg587 side chain also hydrogen bonds with the backbone carbonyl groups of Ala634 and Asn635, as well as the carboxamide group of Asn635 at the end of another α helix (res. Asp616-Phe636). However, in the variant simulations, the neutral hydroxyl group of the Thr587 side chain is unable to form these salt bridges. Due to its smaller size, it also does not form the hydrogen bonds that the Arg587 side chain could. Instead, the hydroxyl group of Thr587 hydrogen bonds with the backbone carbonyl group of Asp583, which could weaken the integrity of the α helix, although this is not observed in the simulations.Overall, the residue swap could weaken the tertiary structure assembly and negatively affect the overall protein folding process. | ||||||||||||||||
| c.1819C>A | L607I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L607I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default, while benign calls are made by PROVEAN and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Stability predictions from FoldX, Rosetta, and premPS are inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for L607I. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | -12.061 | Likely Pathogenic | 0.644 | Likely Pathogenic | Likely Benign | 0.63 | Ambiguous | 0.1 | 1.25 | Ambiguous | 0.94 | Ambiguous | 0.82 | Ambiguous | 0.727 | Likely Pathogenic | -1.99 | Neutral | 0.992 | Probably Damaging | 0.997 | Probably Damaging | -1.54 | Pathogenic | 0.01 | Affected | 0.1079 | 0.3767 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.2041G>A | G681S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G681S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, and FATHMM, while those that predict a pathogenic outcome are SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain result. Overall, the majority of tools lean toward pathogenicity, but the presence of a benign prediction from AlphaMissense‑Optimized and an uncertain Foldetta score leaves the assessment inconclusive. No ClinVar entry exists, so there is no contradiction with clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | -9.913 | Likely Pathogenic | 0.716 | Likely Pathogenic | Likely Benign | 2.11 | Destabilizing | 1.3 | -0.23 | Likely Benign | 0.94 | Ambiguous | 0.41 | Likely Benign | 0.483 | Likely Benign | -5.99 | Deleterious | 0.997 | Probably Damaging | 0.780 | Possibly Damaging | 3.45 | Benign | 0.08 | Tolerated | 0.2591 | 0.4584 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.2182C>T | P728S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P728S is not reported in ClinVar and is present in gnomAD (ID 6‑33441647‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, whereas the majority of tools predict pathogenicity: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results from FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized are treated as unavailable. High‑accuracy consensus methods give a Likely Pathogenic verdict from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and an Uncertain outcome from AlphaMissense‑Optimized; Foldetta also reports Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for P728S, 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 | 0.632174 | Disordered | 0.434760 | Uncertain | 0.725 | 0.567 | 0.625 | 6-33441647-C-T | 1 | 6.20e-7 | -9.047 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 0.89 | Ambiguous | 0.0 | 0.98 | Ambiguous | 0.94 | Ambiguous | 0.54 | Ambiguous | 0.280 | Likely Benign | -6.38 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 0.68 | Pathogenic | 0.00 | Affected | 3.59 | 7 | 0.3571 | 0.3571 | -1 | 1 | 0.8 | -10.04 | |||||||||||||||||||||||||
| c.701G>T | R234L 2D AIThe SynGAP1 missense variant R234L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, polyPhen‑2 HumVar, SIFT, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (7 pathogenic vs. 4 benign) and the pathogenic consensus from the high‑accuracy SGM‑Consensus suggest that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | -11.153 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.38 | Ambiguous | 0.9 | 0.50 | Ambiguous | 0.94 | Ambiguous | 0.20 | Likely Benign | 0.734 | Likely Pathogenic | -4.64 | Deleterious | 0.649 | Possibly Damaging | 0.199 | Benign | 5.78 | Benign | 0.11 | Tolerated | 0.1846 | 0.4783 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.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.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.1226T>C | M409T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized indicates a benign effect, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports a pathogenic outcome; Foldetta remains inconclusive. Overall, the majority of evidence, including the SGM‑Consensus, points to a pathogenic impact for M409T. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -9.194 | Likely Pathogenic | 0.607 | Likely Pathogenic | Likely Benign | 1.41 | Ambiguous | 0.2 | 0.48 | Likely Benign | 0.95 | Ambiguous | 0.96 | Ambiguous | 0.262 | Likely Benign | -3.18 | Deleterious | 0.987 | Probably Damaging | 0.945 | Probably Damaging | 4.17 | Benign | 0.45 | Tolerated | 0.1835 | 0.2391 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||
| c.1289T>C | M430T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430T is reported in gnomAD (6‑33438194‑T‑C) and has no ClinVar entry. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, FoldX (uncertain), Rosetta, Foldetta (uncertain), 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 methods reinforce this view: AlphaMissense‑Optimized is benign, the SGM Consensus is likely benign, and Foldetta is uncertain. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic report. Thus, the variant is most likely benign, and this is not contradictory to ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | 6-33438194-T-C | 1 | 6.19e-7 | -3.430 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 1.89 | Ambiguous | 0.1 | 0.01 | Likely Benign | 0.95 | Ambiguous | 0.43 | Likely Benign | 0.103 | Likely Benign | -1.48 | Neutral | 0.016 | Benign | 0.010 | Benign | 3.48 | Benign | 0.40 | Tolerated | 3.37 | 29 | 0.2002 | 0.3184 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||
| c.1296T>G | C432W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C432W is 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, PROVEAN). High‑accuracy assessments reinforce this: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus indicates a likely pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result, providing no counter‑evidence. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic effect. This conclusion is consistent with the absence of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -13.936 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.17 | Ambiguous | 0.4 | 0.72 | Ambiguous | 0.95 | Ambiguous | 0.58 | Ambiguous | 0.433 | Likely Benign | -10.50 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 3.43 | Benign | 0.00 | Affected | 0.1217 | 0.3246 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1357C>A | H453N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H453N is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. A third set of methods (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) yield uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, the majority of evidence points toward a pathogenic effect for H453N. This conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -8.416 | Likely Pathogenic | 0.789 | Likely Pathogenic | Ambiguous | 0.93 | Ambiguous | 0.1 | 0.97 | Ambiguous | 0.95 | Ambiguous | 0.78 | Ambiguous | 0.347 | Likely Benign | -6.92 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.48 | Benign | 0.09 | Tolerated | 0.1435 | 0.2548 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| c.1384A>G | K462E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K462E is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta and Foldetta are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta is uncertain. Overall, the majority of predictions (7 pathogenic vs. 5 benign) and the high‑accuracy tools support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | -14.696 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.34 | Likely Benign | 0.0 | 1.56 | Ambiguous | 0.95 | Ambiguous | 0.33 | Likely Benign | 0.433 | Likely Benign | -3.88 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 3.49 | Benign | 0.15 | Tolerated | 0.4145 | 0.1022 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1496G>A | R499K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive, providing no evidence for either direction. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign prediction; Foldetta remains uncertain. Overall, the preponderance of evidence points to a benign effect for R499K, and this conclusion is consistent with the absence of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | 4.366 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 1.37 | Ambiguous | 0.1 | 0.53 | Ambiguous | 0.95 | Ambiguous | -0.77 | Ambiguous | 0.248 | Likely Benign | 1.94 | Neutral | 0.001 | Benign | 0.008 | Benign | -1.03 | Pathogenic | 1.00 | Tolerated | 0.3531 | 0.1881 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||||
| c.1688G>C | R563T 2D 3DClick to see structure in 3D Viewer AISynGAP1 R563T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The remaining tools—FoldX, Rosetta, ESM1b, AlphaMissense‑Optimized, and Foldetta—give uncertain or inconclusive results. High‑accuracy methods provide the following: AlphaMissense‑Optimized is unavailable; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic; Foldetta is unavailable. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.039760 | Structured | 0.031987 | Uncertain | 0.876 | 0.209 | 0.000 | -7.088 | In-Between | 0.913 | Likely Pathogenic | Ambiguous | 1.13 | Ambiguous | 0.1 | 0.77 | Ambiguous | 0.95 | Ambiguous | 0.18 | Likely Benign | 0.307 | Likely Benign | -4.77 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.49 | Benign | 0.23 | Tolerated | 0.2115 | 0.3148 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||
| c.1723C>T | R575C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R575C is listed in ClinVar with an “Uncertain” status (ClinVar ID 537013.0) and is present in gnomAD (ID 6‑33440775‑C‑T). Prediction tools that indicate a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of predictions support a pathogenic effect. Thus, the variant is most likely pathogenic, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.021362 | Uncertain | 0.916 | 0.259 | 0.000 | Conflicting | 3 | 6-33440775-C-T | 23 | 1.43e-5 | -11.179 | Likely Pathogenic | 0.630 | Likely Pathogenic | Likely Benign | 1.39 | Ambiguous | 0.2 | 0.50 | Ambiguous | 0.95 | Ambiguous | 0.73 | Ambiguous | 0.715 | Likely Pathogenic | -5.43 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.30 | Pathogenic | 0.02 | Affected | 3.37 | 35 | 0.2969 | 0.1692 | -4 | -3 | 7.0 | -53.05 | 227.7 | 99.2 | 0.0 | 0.0 | 0.0 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg575, located in an α-helix (res. Arg563-Glu578), forms salt bridges with the carboxylate groups of Asp463 and Asp467, and it also hydrogen bonds with the hydroxyl group of Ser466 on an opposing α-helix (res. Ala461-Phe476) in the WT simulations. In the variant simulations, the thiol group of the Cys575 side chain, which is neither positively charged nor particularly hydrophilic, packs against the hydrophobic Met470 on an opposing α-helix (res. Ala461-Arg475). Additionally, although the thiol group is not an effective hydrogen bonder, the Cys575 side chain rotates to hydrogen bond with the backbone carbonyl group of Ser571 in the same α-helix, which could theoretically lower the helix integrity. Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process. | |||||||||||||
| c.1756G>C | D586H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D586H missense variant is not reported in ClinVar and has no gnomAD entry. Prediction tools cluster into two groups: benign predictions come from premPS and SIFT, while the remaining nine tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all indicate pathogenicity. The high‑accuracy methods reinforce this trend: AlphaMissense‑Optimized scores the variant as pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is consistent with the absence of ClinVar annotation, as there is no conflicting status to contradict the prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -10.104 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.3 | 0.89 | Ambiguous | 0.95 | Ambiguous | 0.26 | Likely Benign | 0.672 | Likely Pathogenic | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.23 | Pathogenic | 0.17 | Tolerated | 0.1307 | 0.5558 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.2007T>A | N669K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a Likely Pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.086615 | Uncertain | 0.872 | 0.380 | 0.000 | -10.797 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.39 | Likely Benign | 0.3 | 1.50 | Ambiguous | 0.95 | Ambiguous | 0.94 | Ambiguous | 0.243 | Likely Benign | -5.35 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.41 | Benign | 0.03 | Affected | 0.2647 | 0.3312 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.2007T>G | N669K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus concurs, and the Foldetta stability analysis is inconclusive and therefore not used as evidence. No other tools provide definitive support for benignity. Consequently, the preponderance of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.086615 | Uncertain | 0.872 | 0.380 | 0.000 | -10.797 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.39 | Likely Benign | 0.3 | 1.50 | Ambiguous | 0.95 | Ambiguous | 0.94 | Ambiguous | 0.243 | Likely Benign | -5.35 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.41 | Benign | 0.03 | Affected | 0.2647 | 0.3312 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.2187C>A | N729K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729K has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus call (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. Tools with uncertain or mixed results are Foldetta (protein‑folding stability) and Rosetta. High‑accuracy assessments: AlphaMissense‑Optimized reports a benign effect; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign; Foldetta’s stability prediction is inconclusive. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict the current ClinVar status, which contains no report for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | -5.101 | Likely Benign | 0.648 | Likely Pathogenic | Likely Benign | -0.03 | Likely Benign | 0.1 | 1.92 | Ambiguous | 0.95 | Ambiguous | 0.12 | Likely Benign | 0.036 | Likely Benign | -1.39 | Neutral | 0.109 | Benign | 0.033 | Benign | 3.51 | Benign | 0.47 | Tolerated | 0.1948 | 0.3612 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2187C>G | N729K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729K has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus call (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. Tools with uncertain or mixed results are Foldetta (protein‑folding stability) and Rosetta. High‑accuracy assessments: AlphaMissense‑Optimized reports a benign effect; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign; Foldetta’s stability prediction is inconclusive. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict the current ClinVar status, which contains no report for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | -5.101 | Likely Benign | 0.648 | Likely Pathogenic | Likely Benign | -0.03 | Likely Benign | 0.1 | 1.92 | Ambiguous | 0.95 | Ambiguous | 0.12 | Likely Benign | 0.036 | Likely Benign | -1.39 | Neutral | 0.109 | Benign | 0.033 | Benign | 3.51 | Benign | 0.47 | Tolerated | 0.1948 | 0.3612 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.869T>C | L290P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L290P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously favor a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenicity. No tool in the dataset predicts a benign outcome; the remaining tools (FoldX, Rosetta, Foldetta, premPS) return uncertain results, which are treated as unavailable evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is inconclusive. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.127496 | Structured | 0.399723 | Uncertain | 0.904 | 0.255 | 0.000 | -11.796 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.79 | Ambiguous | 0.1 | 1.10 | Ambiguous | 0.95 | Ambiguous | 0.56 | Ambiguous | 0.727 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.01 | Pathogenic | 0.03 | Affected | 0.3646 | 0.1703 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.953C>G | P318R 2D 3DClick to see structure in 3D Viewer AISynGAP1 P318R is not reported in ClinVar and is absent from gnomAD. In silico predictors that classify the variant as benign: none. Those that predict pathogenicity include SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions from FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy tools give a consistent pathogenic signal: AlphaMissense‑Optimized reports pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; Foldetta remains inconclusive. Overall, the consensus of the majority of predictors supports a pathogenic effect. This conclusion is not contradicted by ClinVar status, which is currently unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.111485 | Structured | 0.400936 | Uncertain | 0.858 | 0.234 | 0.000 | -14.132 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 1.20 | Ambiguous | 0.1 | 0.70 | Ambiguous | 0.95 | Ambiguous | 1.01 | Destabilizing | 0.643 | Likely Pathogenic | -8.01 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.84 | Pathogenic | 0.01 | Affected | 0.1308 | 0.3310 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1064G>T | G355V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G355V is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or unavailable results are reported for FoldX, premPS, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect. Foldetta’s stability prediction is unavailable. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.388832 | Uncertain | 0.810 | 0.354 | 0.125 | -10.111 | Likely Pathogenic | 0.675 | Likely Pathogenic | Likely Benign | 1.78 | Ambiguous | 0.6 | 0.14 | Likely Benign | 0.96 | Ambiguous | 0.53 | Ambiguous | 0.346 | Likely Benign | -7.59 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.78 | Pathogenic | 0.04 | Affected | 0.1221 | 0.4685 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1226T>G | M409R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409R is not reported in ClinVar and is present in gnomAD (ID 6‑33438131‑T‑G). Functional prediction tools cluster into two groups: benign (REVEL, SIFT, FATHMM, Rosetta) and pathogenic (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). Three tools give uncertain results (FoldX, Foldetta, 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 are mixed: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the balance of evidence favors a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | 6-33438131-T-G | -12.795 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 1.47 | Ambiguous | 0.4 | 0.44 | Likely Benign | 0.96 | Ambiguous | 1.30 | Destabilizing | 0.485 | Likely Benign | -4.39 | Deleterious | 0.877 | Possibly Damaging | 0.807 | Possibly Damaging | 4.15 | Benign | 0.27 | Tolerated | 3.38 | 28 | 0.1537 | 0.0957 | -1 | 0 | -6.4 | 24.99 | ||||||||||||||||||||||||||
| c.1228A>G | S410G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S410G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) 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 evidence points to a benign impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -7.147 | In-Between | 0.137 | Likely Benign | Likely Benign | 0.58 | Ambiguous | 0.1 | 1.33 | Ambiguous | 0.96 | Ambiguous | 0.85 | Ambiguous | 0.117 | Likely Benign | -2.54 | Deleterious | 0.952 | Possibly Damaging | 0.145 | Benign | 4.13 | Benign | 0.19 | Tolerated | 0.2651 | 0.5143 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||
| c.1583C>T | P528L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528L missense variant is listed in ClinVar with an Uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include premPS. All other evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict it to be pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized reports an uncertain outcome; the SGM‑Consensus, which aggregates the four high‑confidence predictors, indicates a likely pathogenic effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also yields an uncertain result. Taken together, the overwhelming majority of tools support a pathogenic interpretation. Therefore, the variant is most likely pathogenic, a conclusion that does not contradict its ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | Uncertain | 1 | -13.752 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 1.31 | Ambiguous | 0.1 | 0.61 | Ambiguous | 0.96 | Ambiguous | 0.19 | Likely Benign | 0.555 | Likely Pathogenic | -9.65 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.1975 | 0.5574 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||
| c.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.1078G>C | E360Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and premPS, while a majority of tools predict a pathogenic outcome: SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E360Q, 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 | C2 | 0.250310 | Structured | 0.421183 | Uncertain | 0.955 | 0.498 | 0.250 | -11.012 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.55 | Ambiguous | 0.1 | 1.38 | Ambiguous | 0.97 | Ambiguous | -0.02 | Likely Benign | 0.343 | Likely Benign | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 1.61 | Pathogenic | 0.03 | Affected | 0.1824 | 0.8282 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1360A>C | I454L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The remaining tools—FoldX, Rosetta, Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized—yield uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward benign, and Foldetta also uncertain. Overall, the majority of reliable predictors and the SGM Consensus favor a benign classification. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -7.852 | In-Between | 0.786 | Likely Pathogenic | Ambiguous | 0.57 | Ambiguous | 0.1 | 1.36 | Ambiguous | 0.97 | Ambiguous | 0.80 | Ambiguous | 0.246 | Likely Benign | -1.98 | Neutral | 0.908 | Possibly Damaging | 0.943 | Probably Damaging | 3.51 | Benign | 0.26 | Tolerated | 0.0653 | 0.2857 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1862G>A | R621Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R621Q is listed in ClinVar (ID 578137.0) as benign and is present in gnomAD (variant ID 6‑33440914‑G‑A). Functional prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX, Rosetta, or Foldetta supports a benign outcome. Overall, the preponderance of predictions indicates a likely pathogenic effect, which contradicts the benign classification reported in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.084420 | Uncertain | 0.945 | 0.216 | 0.000 | Likely Benign | 1 | 6-33440914-G-A | 19 | 1.18e-5 | -14.682 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.81 | Ambiguous | 0.1 | 1.13 | Ambiguous | 0.97 | Ambiguous | 1.35 | Destabilizing | 0.621 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.82 | Benign | 0.01 | Affected | 3.37 | 35 | 0.2590 | 0.1963 | 1 | 1 | 1.0 | -28.06 | 243.7 | 54.3 | 0.0 | 0.0 | -0.4 | 0.2 | X | X | Potentially Pathogenic | The guanidinium group of Arg621, located in an α helix (res. Glu617-Asn635), forms a salt bridge with Glu525 in a nearby loop and stacks with Leu635. In the variant simulations, the carboxamide side chain of Gln621, which can act as both a hydrogen bond acceptor and donor, also stacks with Leu635 but can only sporadically hydrogen bond with Glu525.Accordingly, the residue swap could affect the tertiary structure integrity by disrupting the salt bridge formation. Additionally, due to its location at the GAP-Ras interface, the residue swap could impact the complex formation with the GTPase, but this cannot be investigated using solvent-only simulations. | ||||||||||||
| c.1904A>C | N635T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N635T is not 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and ESM1b; polyPhen‑2 HumVar, however, classifies it as benign. 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, is uncertain, and FoldX and premPS also yield uncertain results. Overall, the majority of evidence (five benign vs. four pathogenic) supports a benign classification. 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. | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -11.705 | Likely Pathogenic | 0.256 | Likely Benign | Likely Benign | 1.50 | Ambiguous | 0.1 | 0.44 | Likely Benign | 0.97 | Ambiguous | 0.81 | Ambiguous | 0.240 | Likely Benign | -5.58 | Deleterious | 0.536 | Possibly Damaging | 0.184 | Benign | 2.98 | Benign | 0.04 | Affected | 0.1206 | 0.4032 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||
| c.2006A>T | N669I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N669I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include premPS and FATHMM, whereas the remaining ten tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the majority‑vote SGM‑Consensus—predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain (treated as unavailable), SGM‑Consensus as likely pathogenic, and Foldetta as uncertain (also treated as unavailable). The overall consensus of the available predictions leans strongly toward pathogenicity, and this conclusion does not conflict with the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.086615 | Uncertain | 0.872 | 0.380 | 0.000 | -13.324 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 0.84 | Ambiguous | 0.0 | 1.09 | Ambiguous | 0.97 | Ambiguous | 0.31 | Likely Benign | 0.517 | Likely Pathogenic | -8.18 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.34 | Benign | 0.00 | Affected | 0.0749 | 0.4697 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.610T>A | S204T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S204T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic effect. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of reliable predictors classify S204T as benign, and this conclusion does not contradict the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -4.164 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.75 | Ambiguous | 0.1 | 1.19 | Ambiguous | 0.97 | Ambiguous | -0.52 | Ambiguous | 0.104 | Likely Benign | 0.55 | Neutral | 0.462 | Possibly Damaging | 0.173 | Benign | 4.19 | Benign | 1.00 | Tolerated | 0.0857 | 0.5063 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| 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.931C>A | H311N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311N missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of evaluated tools predict pathogenicity, suggesting that H311N is most likely pathogenic. This prediction does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -9.545 | Likely Pathogenic | 0.661 | Likely Pathogenic | Likely Benign | 0.82 | Ambiguous | 0.1 | 1.12 | Ambiguous | 0.97 | Ambiguous | 0.72 | Ambiguous | 0.475 | Likely Benign | -5.35 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.89 | Pathogenic | 0.06 | Tolerated | 0.1566 | 0.2380 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| c.935T>A | F312Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a deleterious effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default, all of which classify the change as pathogenic. No tool in the dataset predicts a benign outcome. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta provide uncertain results. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -7.571 | In-Between | 0.949 | Likely Pathogenic | Ambiguous | 1.04 | Ambiguous | 0.1 | 0.89 | Ambiguous | 0.97 | Ambiguous | 0.99 | Ambiguous | 0.744 | Likely Pathogenic | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 1.21 | Pathogenic | 0.02 | Affected | 0.1443 | 0.2728 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.967C>A | L323M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L323M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—Foldetta, premPS, AlphaMissense‑Default, ESM1b, and Rosetta—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Taken together, the evidence leans toward a benign impact for the variant, and this assessment does not contradict any ClinVar annotation, as none exists for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.268042 | Structured | 0.428564 | Uncertain | 0.956 | 0.369 | 0.000 | -7.065 | In-Between | 0.427 | Ambiguous | Likely Benign | 0.11 | Likely Benign | 0.1 | 1.82 | Ambiguous | 0.97 | Ambiguous | 0.93 | Ambiguous | 0.270 | Likely Benign | -1.02 | Neutral | 0.997 | Probably Damaging | 0.939 | Probably Damaging | 0.64 | Pathogenic | 0.03 | Affected | 0.0637 | 0.3010 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1066C>T | R356C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R356C is listed in ClinVar as Benign (ClinVar ID 469145.0) and is present in gnomAD (ID 6‑33437971‑C‑T). Functional prediction tools cluster into two groups: benign predictions from REVEL and AlphaMissense‑Optimized, and pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic effect, contradicting the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.219301 | Structured | 0.395028 | Uncertain | 0.802 | 0.373 | 0.250 | Likely Benign | 1 | 6-33437971-C-T | 5 | 3.10e-6 | -11.827 | Likely Pathogenic | 0.774 | Likely Pathogenic | Likely Benign | 0.76 | Ambiguous | 0.0 | 1.19 | Ambiguous | 0.98 | Ambiguous | 0.84 | Ambiguous | 0.312 | Likely Benign | -7.12 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 1.67 | Pathogenic | 0.00 | Affected | 3.39 | 22 | 0.3238 | 0.3618 | -4 | -3 | 7.0 | -53.05 | 212.3 | 91.0 | -0.1 | 0.3 | -0.3 | 0.1 | X | Potentially Pathogenic | Arg356 is located in a loop that includes a short helical section and connects two anti-parallel β sheet strands (res. Gly341-Pro349, res. Thr359-Pro364). In the WT simulations, the guanidinium group of Arg356 alternately forms salt bridges with the carboxylate groups of the GAP domain residues, Glu446 and Glu698. Arg356 also forms hydrogen bonds with the hydroxyl group of the GAP domain residue Thr691 and interacts with Met409 at the C2-GAP interface.In the variant simulations, the Cys356 mutation fails to maintain any of the Arg356 interactions and only occasionally forms weak hydrogen bonds with nearby C2 domain residues (e.g., Gln407). Although no negative structural effects are observed during the simulations, Arg356 is located at the C2 and GAP domain interface, making the residue swap potentially detrimental to the tertiary structure assembly. | |||||||||||||
| c.1318A>C | N440H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenicity is suggested only by polyPhen‑2 HumDiv and ESM1b, while FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta’s stability prediction 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 | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -8.064 | Likely Pathogenic | 0.226 | Likely Benign | Likely Benign | 1.12 | Ambiguous | 0.1 | 0.83 | Ambiguous | 0.98 | Ambiguous | 0.00 | Likely Benign | 0.140 | Likely Benign | -2.48 | Neutral | 0.835 | Possibly Damaging | 0.217 | Benign | 3.40 | Benign | 0.19 | Tolerated | 0.0935 | 0.3270 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.1320T>A | N440K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440K is not 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, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. The remaining methods—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Based on the overall distribution of predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.114 | Likely Pathogenic | 0.895 | Likely Pathogenic | Ambiguous | 0.92 | Ambiguous | 0.1 | 1.04 | Ambiguous | 0.98 | Ambiguous | 0.40 | Likely Benign | 0.058 | Likely Benign | -1.97 | Neutral | 0.206 | Benign | 0.021 | Benign | 3.50 | Benign | 0.19 | Tolerated | 0.1660 | 0.2550 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.1320T>G | N440K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440K is not 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, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. The remaining methods—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Based on the overall distribution of predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.114 | Likely Pathogenic | 0.895 | Likely Pathogenic | Ambiguous | 0.92 | Ambiguous | 0.1 | 1.04 | Ambiguous | 0.98 | Ambiguous | 0.40 | Likely Benign | 0.057 | Likely Benign | -1.97 | Neutral | 0.206 | Benign | 0.021 | Benign | 3.50 | Benign | 0.19 | Tolerated | 0.1660 | 0.2550 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.1528A>G | I510V 2D 3DClick to see structure in 3D Viewer AISynGAP1 I510V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Pathogenic predictions arise from polyPhen‑2 HumDiv, SIFT, FATHMM, and premPS. FoldX and Rosetta analyses are inconclusive, and Foldetta stability assessment is unavailable. High‑accuracy methods reinforce the benign trend: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta provides no definitive result. Overall, the majority of evidence points to a benign effect for I510V, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -6.072 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 1.45 | Ambiguous | 0.2 | 0.50 | Ambiguous | 0.98 | Ambiguous | 1.13 | Destabilizing | 0.461 | Likely Benign | -1.00 | Neutral | 0.792 | Possibly Damaging | 0.332 | Benign | -1.36 | Pathogenic | 0.02 | Affected | 0.0999 | 0.2291 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.1591T>G | C531G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX and AlphaMissense‑Optimized, while the majority of other in silico predictors (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) indicate a pathogenic impact. Uncertain results come from Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the balance of evidence leans toward pathogenicity, with no ClinVar entry to contradict this assessment. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.017941 | Uncertain | 0.878 | 0.401 | 0.000 | -10.037 | Likely Pathogenic | 0.577 | Likely Pathogenic | Likely Benign | 0.47 | Likely Benign | 0.3 | 1.49 | Ambiguous | 0.98 | Ambiguous | 1.42 | Destabilizing | 0.545 | Likely Pathogenic | -9.76 | Deleterious | 0.985 | Probably Damaging | 0.832 | Possibly Damaging | -1.24 | Pathogenic | 0.00 | Affected | 0.2653 | 0.2297 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.1768A>G | S590G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S590G is listed in ClinVar (ID 1721675.0) with an uncertain significance status and is present in gnomAD (6‑33440820‑A‑G). Functional prediction tools that report a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic majority. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive, as are FoldX, Rosetta, and premPS. Overall, the majority of evidence points toward a pathogenic impact, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | Conflicting | 2 | 6-33440820-A-G | 14 | 8.67e-6 | -14.277 | Likely Pathogenic | 0.574 | Likely Pathogenic | Likely Benign | 0.67 | Ambiguous | 0.1 | 1.28 | Ambiguous | 0.98 | Ambiguous | 0.71 | Ambiguous | 0.379 | Likely Benign | -3.92 | Deleterious | 1.000 | Probably Damaging | 0.922 | Probably Damaging | 3.42 | Benign | 0.06 | Tolerated | 3.37 | 35 | 0.2627 | 0.4118 | 1 | 0 | 0.4 | -30.03 | 186.7 | 49.4 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | In the WT simulations, the hydroxyl group of Ser590, located on an α helix (res. Glu582-Met603), forms hydrogen bonds with the backbone carbonyl of Ala634 and/or the carboxamide group of the Asn635 side chain at the end of the opposing α helix (res. Thr619-Ala634).The residue swap could weaken the integrity of the α helix, as glycine is known as an “α helix breaker.” However, no discernible difference was observed between the WT and variant simulations in this regard. Importantly, Gly590 cannot form hydrogen bonds with the opposing helix in the same way that serine can, which could weaken the tertiary structure assembly between the two helices. | |||||||||||||
| c.1807A>G | M603V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M603V is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from premPS and SIFT, while pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. The remaining tools—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—return uncertain or inconclusive results. High‑accuracy assessments reinforce the pathogenic signal: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic, and AlphaMissense‑Optimized is uncertain; Foldetta also remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for M603V. 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 | GAP | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -10.442 | Likely Pathogenic | 0.800 | Likely Pathogenic | Ambiguous | 1.34 | Ambiguous | 0.2 | 0.62 | Ambiguous | 0.98 | Ambiguous | -0.15 | Likely Benign | 0.668 | Likely Pathogenic | -3.48 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -0.92 | Pathogenic | 0.09 | Tolerated | 0.2698 | 0.2601 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||
| c.1816A>C | S606R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas a separate group predicts pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with uncertain outcomes are Foldetta, premPS, and Rosetta. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains inconclusive. Overall, the majority of high‑confidence predictions and the consensus vote indicate a pathogenic effect. Because ClinVar contains no entry for this variant, there is no contradiction between the computational evidence and clinical annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -12.900 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.15 | Likely Benign | 0.4 | 1.80 | Ambiguous | 0.98 | Ambiguous | 0.82 | Ambiguous | 0.252 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.38 | Benign | 0.08 | Tolerated | 0.0819 | 0.2750 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1818T>A | S606R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas a separate group predicts pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with uncertain outcomes are Foldetta, premPS, and Rosetta. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains inconclusive. Overall, the majority of high‑confidence predictions and the consensus vote indicate a pathogenic effect. Because ClinVar contains no entry for this variant, there is no contradiction between the computational evidence and clinical annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -12.900 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.15 | Likely Benign | 0.4 | 1.80 | Ambiguous | 0.98 | Ambiguous | 0.82 | Ambiguous | 0.246 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.38 | Benign | 0.08 | Tolerated | 0.0819 | 0.2750 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1818T>G | S606R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606R is not reported in ClinVar or gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas a majority predict pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. High‑accuracy methods confirm the pathogenic trend: AlphaMissense‑Optimized is pathogenic, SGM Consensus is Likely Pathogenic, and Foldetta remains uncertain. Overall, the evidence points to the variant being most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -12.900 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.15 | Likely Benign | 0.4 | 1.80 | Ambiguous | 0.98 | Ambiguous | 0.82 | Ambiguous | 0.246 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.38 | Benign | 0.08 | Tolerated | 0.0819 | 0.2750 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| 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.1475A>C | K492T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K492T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the majority—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized—predict a pathogenic impact. Four methods (FoldX, Rosetta, Foldetta, premPS) return uncertain results. High‑accuracy predictors give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta remains uncertain. Overall, the evidence strongly favors a pathogenic classification, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -16.126 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.09 | Ambiguous | 0.1 | 0.88 | Ambiguous | 0.99 | Ambiguous | 0.98 | Ambiguous | 0.595 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.96 | Benign | 0.04 | Affected | 0.1691 | 0.2825 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1547C>G | A516G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A516G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are limited to SIFT, whereas the remaining seven tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) all predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. No stability‑change predictions are definitive. Overall, the majority of evidence points to a pathogenic impact for A516G. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -10.673 | Likely Pathogenic | 0.864 | Likely Pathogenic | Ambiguous | 0.86 | Ambiguous | 0.2 | 1.12 | Ambiguous | 0.99 | Ambiguous | 0.88 | Ambiguous | 0.557 | Likely Pathogenic | -3.52 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.31 | Pathogenic | 0.10 | Tolerated | 0.2379 | 0.4370 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1613A>G | E538G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E538G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No folding‑stability result is definitive. Overall, the balance of evidence, including the majority‑vote SGM Consensus and the higher number of pathogenic predictions, points to a pathogenic effect for E538G. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.033501 | Uncertain | 0.938 | 0.359 | 0.000 | -9.258 | Likely Pathogenic | 0.701 | Likely Pathogenic | Likely Benign | 0.91 | Ambiguous | 0.0 | 1.07 | Ambiguous | 0.99 | Ambiguous | 0.31 | Likely Benign | 0.285 | Likely Benign | -5.10 | Deleterious | 0.993 | Probably Damaging | 0.700 | Possibly Damaging | 3.33 | Benign | 0.03 | Affected | 0.3173 | 0.3713 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1625A>G | N542S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N542S is listed in ClinVar as benign (ClinVar ID 833567.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include SIFT and AlphaMissense‑Optimized, whereas the majority of tools predict pathogenicity: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, SGM‑Consensus predicting likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect, which is in conflict with the ClinVar benign designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | Likely Benign | 1 | -9.675 | Likely Pathogenic | 0.767 | Likely Pathogenic | Likely Benign | 0.98 | Ambiguous | 0.1 | 0.99 | Ambiguous | 0.99 | Ambiguous | 0.91 | Ambiguous | 0.752 | Likely Pathogenic | -4.40 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | -1.36 | Pathogenic | 0.13 | Tolerated | 3.37 | 35 | 0.3054 | 0.5719 | 1 | 1 | 2.7 | -27.03 | 212.5 | 32.1 | 0.0 | 0.0 | -0.6 | 0.3 | X | Potentially Pathogenic | Asn542 is located in an α-helix (res. Ala533-Val560) next to an α-α loop between two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the carboxamide group of the Asn542 side chain forms a hydrogen bond with the backbone carbonyl group of Asn523 and packs favourably against Glu522 from the loop. In contrast, in the variant simulations, the hydroxyl group of the Ser542 side chain is unable to maintain either the hydrogen bond with Asn523 or the packing against the Glu522 side chain. Instead, the hydroxyl group of Ser542 occasionally forms a hydrogen bond with the backbone carbonyl group of Glu538.Altogether, the residue swap results in a looser helix-loop association, which is especially evident in the third replica simulation, where Asn523 moves away from its initial placement next to the α-helix. In short, based on the simulations, the residue swap weakens the GAP domain tertiary structure assembly, which in turn could negatively affect protein folding. | ||||||||||||||||
| c.911A>G | D304G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default, FoldX, Rosetta, and Foldetta are uncertain and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta remaining uncertain. Overall, the majority of tools (five pathogenic vs. four benign) and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -2.713 | Likely Benign | 0.546 | Ambiguous | Likely Benign | 1.02 | Ambiguous | 0.2 | 0.95 | Ambiguous | 0.99 | Ambiguous | 0.47 | Likely Benign | 0.380 | Likely Benign | -5.32 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.75 | Pathogenic | 0.02 | Affected | 0.4590 | 0.6451 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||
| c.1208A>C | K403T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K403T missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; SGM‑Consensus predicts likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Other stability predictors (FoldX, Rosetta, premPS) are also uncertain. Overall, the consensus of the majority of tools indicates a pathogenic effect. This conclusion is not contradicted by ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -13.135 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.41 | Ambiguous | 0.1 | 0.59 | Ambiguous | 1.00 | Ambiguous | 0.67 | Ambiguous | 0.522 | Likely Pathogenic | -5.43 | Deleterious | 0.999 | Probably Damaging | 1.000 | Probably Damaging | 3.73 | Benign | 0.01 | Affected | 0.1861 | 0.4230 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1459A>C | N487H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N487H has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus) predict a pathogenic or likely pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from these tools contradicts the lack of ClinVar annotation. Overall, the preponderance of pathogenic predictions indicates that the variant is most likely pathogenic, consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -11.403 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 1.15 | Ambiguous | 0.1 | 0.84 | Ambiguous | 1.00 | Ambiguous | 0.72 | Ambiguous | 0.548 | Likely Pathogenic | -4.97 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.68 | Benign | 0.00 | Affected | 0.1123 | 0.3411 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.1802C>T | A601V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601V is listed in ClinVar (ID 968190.0) with an uncertain clinical significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Rosetta and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. Four tools (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertain significance rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | Uncertain | 1 | -10.447 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 1.64 | Ambiguous | 0.1 | 0.35 | Likely Benign | 1.00 | Ambiguous | 0.81 | Ambiguous | 0.535 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.74 | Benign | 0.03 | Affected | 3.37 | 35 | 0.1338 | 0.5263 | 0 | 0 | 2.4 | 28.05 | 228.5 | -45.5 | 0.0 | 0.0 | 0.4 | 0.5 | X | Potentially Benign | The methyl side chain of Ala601, located on an α helix (res. Glu582-Met603), packs hydrophobically against other hydrophobic residues in the inter-helix space (e.g., Phe597, Leu598, Leu506, Phe608).In the variant simulations, Val601, which has similar size and physicochemical properties to alanine, resides in the inter-helix hydrophobic space in a similar manner to Ala601 in the WT, causing no apparent negative effect on the protein structure. However, the effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||||||||
| c.632G>A | S211N 2D  AIThe SynGAP1 S211N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and premPS. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, the overall prediction leans toward pathogenicity, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -9.995 | Likely Pathogenic | 0.794 | Likely Pathogenic | Ambiguous | 0.60 | Ambiguous | 1.2 | 1.39 | Ambiguous | 1.00 | Ambiguous | 1.21 | Destabilizing | 0.174 | Likely Benign | -2.22 | Neutral | 0.982 | Probably Damaging | 0.747 | Possibly Damaging | 3.95 | Benign | 0.09 | Tolerated | 0.1534 | 0.4863 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
| c.724T>A | W242R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant W242R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess evolutionary conservation and protein function uniformly indicate a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Consequently, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | -11.948 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.85 | Ambiguous | 0.5 | 1.15 | Ambiguous | 1.00 | Ambiguous | 1.34 | Destabilizing | 0.859 | Likely Pathogenic | -12.71 | Deleterious | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | 3.40 | 14 | 0.4206 | 0.0771 | -3 | 2 | -3.6 | -30.03 | |||||||||||||||||||||||||||
| c.724T>C | W242R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242R is reported in gnomAD (ID 6‑33435575‑T‑C) but has no ClinVar entry. Across the evaluated predictors, every tool that provides a definitive call classifies the substitution as pathogenic: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No predictor reports a benign effect. FoldX, Rosetta, and Foldetta return uncertain results and are treated as unavailable evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta remains inconclusive. Consequently, the variant is most likely pathogenic based on the consensus of pathogenic predictions, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | 6-33435575-T-C | 2 | 1.24e-6 | -11.948 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.85 | Ambiguous | 0.5 | 1.15 | Ambiguous | 1.00 | Ambiguous | 1.34 | Destabilizing | 0.858 | Likely Pathogenic | -12.71 | Deleterious | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | 3.40 | 14 | 0.4206 | 0.0771 | -3 | 2 | -3.6 | -30.03 | ||||||||||||||||||||||||
| c.746C>T | A249V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A249V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, no high‑accuracy tool provides a definitive pathogenic or benign verdict. Overall, the majority of available predictions (seven pathogenic vs. three benign) lean toward a pathogenic interpretation. This assessment does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -9.417 | Likely Pathogenic | 0.856 | Likely Pathogenic | Ambiguous | 1.48 | Ambiguous | 0.6 | 0.51 | Ambiguous | 1.00 | Ambiguous | 0.41 | Likely Benign | 0.652 | Likely Pathogenic | -2.47 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 5.76 | Benign | 0.03 | Affected | 0.0737 | 0.4677 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.877C>T | R293C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R293C is listed in ClinVar with an uncertain significance (ClinVar ID 2500611.0) and is present in gnomAD (6‑33437782‑C‑T). Prediction tools that classify the variant as benign include premPS, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Consequently, the overwhelming majority of computational evidence indicates a pathogenic impact for R293C. This prediction aligns with the ClinVar designation of uncertain significance, not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.338192 | Uncertain | 0.924 | 0.269 | 0.125 | Uncertain | 1 | 6-33437782-C-T | 3 | 1.86e-6 | -12.844 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 1.38 | Ambiguous | 0.1 | 0.62 | Ambiguous | 1.00 | Ambiguous | 0.02 | Likely Benign | 0.579 | Likely Pathogenic | -7.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.46 | Pathogenic | 0.00 | Affected | 3.38 | 23 | 0.3031 | 0.4363 | -4 | -3 | 7.0 | -53.05 | 226.0 | 96.5 | 0.0 | 0.0 | 0.1 | 0.1 | X | X | X | Potentially Pathogenic | The guanidinium group of the Arg293 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), packs against the phenol ring of the Tyr281 side chain or forms a salt bridge with the carboxylate group of Glu283 on the outer side of the C2 domain. The positively charged guanidinium side chain of arginine is on the outside surface of the hydrophobic C2 domain, resulting in a twist in the β strand. Although this twist is maintained in the variant simulations, replacing the positively charged residue with a more hydrophobic one, such as cysteine, could remove the twist during protein folding.Because Arg293 is positioned at the C2 and PH domain interface, the residue swap could significantly impact the tertiary structure assembly. Notably, Arg293 is located at the SynGAP-Ras interface, and its role in complex formation cannot be fully understood through solvent-only simulations. | |||||||||||
| c.965C>A | A322D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A322D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The remaining tools—FoldX, Rosetta, ESM1b, and AlphaMissense‑Default—return uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta indicates no significant stability change (uncertain). Overall, the preponderance of evidence (seven benign predictions versus one pathogenic) suggests the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -7.184 | In-Between | 0.411 | Ambiguous | Likely Benign | 0.65 | Ambiguous | 0.1 | 1.35 | Ambiguous | 1.00 | Ambiguous | 0.34 | Likely Benign | 0.246 | Likely Benign | -0.95 | Neutral | 0.270 | Benign | 0.136 | Benign | 1.96 | Pathogenic | 0.32 | Tolerated | 0.1646 | 0.1660 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||
| c.1012G>T | D338Y 2D AIThe SynGAP1 D338Y missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools largely agree on a deleterious effect: premPS is the sole predictor labeling it benign, whereas the remaining seven tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—classify it as pathogenic. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments further support a pathogenic interpretation: the SGM Consensus (derived from a unanimous majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, AlphaMissense‑Optimized remains uncertain, and Foldetta is also uncertain. Overall, the preponderance of evidence indicates that D338Y is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -14.190 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 1.10 | Ambiguous | 1.3 | 0.91 | Ambiguous | 1.01 | Ambiguous | 0.22 | Likely Benign | 0.552 | Likely Pathogenic | -6.49 | Deleterious | 0.989 | Probably Damaging | 0.832 | Possibly Damaging | 1.66 | Pathogenic | 0.00 | Affected | 0.0687 | 0.5609 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| 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.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.1127G>A | G376D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G376D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. The remaining tools—Rosetta, Foldetta, premPS, and ESM1b—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain stability change. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.680603 | Disordered | 0.428979 | Uncertain | 0.326 | 0.869 | 0.625 | -7.125 | In-Between | 0.569 | Likely Pathogenic | Likely Benign | 3.10 | Destabilizing | 1.1 | -1.08 | Ambiguous | 1.01 | Ambiguous | 0.52 | Ambiguous | 0.572 | Likely Pathogenic | -1.05 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.32 | Pathogenic | 0.09 | Tolerated | 0.1938 | 0.1235 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||
| c.1279C>G | H427D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H427D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. 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 the available tools suggests pathogenicity, and the absence of a ClinVar classification means there is no contradiction. Therefore, based on the current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -3.684 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.76 | Ambiguous | 0.1 | 1.26 | Ambiguous | 1.01 | Ambiguous | 0.10 | Likely Benign | 0.163 | Likely Benign | -1.43 | Neutral | 0.677 | Possibly Damaging | 0.236 | Benign | 3.58 | Benign | 0.12 | Tolerated | 0.2241 | 0.1678 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.1339G>T | V447F 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V447F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports an uncertain effect on protein folding. Overall, the majority of predictions lean toward pathogenicity, suggesting the variant is most likely pathogenic, a conclusion that does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | Uncertain | 1 | -8.673 | Likely Pathogenic | 0.701 | Likely Pathogenic | Likely Benign | 1.40 | Ambiguous | 0.3 | 0.61 | Ambiguous | 1.01 | Ambiguous | 0.20 | Likely Benign | 0.206 | Likely Benign | -2.62 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | 0.0551 | 0.3055 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||
| c.1440G>C | E480D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E480D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, whereas polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. The remaining tools—FoldX, Rosetta, premPS, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority, and Foldetta remains uncertain. Overall, the balance of evidence favors a benign classification for E480D, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -3.001 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.62 | Ambiguous | 0.2 | 1.39 | Ambiguous | 1.01 | Ambiguous | 0.61 | Ambiguous | 0.405 | Likely Benign | -0.77 | Neutral | 0.989 | Probably Damaging | 0.979 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 0.1526 | 0.4130 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1440G>T | E480D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E480D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic outcome. The remaining tools—FoldX, Rosetta, premPS, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward benign, and Foldetta providing no definitive stability change. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -3.001 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.62 | Ambiguous | 0.2 | 1.39 | Ambiguous | 1.01 | Ambiguous | 0.61 | Ambiguous | 0.405 | Likely Benign | -0.77 | Neutral | 0.989 | Probably Damaging | 0.979 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 0.1526 | 0.4130 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1476A>C | K492N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K492N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No folding‑stability predictions are definitive. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.048 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 1.09 | Ambiguous | 1.01 | Ambiguous | 1.25 | Destabilizing | 0.512 | Likely Pathogenic | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.92 | Benign | 0.00 | Affected | 0.2814 | 0.0926 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1476A>T | K492N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K492N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No folding‑stability predictions are definitive. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.048 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 1.09 | Ambiguous | 1.01 | Ambiguous | 1.25 | Destabilizing | 0.512 | Likely Pathogenic | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.92 | Benign | 0.00 | Affected | 0.2814 | 0.0926 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1804A>G | I602V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I602V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the change as benign include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, SIFT, and FATHMM. Uncertain or inconclusive results come from FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta’s stability analysis remains 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. | Likely Benign | GAP | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -6.317 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 1.24 | Ambiguous | 0.0 | 0.78 | Ambiguous | 1.01 | Ambiguous | 1.01 | Destabilizing | 0.309 | Likely Benign | -0.84 | Neutral | 0.528 | Possibly Damaging | 0.179 | Benign | -1.89 | Pathogenic | 0.03 | Affected | 0.1173 | 0.3326 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.1844C>T | P615L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P615L is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS and Rosetta, whereas the remaining tools—REVEL, FoldX, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, PROVEAN, 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 of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity, and Foldetta yields an uncertain result. Taken together, the overwhelming majority of computational evidence indicates that P615L is likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -11.884 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.03 | Destabilizing | 0.4 | -0.01 | Likely Benign | 1.01 | Ambiguous | 0.50 | Likely Benign | 0.699 | Likely Pathogenic | -9.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.13 | Pathogenic | 0.04 | Affected | 0.1949 | 0.4692 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.2081C>G | A694G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A694G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. 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 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 | GAP | 0.127496 | Structured | 0.352199 | Uncertain | 0.938 | 0.269 | 0.000 | -3.420 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.86 | Ambiguous | 0.0 | 1.16 | Ambiguous | 1.01 | Ambiguous | 0.86 | Ambiguous | 0.093 | Likely Benign | -1.90 | Neutral | 0.866 | Possibly Damaging | 0.171 | Benign | 3.50 | Benign | 0.05 | Affected | 0.2015 | 0.3387 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| 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.1063G>T | G355W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G355W is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL and premPS, and pathogenic predictions from SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, SGM‑Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.388832 | Uncertain | 0.810 | 0.354 | 0.125 | -12.316 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 1.16 | Ambiguous | 0.5 | 0.88 | Ambiguous | 1.02 | Ambiguous | 0.18 | Likely Benign | 0.455 | Likely Benign | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.73 | Pathogenic | 0.00 | Affected | 0.0796 | 0.4360 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||
| c.1244A>G | E415G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E415G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑based methods (FoldX, Rosetta, premPS) and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for E415G. This prediction is consistent with the lack of ClinVar annotation and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -12.244 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 1.16 | Ambiguous | 0.2 | 0.88 | Ambiguous | 1.02 | Ambiguous | 0.65 | Ambiguous | 0.432 | Likely Benign | -6.45 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.20 | Benign | 0.01 | Affected | 0.2518 | 0.3158 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1426T>C | F476L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. No other tools provide definitive evidence. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -10.109 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 1.04 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | 0.196 | Likely Benign | -1.10 | Neutral | 0.997 | Probably Damaging | 0.978 | Probably Damaging | 3.53 | Benign | 0.60 | Tolerated | 3.40 | 22 | 0.1653 | 0.2916 | 2 | 0 | 1.0 | -34.02 | 235.9 | 16.1 | 0.0 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | In the WT simulations, the phenyl ring of Phe476, located at the end of an α-helix (res. Ala461-Phe476), packs with the hydrophobic side chains of Leu482 and Ile483. Additionally, Phe476 stacks with the Arg475 side chain on the preceding α-α loop connecting the two α-helices (res. Ala461-Phe476 and res. Leu489-Glu519) near the GAP-Ras interface.In the variant simulations, Leu476 can maintain hydrophobic packing with neighboring residues, although not as efficiently as the phenylalanine in the WT system. The absence of Phe476/Arg475 stacking weakens the integrity of the α-helix end in the variant simulations. Nonetheless, no large-scale adverse effects are observed in the simulations. Lastly, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||||||||||
| c.1428C>A | F476L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. No other tools provide definitive evidence. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -10.109 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 1.04 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | 0.180 | Likely Benign | -1.10 | Neutral | 0.997 | Probably Damaging | 0.978 | Probably Damaging | 3.53 | Benign | 0.60 | Tolerated | 3.40 | 22 | 0.1653 | 0.2916 | 2 | 0 | 1.0 | -34.02 | 235.9 | 16.1 | 0.0 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | In the WT simulations, the phenyl ring of Phe476, located at the end of an α-helix (res. Ala461-Phe476), packs with the hydrophobic side chains of Leu482 and Ile483. Additionally, Phe476 stacks with the Arg475 side chain on the preceding α-α loop connecting the two α-helices (res. Ala461-Phe476 and res. Leu489-Glu519) near the GAP-Ras interface.In the variant simulations, Leu476 can maintain hydrophobic packing with neighboring residues, although not as efficiently as the phenylalanine in the WT system. The absence of Phe476/Arg475 stacking weakens the integrity of the α-helix end in the variant simulations. Nonetheless, no large-scale adverse effects are observed in the simulations. Lastly, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||||||||||
| c.1428C>G | F476L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438460‑C‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that returned uncertain results—FoldX, Rosetta, Foldetta, and premPS—do not contribute to the assessment. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, with two pathogenic and two benign calls; Foldetta also reports an uncertain stability change. Overall, the balance of evidence favors a pathogenic effect for F476L, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | Uncertain | 2 | 6-33438460-C-G | 4 | 2.48e-6 | -10.109 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 1.04 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | 0.180 | Likely Benign | -1.10 | Neutral | 0.997 | Probably Damaging | 0.978 | Probably Damaging | 3.53 | Benign | 0.60 | Tolerated | 3.40 | 22 | 0.1653 | 0.2916 | 2 | 0 | 1.0 | -34.02 | 235.9 | 16.1 | 0.0 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | In the WT simulations, the phenyl ring of Phe476, located at the end of an α-helix (res. Ala461-Phe476), packs with the hydrophobic side chains of Leu482 and Ile483. Additionally, Phe476 stacks with the Arg475 side chain on the preceding α-α loop connecting the two α-helices (res. Ala461-Phe476 and res. Leu489-Glu519) near the GAP-Ras interface.In the variant simulations, Leu476 can maintain hydrophobic packing with neighboring residues, although not as efficiently as the phenylalanine in the WT system. The absence of Phe476/Arg475 stacking weakens the integrity of the α-helix end in the variant simulations. Nonetheless, no large-scale adverse effects are observed in the simulations. Lastly, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||||||
| c.1644G>C | E548D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E548D variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, premPS, SIFT, and FATHMM, whereas a separate group predicts pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are uncertain or unavailable are FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a pathogenic verdict (2 pathogenic, 1 benign, 1 uncertain). Foldetta’s stability prediction is unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.054297 | Structured | 0.008632 | Uncertain | 0.965 | 0.288 | 0.000 | -7.359 | In-Between | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.74 | Ambiguous | 0.1 | 1.29 | Ambiguous | 1.02 | Ambiguous | 0.32 | Likely Benign | 0.254 | Likely Benign | -2.85 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | 3.51 | Benign | 0.09 | Tolerated | 0.1374 | 0.2524 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1644G>T | E548D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E548D variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, premPS, SIFT, and FATHMM, whereas a separate group predicts a pathogenic effect: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are uncertain or unavailable are FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a pathogenic verdict (2 pathogenic, 1 benign, 1 uncertain). Foldetta’s stability prediction is unavailable. Overall, the majority of evidence points to a pathogenic impact for E548D, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.054297 | Structured | 0.008632 | Uncertain | 0.965 | 0.288 | 0.000 | -7.359 | In-Between | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.74 | Ambiguous | 0.1 | 1.29 | Ambiguous | 1.02 | Ambiguous | 0.32 | Likely Benign | 0.254 | Likely Benign | -2.85 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | 3.51 | Benign | 0.09 | Tolerated | 0.1374 | 0.2524 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1687A>T | R563W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R563W is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. No evidence from the uncertain tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) supports either outcome. Overall, the balance of evidence favors a pathogenic classification for R563W, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.039760 | Structured | 0.031987 | Uncertain | 0.876 | 0.209 | 0.000 | -12.454 | Likely Pathogenic | 0.854 | Likely Pathogenic | Ambiguous | 1.25 | Ambiguous | 0.1 | 0.79 | Ambiguous | 1.02 | Ambiguous | 0.34 | Likely Benign | 0.302 | Likely Benign | -6.75 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.42 | Benign | 0.01 | Affected | 0.1378 | 0.2088 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||
| c.2012A>G | D671G 2D AIThe SynGAP1 D671G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. No evidence from these tools contradicts the pathogenic prediction. Overall, the balance of evidence favors a pathogenic classification for D671G, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -10.346 | Likely Pathogenic | 0.857 | Likely Pathogenic | Ambiguous | 0.50 | Ambiguous | 0.5 | 1.53 | Ambiguous | 1.02 | Ambiguous | 0.00 | Likely Benign | 0.279 | Likely Benign | -4.78 | Deleterious | 0.995 | Probably Damaging | 0.946 | Probably Damaging | 3.45 | Benign | 0.01 | Affected | 0.4032 | 0.5823 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| 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.937G>A | E313K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313K is listed in ClinVar as Benign (ClinVar ID 3695040.0) and is not reported in gnomAD. Prediction tools that report a benign effect are absent; all available predictors that provide a definitive call classify the variant as pathogenic. These include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus indicates Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is Uncertain. Based on the overwhelming pathogenic predictions, the variant is most likely pathogenic, which contradicts its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | Likely Benign | 1 | -12.902 | Likely Pathogenic | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.64 | Ambiguous | 0.6 | 1.40 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | 0.575 | Likely Pathogenic | -3.31 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 1.90 | Pathogenic | 0.02 | Affected | 0.2540 | 0.7708 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||
| c.938A>C | E313A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313A is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized, whereas the remaining pathogenic‑or‑likely‑pathogenic predictors are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | -14.591 | Likely Pathogenic | 0.747 | Likely Pathogenic | Likely Benign | 1.07 | Ambiguous | 0.3 | 0.97 | Ambiguous | 1.02 | Ambiguous | 0.62 | Ambiguous | 0.680 | Likely Pathogenic | -4.88 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.88 | Pathogenic | 0.02 | Affected | 0.3416 | 0.6743 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1318A>T | N440Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, AlphaMissense‑Default, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yielding an uncertain stability change. Overall, the majority of predictions lean toward a benign interpretation, and this is consistent with the lack of ClinVar annotation. Therefore, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.586 | Likely Pathogenic | 0.674 | Likely Pathogenic | Likely Benign | 0.81 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.03 | Ambiguous | 0.20 | Likely Benign | 0.135 | Likely Benign | -3.81 | Deleterious | 0.931 | Possibly Damaging | 0.230 | Benign | 3.43 | Benign | 0.07 | Tolerated | 0.0535 | 0.3624 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.1337A>C | E446A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E446A is not reported in ClinVar and is absent from gnomAD. In silico predictors that classify the variant as benign include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Predictors that classify it as pathogenic comprise SGM‑Consensus, PROVEAN, 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, and PROVEAN) indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yielded an inconclusive result and is treated as unavailable. Overall, the majority of predictions lean toward pathogenicity, and this conclusion is not contradicted by the absence of a ClinVar entry. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | -9.868 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 1.66 | Ambiguous | 0.7 | 0.39 | Likely Benign | 1.03 | Ambiguous | 0.67 | Ambiguous | 0.443 | Likely Benign | -5.60 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.3195 | 0.5877 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1337A>T | E446V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E446V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, premPS, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (8 pathogenic vs. 3 benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | -12.231 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 1.72 | Ambiguous | 0.7 | 0.34 | Likely Benign | 1.03 | Ambiguous | 0.37 | Likely Benign | 0.513 | Likely Pathogenic | -6.55 | Deleterious | 0.995 | Probably Damaging | 0.983 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 0.0618 | 0.6433 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1381G>T | A461S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 (HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv), SIFT, and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta’s stability analysis is also unavailable. Overall, the balance of evidence leans toward a benign effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -10.663 | Likely Pathogenic | 0.309 | Likely Benign | Likely Benign | 0.87 | Ambiguous | 0.0 | 1.18 | Ambiguous | 1.03 | Ambiguous | 0.63 | Ambiguous | 0.236 | Likely Benign | -2.74 | Deleterious | 0.600 | Possibly Damaging | 0.289 | Benign | 3.36 | Benign | 0.02 | Affected | 0.2401 | 0.4551 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1399G>A | D467N 2D 3DClick to see structure in 3D Viewer AISynGAP1 D467N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a predominance of pathogenic calls: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of the four high‑accuracy predictors) all predict a deleterious effect. Benign predictions come from FoldX, premPS, and SIFT. Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy methods specifically give an uncertain result for AlphaMissense‑Optimized, a pathogenic verdict for the SGM‑Consensus, and an uncertain outcome for Foldetta. Overall, the balance of evidence favors a pathogenic impact for D467N, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -11.881 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.43 | Likely Benign | 0.1 | 1.63 | Ambiguous | 1.03 | Ambiguous | 0.38 | Likely Benign | 0.673 | Likely Pathogenic | -4.82 | Deleterious | 0.987 | Probably Damaging | 0.990 | Probably Damaging | -1.22 | Pathogenic | 0.06 | Tolerated | 0.0936 | 0.4879 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1429A>G | M477V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477V is listed in ClinVar with no submitted interpretation and is present in the gnomAD database (variant ID 6‑33438461‑A‑G). Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict benign or likely benign. Only two tools predict a pathogenic outcome: polyPhen2_HumDiv and FATHMM. Predictions from FoldX and Foldetta are uncertain. High‑accuracy methods reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, while Foldetta remains inconclusive. Taken together, the majority of evidence supports a benign classification for M477V, and this assessment does not contradict the ClinVar status, which currently has no pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | 6-33438461-A-G | 1 | 6.20e-7 | -3.995 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 1.64 | Ambiguous | 0.3 | 0.42 | Likely Benign | 1.03 | Ambiguous | 0.24 | Likely Benign | 0.209 | Likely Benign | -1.04 | Neutral | 0.716 | Possibly Damaging | 0.204 | Benign | -1.19 | Pathogenic | 0.22 | Tolerated | 3.37 | 34 | 0.3093 | 0.3445 | 1 | 2 | 2.3 | -32.06 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||
| c.1439A>C | E480A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E480A is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only SIFT, whereas a majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from the four pathogenic‑predicted tools above) as likely pathogenic, and Foldetta as uncertain. Because most evidence points to a deleterious effect, the variant is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -13.192 | Likely Pathogenic | 0.931 | Likely Pathogenic | Ambiguous | 0.91 | Ambiguous | 0.1 | 1.15 | Ambiguous | 1.03 | Ambiguous | 0.55 | Ambiguous | 0.694 | Likely Pathogenic | -5.04 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.25 | Pathogenic | 0.09 | Tolerated | 0.3468 | 0.6635 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1445T>G | L482R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, while FoldX, Rosetta, and Foldetta return uncertain results. In a consensus framework, the SGM‑Consensus score is “Likely Pathogenic,” reflecting the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus is Likely Pathogenic, and Foldetta remains inconclusive. Taken together, the overwhelming majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -14.684 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.74 | Ambiguous | 0.1 | 1.31 | Ambiguous | 1.03 | Ambiguous | 1.53 | Destabilizing | 0.878 | Likely Pathogenic | -5.92 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | -1.27 | Pathogenic | 0.01 | Affected | 0.1255 | 0.0679 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1588A>G | K530E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K530E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and polyPhen‑2 HumVar, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus remains Likely Pathogenic, and Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for K530E. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | -14.450 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.79 | Ambiguous | 0.2 | 1.27 | Ambiguous | 1.03 | Ambiguous | 0.43 | Likely Benign | 0.581 | Likely Pathogenic | -3.45 | Deleterious | 0.703 | Possibly Damaging | 0.276 | Benign | -1.57 | Pathogenic | 0.00 | Affected | 0.2505 | 0.0810 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.2009T>G | L670R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L670R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of reliable predictions indicate a benign effect. There is no ClinVar annotation to contradict this assessment, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.161087 | Structured | 0.090855 | Uncertain | 0.812 | 0.385 | 0.000 | -9.801 | Likely Pathogenic | 0.552 | Ambiguous | Likely Benign | 0.64 | Ambiguous | 0.1 | 1.42 | Ambiguous | 1.03 | Ambiguous | 0.67 | Ambiguous | 0.193 | Likely Benign | -1.74 | Neutral | 0.993 | Probably Damaging | 0.755 | Possibly Damaging | 3.43 | Benign | 0.41 | Tolerated | 0.1327 | 0.1145 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||
| 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.722A>C | K241T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are reported by Rosetta and FATHMM. Two tools (Foldetta and premPS) give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta remains uncertain. Overall, the consensus of the majority of evidence points to a pathogenic effect for K241T, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.911 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 2.00 | Destabilizing | 0.4 | 0.06 | Likely Benign | 1.03 | Ambiguous | 0.60 | Ambiguous | 0.853 | Likely Pathogenic | -5.14 | Deleterious | 0.995 | Probably Damaging | 0.747 | Possibly Damaging | 5.74 | Benign | 0.03 | Affected | 0.2021 | 0.3951 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.723A>C | K241N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.198 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 1.13 | Ambiguous | 1.03 | Ambiguous | 0.89 | Ambiguous | 0.663 | Likely Pathogenic | -4.23 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.81 | Benign | 0.03 | Affected | 0.3426 | 0.1872 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.723A>T | K241N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported for FoldX, Rosetta, Foldetta, and premPS and are not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.198 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 1.13 | Ambiguous | 1.03 | Ambiguous | 0.89 | Ambiguous | 0.663 | Likely Pathogenic | -4.23 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.81 | Benign | 0.03 | Affected | 0.3426 | 0.1872 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.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.970C>T | R324W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R324W is listed in ClinVar with an uncertain significance (ClinVar ID 845180.0) and is present in gnomAD (ID 6‑33437875‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other stability or functional scores are available. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a leaning toward pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.257454 | Structured | 0.426893 | Uncertain | 0.954 | 0.397 | 0.000 | Uncertain | 1 | 6-33437875-C-T | 2 | 1.24e-6 | -12.906 | Likely Pathogenic | 0.694 | Likely Pathogenic | Likely Benign | 1.49 | Ambiguous | 0.3 | 0.56 | Ambiguous | 1.03 | Ambiguous | 0.66 | Ambiguous | 0.481 | Likely Benign | -3.12 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.82 | Pathogenic | 0.16 | Tolerated | 3.39 | 22 | 0.1517 | 0.4361 | 2 | -3 | 3.6 | 30.03 | 256.6 | 39.1 | 0.0 | 0.1 | 0.3 | 0.2 | X | Potentially Pathogenic | The guanidinium group of Arg324, located at the end of an anti-parallel β sheet strand (res. Ala322-Asp330), faces outward and frequently forms a salt bridge with the carboxylate group of the Asp288 side chain, which is part of a β strand end (res. Met289-Pro298). In the variant simulations, the indole ring of the Trp324 side chain cannot maintain a similar interaction with the negatively charged carboxylate side chain of Asp288, potentially compromising the folding of the anti-parallel β sheet assembly. However, the residue swap does not appear to negatively impact the protein structure or its integrity based on the simulations. | |||||||||||||
| c.979C>G | L327V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L327V is reported in gnomAD (ID 6‑33437884‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.335645 | Structured | 0.409189 | Uncertain | 0.939 | 0.490 | 0.000 | 6-33437884-C-G | 3 | 1.86e-6 | -8.978 | Likely Pathogenic | 0.148 | Likely Benign | Likely Benign | 1.38 | Ambiguous | 0.1 | 0.67 | Ambiguous | 1.03 | Ambiguous | 1.31 | Destabilizing | 0.208 | Likely Benign | -1.87 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.66 | Benign | 0.13 | Tolerated | 3.38 | 23 | 0.1648 | 0.4206 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||
| c.1012G>C | D338H 2D AIThe SynGAP1 missense variant D338H is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to premPS, whereas the remaining 11 tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for D338H, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -12.325 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 1.32 | Ambiguous | 1.2 | 0.76 | Ambiguous | 1.04 | Ambiguous | 0.18 | Likely Benign | 0.515 | Likely Pathogenic | -4.42 | Deleterious | 0.966 | Probably Damaging | 0.770 | Possibly Damaging | 1.71 | Pathogenic | 0.01 | Affected | 0.1671 | 0.6654 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1319A>T | N440I 2D AISynGAP1 missense variant N440I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely pathogenic; Foldetta remains inconclusive. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.365 | Likely Pathogenic | 0.778 | Likely Pathogenic | Likely Benign | 0.97 | Ambiguous | 0.9 | 1.10 | Ambiguous | 1.04 | Ambiguous | 0.10 | Likely Benign | 0.100 | Likely Benign | -4.07 | Deleterious | 0.322 | Benign | 0.109 | Benign | 3.47 | Benign | 0.03 | Affected | 0.0554 | 0.3772 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.1648G>T | A550S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A550S missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated predictors—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently classify the variant as pathogenic. FoldX, Rosetta, Foldetta, and premPS yield uncertain or inconclusive results and are therefore not considered evidence for either side. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for A550S. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | -12.166 | Likely Pathogenic | 0.569 | Likely Pathogenic | Likely Benign | 1.00 | Ambiguous | 0.1 | 1.08 | Ambiguous | 1.04 | Ambiguous | 0.80 | Ambiguous | 0.753 | Likely Pathogenic | -2.69 | Deleterious | 0.976 | Probably Damaging | 0.907 | Possibly Damaging | -1.29 | Pathogenic | 0.02 | Affected | 0.1739 | 0.3615 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1754C>T | A585V 2D AIThe SynGAP1 missense variant A585V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and SIFT, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.055884 | Uncertain | 0.880 | 0.244 | 0.000 | -10.843 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.95 | Ambiguous | 1.4 | 1.12 | Ambiguous | 1.04 | Ambiguous | 0.51 | Ambiguous | 0.420 | Likely Benign | -3.35 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | -1.27 | Pathogenic | 0.10 | Tolerated | 0.1004 | 0.3496 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.1843C>G | P615A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P615A variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include SIFT and Rosetta, whereas the majority of predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score (Likely Pathogenic) all suggest a pathogenic impact. Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta’s stability analysis is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for P615A, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -12.156 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 1.73 | Ambiguous | 0.3 | 0.35 | Likely Benign | 1.04 | Ambiguous | 0.85 | Ambiguous | 0.693 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.25 | Pathogenic | 0.10 | Tolerated | 0.3169 | 0.3214 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1897C>A | L633M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L633M has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain or inconclusive results. 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 is also inconclusive. Overall, the majority of definitive predictions (5 pathogenic vs. 4 benign) lean toward a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.045352 | Structured | 0.045407 | Uncertain | 0.952 | 0.252 | 0.000 | -10.300 | Likely Pathogenic | 0.718 | Likely Pathogenic | Likely Benign | 0.61 | Ambiguous | 0.1 | 1.47 | Ambiguous | 1.04 | Ambiguous | 0.90 | Ambiguous | 0.355 | Likely Benign | -1.99 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.77 | Benign | 0.01 | Affected | 0.0984 | 0.2683 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.707C>G | A236G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A236G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, premPS, and PROVEAN. Four tools (FoldX, Rosetta, Foldetta, and ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign, while Foldetta remains uncertain. Overall, the majority of available predictions support a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -7.412 | In-Between | 0.162 | Likely Benign | Likely Benign | 0.92 | Ambiguous | 0.1 | 1.15 | Ambiguous | 1.04 | Ambiguous | 1.09 | Destabilizing | 0.615 | Likely Pathogenic | -3.35 | Deleterious | 0.067 | Benign | 0.028 | Benign | 5.74 | Benign | 0.07 | Tolerated | 0.2200 | 0.3899 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.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.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.1182A>C | K394N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K394N 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, FATHMM, and polyPhen‑2 HumVar. Those that agree on a pathogenic effect are Rosetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta as uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | -7.408 | In-Between | 0.861 | Likely Pathogenic | Ambiguous | 0.08 | Likely Benign | 0.1 | 2.02 | Destabilizing | 1.05 | Ambiguous | 0.66 | Ambiguous | 0.299 | Likely Benign | -3.17 | Deleterious | 0.535 | Possibly Damaging | 0.188 | Benign | 4.60 | Benign | 0.01 | Affected | 0.4353 | 0.2654 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
| c.1182A>T | K394N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K394N missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a mixed signal: benign calls come from REVEL, FoldX, FATHMM, and polyPhen‑2 HumVar, while pathogenic calls come from Rosetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, AlphaMissense‑Optimized) return uncertain results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as pathogenic; and Foldetta is uncertain. Taken together, the majority of evidence—including the high‑accuracy consensus—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. | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | -7.408 | In-Between | 0.861 | Likely Pathogenic | Ambiguous | 0.08 | Likely Benign | 0.1 | 2.02 | Destabilizing | 1.05 | Ambiguous | 0.66 | Ambiguous | 0.299 | Likely Benign | -3.17 | Deleterious | 0.535 | Possibly Damaging | 0.188 | Benign | 4.60 | Benign | 0.01 | Affected | 0.4353 | 0.2654 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
| 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.1306G>C | E436Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E436Q is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include premPS and FATHMM, while the majority of tools predict a pathogenic outcome: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the consensus of pathogenic predictions outweighs benign ones, and the high‑accuracy tools reinforce a pathogenic classification. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -12.413 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.51 | Ambiguous | 0.1 | 1.58 | Ambiguous | 1.05 | Ambiguous | 0.50 | Likely Benign | 0.607 | Likely Pathogenic | -2.76 | Deleterious | 0.992 | Probably Damaging | 0.946 | Probably Damaging | 4.64 | Benign | 0.01 | Affected | 0.1237 | 0.5809 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1079A>T | E360V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only premPS, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) uniformly predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the overwhelming majority of reliable predictors classify E360V as pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.421183 | Uncertain | 0.955 | 0.498 | 0.250 | -14.388 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 1.11 | Ambiguous | 1.06 | Ambiguous | 0.03 | Likely Benign | 0.627 | Likely Pathogenic | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 1.57 | Pathogenic | 0.00 | Affected | 0.1143 | 0.8670 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1538T>A | F513Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SIFT classifies it as benign, whereas REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenicity. Stability‑based methods (FoldX, Rosetta, Foldetta) and AlphaMissense‑Optimized return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as uncertain. With 10 of 12 evaluated tools indicating pathogenicity and no conflicting ClinVar annotation, the variant is most likely pathogenic, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -10.022 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 1.09 | Ambiguous | 0.2 | 1.03 | Ambiguous | 1.06 | Ambiguous | 1.09 | Destabilizing | 0.791 | Likely Pathogenic | -2.92 | Deleterious | 0.988 | Probably Damaging | 0.976 | Probably Damaging | -1.39 | Pathogenic | 0.07 | Tolerated | 0.1046 | 0.1087 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1589A>C | K530T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530T missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include only premPS, whereas the remaining nine tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of the pathogenic‑predominant tools) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a deleterious impact. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently contains no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | -11.506 | Likely Pathogenic | 0.852 | Likely Pathogenic | Ambiguous | 1.06 | Ambiguous | 0.3 | 1.06 | Ambiguous | 1.06 | Ambiguous | 0.27 | Likely Benign | 0.610 | Likely Pathogenic | -5.17 | Deleterious | 0.921 | Possibly Damaging | 0.950 | Probably Damaging | -1.63 | Pathogenic | 0.00 | Affected | 0.1351 | 0.2780 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.601G>C | D201H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201H missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM. Those that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions (seven pathogenic vs. three benign) indicate that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -8.595 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 0.68 | Ambiguous | 0.2 | 1.43 | Ambiguous | 1.06 | Ambiguous | 0.44 | Likely Benign | 0.284 | Likely Benign | -3.45 | Deleterious | 1.000 | Probably Damaging | 0.960 | Probably Damaging | 4.04 | Benign | 0.03 | Affected | 0.1152 | 0.5838 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.614T>G | I205S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I205S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and ESM1b. Tools with uncertain or inconclusive results (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions lean toward a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -8.694 | Likely Pathogenic | 0.518 | Ambiguous | Likely Benign | 1.17 | Ambiguous | 0.2 | 0.95 | Ambiguous | 1.06 | Ambiguous | 0.88 | Ambiguous | 0.178 | Likely Benign | -2.73 | Deleterious | 0.838 | Possibly Damaging | 0.368 | Benign | 4.12 | Benign | 0.24 | Tolerated | 0.2346 | 0.0800 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||
| c.632G>T | S211I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S211I missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. No evidence from FoldX or Rosetta is available. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -17.090 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 1.06 | Ambiguous | 1.1 | 1.05 | Ambiguous | 1.06 | Ambiguous | 0.12 | Likely Benign | 0.251 | Likely Benign | -4.94 | Deleterious | 0.995 | Probably Damaging | 0.767 | Possibly Damaging | 3.90 | Benign | 0.01 | Affected | 0.0909 | 0.5220 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.682A>C | T228P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T228P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FATHMM, Rosetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is inconclusive, but the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -8.559 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 1.65 | Ambiguous | 0.6 | 0.47 | Likely Benign | 1.06 | Ambiguous | 0.21 | Likely Benign | 0.690 | Likely Pathogenic | -3.54 | Deleterious | 0.984 | Probably Damaging | 0.690 | Possibly Damaging | 5.64 | Benign | 0.02 | Affected | 0.2207 | 0.6360 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.703T>G | S235A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235A has no ClinVar entry and is not present in gnomAD. Prediction tools that indicate benign effects include Rosetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic; Foldetta remains uncertain. Overall, the balance of evidence leans toward a benign interpretation, but the SGM Consensus introduces a pathogenic signal, resulting in a conflicting prediction profile. This assessment does not contradict ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -10.861 | Likely Pathogenic | 0.707 | Likely Pathogenic | Likely Benign | 1.92 | Ambiguous | 0.1 | 0.19 | Likely Benign | 1.06 | Ambiguous | 0.48 | Likely Benign | 0.646 | Likely Pathogenic | -2.52 | Deleterious | 0.002 | Benign | 0.004 | Benign | 5.49 | Benign | 0.01 | Affected | 0.5168 | 0.4563 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.721A>G | K241E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K241E missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include SIFT and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -12.582 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.75 | Ambiguous | 0.1 | 1.36 | Ambiguous | 1.06 | Ambiguous | 0.68 | Ambiguous | 0.878 | Likely Pathogenic | -3.43 | Deleterious | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 6.00 | Benign | 0.10 | Tolerated | 0.3610 | 0.1179 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.743G>A | R248Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248Q is catalogued in gnomAD (ID 6‑33435594‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: benign predictions come from FoldX and FATHMM, whereas pathogenic predictions are made by REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R248Q, and this conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | 6-33435594-G-A | 2 | 1.24e-6 | -10.573 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.45 | Likely Benign | 0.2 | 1.67 | Ambiguous | 1.06 | Ambiguous | 1.05 | Destabilizing | 0.739 | Likely Pathogenic | -3.34 | Deleterious | 0.999 | Probably Damaging | 0.715 | Possibly Damaging | 5.74 | Benign | 0.01 | Affected | 3.41 | 14 | 0.2572 | 0.2549 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||
| c.1259T>A | F420Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420Y is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show mixed results. Benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are reported by premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments indicate that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -12.138 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 1.18 | Ambiguous | 0.1 | 0.96 | Ambiguous | 1.07 | Ambiguous | 1.31 | Destabilizing | 0.228 | Likely Benign | -2.80 | Deleterious | 0.306 | Benign | 0.100 | Benign | 3.09 | Benign | 0.03 | Affected | 0.1609 | 0.1498 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1351C>A | L451I 2D AIThe SynGAP1 L451I missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results come from FoldX, Rosetta, premPS, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is also inconclusive. Overall, the majority of available predictions (five pathogenic versus four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar record. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -11.046 | Likely Pathogenic | 0.658 | Likely Pathogenic | Likely Benign | 1.43 | Ambiguous | 0.8 | 0.70 | Ambiguous | 1.07 | Ambiguous | 0.94 | Ambiguous | 0.284 | Likely Benign | -1.94 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.75 | Benign | 0.02 | Affected | 0.0681 | 0.2958 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1496G>T | R499I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the change as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely pathogenic. No tool predicts a benign outcome; the remaining predictions (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are uncertain or inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the overwhelming majority of evidence supports a pathogenic effect, and this is consistent with the absence of a ClinVar entry; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | -9.069 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 1.53 | Ambiguous | 0.1 | 0.61 | Ambiguous | 1.07 | Ambiguous | 0.57 | Ambiguous | 0.713 | Likely Pathogenic | -5.50 | Deleterious | 0.998 | Probably Damaging | 0.922 | Probably Damaging | -1.47 | Pathogenic | 0.00 | Affected | 0.1401 | 0.2146 | -2 | -3 | 9.0 | -43.03 | |||||||||||||||||||||||||||||
| c.1543C>T | R515C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R515C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438786‑C‑T). Prediction tools that indicate a benign effect include only AlphaMissense‑Optimized. All other evaluated predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN)—classify the variant as pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other high‑accuracy tools provide a definitive prediction. Based on the overall consensus, the variant is most likely pathogenic, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | Uncertain | 1 | 6-33438786-C-T | 1 | 6.20e-7 | -10.973 | Likely Pathogenic | 0.628 | Likely Pathogenic | Likely Benign | 1.00 | Ambiguous | 0.0 | 1.13 | Ambiguous | 1.07 | Ambiguous | 0.72 | Ambiguous | 0.691 | Likely Pathogenic | -5.49 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.3055 | 0.1546 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||
| c.1691A>C | E564A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E564A is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include premPS and SIFT, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023534 | Structured | 0.038418 | Uncertain | 0.891 | 0.208 | 0.000 | -14.506 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.64 | Ambiguous | 0.1 | 1.49 | Ambiguous | 1.07 | Ambiguous | 0.24 | Likely Benign | 0.765 | Likely Pathogenic | -5.91 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.33 | Pathogenic | 0.12 | Tolerated | 0.3201 | 0.4918 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1864A>T | T622S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T622S is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from SIFT and AlphaMissense‑Optimized, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign, whereas the SGM‑Consensus predicts it to be likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No other folding‑stability tools provide conclusive evidence. Overall, the preponderance of predictions, including the SGM‑Consensus, indicates that T622S is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.071403 | Uncertain | 0.957 | 0.198 | 0.000 | -9.840 | Likely Pathogenic | 0.669 | Likely Pathogenic | Likely Benign | 0.78 | Ambiguous | 0.1 | 1.36 | Ambiguous | 1.07 | Ambiguous | 0.80 | Ambiguous | 0.705 | Likely Pathogenic | -3.52 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.50 | Pathogenic | 0.09 | Tolerated | 0.2523 | 0.3183 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1865C>G | T622S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T622S is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from SIFT and AlphaMissense‑Optimized, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign, whereas the SGM‑Consensus predicts it to be likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No other folding‑stability tools provide conclusive evidence. Overall, the preponderance of predictions, including the SGM‑Consensus, indicates that T622S is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.071403 | Uncertain | 0.957 | 0.198 | 0.000 | -9.840 | Likely Pathogenic | 0.669 | Likely Pathogenic | Likely Benign | 0.78 | Ambiguous | 0.1 | 1.36 | Ambiguous | 1.07 | Ambiguous | 0.80 | Ambiguous | 0.595 | Likely Pathogenic | -3.52 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.50 | Pathogenic | 0.09 | Tolerated | 0.2523 | 0.3183 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1867C>T | L623F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L623F is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated 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, and PROVEAN)—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No predictions are missing or inconclusive. Based on the overwhelming agreement among pathogenic predictions and the lack of a benign signal, 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 | 0.175930 | Structured | 0.060667 | Uncertain | 0.962 | 0.211 | 0.000 | -11.655 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 1.22 | Ambiguous | 0.2 | 0.92 | Ambiguous | 1.07 | Ambiguous | 0.57 | Ambiguous | 0.440 | Likely Benign | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.65 | Pathogenic | 0.02 | Affected | 0.0838 | 0.3016 | 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.893C>T | P298L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P298L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome; and Foldetta’s stability prediction is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -7.334 | In-Between | 0.107 | Likely Benign | Likely Benign | 0.60 | Ambiguous | 0.2 | 1.53 | Ambiguous | 1.07 | Ambiguous | -0.16 | Likely Benign | 0.267 | Likely Benign | -0.82 | Neutral | 0.885 | Possibly Damaging | 0.589 | Possibly Damaging | 1.91 | Pathogenic | 0.21 | Tolerated | 0.2137 | 0.6795 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
| c.896G>T | R299L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Stability‑based methods FoldX, Rosetta, Foldetta, and premPS returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of consensus predictions favor a pathogenic effect, and the high‑accuracy tools do not overturn this trend. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for R299L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | -5.171 | Likely Benign | 0.645 | Likely Pathogenic | Likely Benign | 1.37 | Ambiguous | 0.6 | 0.77 | Ambiguous | 1.07 | Ambiguous | 0.59 | Ambiguous | 0.356 | Likely Benign | -4.03 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.65 | Pathogenic | 0.02 | Affected | 0.2027 | 0.5202 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.978T>A | H326Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and SIFT, whereas a majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools, Foldetta (combining FoldX‑MD and Rosetta) and Rosetta alone, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for H326Q. This conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.342579 | Structured | 0.418150 | Uncertain | 0.944 | 0.455 | 0.000 | -8.688 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.46 | Likely Benign | 0.1 | 1.67 | Ambiguous | 1.07 | Ambiguous | 1.00 | Destabilizing | 0.444 | Likely Benign | -6.89 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.07 | Pathogenic | 0.10 | Tolerated | 0.1485 | 0.3500 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.978T>G | H326Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and SIFT, whereas a majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools, Foldetta (combining FoldX‑MD and Rosetta) and Rosetta alone, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also indicates likely pathogenic, while Foldetta remains uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for H326Q. This conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.342579 | Structured | 0.418150 | Uncertain | 0.944 | 0.455 | 0.000 | -8.688 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.46 | Likely Benign | 0.1 | 1.67 | Ambiguous | 1.07 | Ambiguous | 1.00 | Destabilizing | 0.444 | Likely Benign | -6.89 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.07 | Pathogenic | 0.10 | Tolerated | 0.1485 | 0.3500 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.1180A>C | K394Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K394Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic outcome are SIFT and Rosetta. The remaining tools—Foldetta, premPS, ESM1b, and AlphaMissense‑Default—return uncertain results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also leans toward benign, with two benign votes and two uncertain votes. Foldetta’s stability prediction is uncertain and thus not considered. Overall, the majority of reliable predictions indicate a benign effect, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | -7.261 | In-Between | 0.468 | Ambiguous | Likely Benign | 0.15 | Likely Benign | 0.0 | 2.00 | Destabilizing | 1.08 | Ambiguous | 0.64 | Ambiguous | 0.330 | Likely Benign | -2.46 | Neutral | 0.001 | Benign | 0.009 | Benign | 4.61 | Benign | 0.01 | Affected | 0.5365 | 0.2106 | Weaken | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| 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.1348G>T | A450S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A450S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining methods—FoldX, Rosetta, Foldetta, and premPS—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus unavailable; Foldetta is uncertain. Overall, the balance of evidence (five benign versus four pathogenic predictions, with three uncertain) suggests the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -9.257 | Likely Pathogenic | 0.274 | Likely Benign | Likely Benign | 0.81 | Ambiguous | 0.0 | 1.35 | Ambiguous | 1.08 | Ambiguous | 0.69 | Ambiguous | 0.268 | Likely Benign | -2.70 | Deleterious | 0.965 | Probably Damaging | 0.972 | Probably Damaging | 3.47 | Benign | 0.10 | Tolerated | 0.2003 | 0.4322 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1363C>A | L455M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L455M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. No folding‑stability method provides a definitive result. Consequently, the computational evidence does not favor either benign or pathogenic classification. The variant’s status is therefore inconclusive, and this lack of consensus does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -10.086 | Likely Pathogenic | 0.802 | Likely Pathogenic | Ambiguous | 0.88 | Ambiguous | 0.0 | 1.27 | Ambiguous | 1.08 | Ambiguous | 0.59 | Ambiguous | 0.147 | Likely Benign | -1.64 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.25 | Benign | 0.11 | Tolerated | 0.0606 | 0.3362 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1486G>A | E496K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E496K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FoldX, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. Uncertain predictions come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Overall, the evidence strongly favors a pathogenic classification for E496K, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | -15.795 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.38 | Likely Benign | 0.1 | 1.77 | Ambiguous | 1.08 | Ambiguous | 0.76 | Ambiguous | 0.743 | Likely Pathogenic | -3.58 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.40 | Pathogenic | 0.04 | Affected | 0.1810 | 0.3528 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.704C>G | S235C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FATHMM and Rosetta, whereas a majority of tools (REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Results from high‑accuracy methods are mixed: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta is uncertain. Because the uncertain predictions are treated as unavailable, the overall evidence still favors pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -11.350 | Likely Pathogenic | 0.800 | Likely Pathogenic | Ambiguous | 1.74 | Ambiguous | 0.1 | 0.42 | Likely Benign | 1.08 | Ambiguous | 0.76 | Ambiguous | 0.878 | Likely Pathogenic | -4.24 | Deleterious | 0.977 | Probably Damaging | 0.620 | Possibly Damaging | 5.45 | Benign | 0.00 | Affected | 0.1284 | 0.6015 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.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.1034T>A | L345Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L345Q is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into benign (REVEL, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM). FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is unavailable. Overall, the majority of predictions lean toward pathogenicity, while the single high‑accuracy tool that is definitive is benign. Thus, the variant is most likely pathogenic based on the collective evidence, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.260850 | Structured | 0.354989 | Uncertain | 0.936 | 0.478 | 0.125 | -6.034 | Likely Benign | 0.213 | Likely Benign | Likely Benign | 1.32 | Ambiguous | 0.1 | 0.86 | Ambiguous | 1.09 | Ambiguous | 1.26 | Destabilizing | 0.218 | Likely Benign | -3.67 | Deleterious | 0.993 | Probably Damaging | 0.844 | Possibly Damaging | 1.82 | Pathogenic | 0.03 | Affected | 0.0937 | 0.0842 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||
| c.1219C>G | Q407E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q407E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all predict a pathogenic outcome. AlphaMissense‑Default, FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools and the SGM Consensus support a pathogenic classification, while a minority predict benign. No ClinVar entry exists to contradict these predictions. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | -12.631 | Likely Pathogenic | 0.466 | Ambiguous | Likely Benign | 0.50 | Ambiguous | 0.1 | 1.68 | Ambiguous | 1.09 | Ambiguous | 1.30 | Destabilizing | 0.243 | Likely Benign | -2.66 | Deleterious | 0.989 | Probably Damaging | 0.930 | Probably Damaging | 3.96 | Benign | 0.03 | Affected | 0.1199 | 0.2000 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.1530T>G | I510M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I510M missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign impact include PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (benign), ESM1b (uncertain), FATHMM (pathogenic), and PROVEAN (benign)—also favors benign. Foldetta, a protein‑folding stability method, yielded an uncertain outcome. Taken together, the consensus of the most reliable predictors indicates a benign effect. This conclusion does not contradict the ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -7.988 | In-Between | 0.235 | Likely Benign | Likely Benign | 0.56 | Ambiguous | 0.3 | 1.61 | Ambiguous | 1.09 | Ambiguous | 0.55 | Ambiguous | 0.532 | Likely Pathogenic | -0.97 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.42 | Pathogenic | 0.02 | Affected | 0.0674 | 0.1789 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||
| c.2029A>G | S677G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677G 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, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. Predictions that are inconclusive—FoldX, Rosetta, Foldetta, and premPS—are treated as unavailable. High‑accuracy assessments reinforce the benign interpretation: 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, remains uncertain. Overall, the evidence supports a benign classification for S677G, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | -5.126 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.98 | Ambiguous | 0.1 | 1.20 | Ambiguous | 1.09 | Ambiguous | 0.64 | Ambiguous | 0.126 | Likely Benign | -1.38 | Neutral | 0.002 | Benign | 0.001 | Benign | 3.30 | Benign | 0.26 | Tolerated | 0.2885 | 0.5325 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.640C>A | L214M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L214M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are PROVEAN and FATHMM, whereas the majority of tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; the remaining tools (FoldX, Rosetta, Foldetta, premPS) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs two benign) and Foldetta is uncertain. Thus, the available evidence points to a pathogenic effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.155435 | Structured | 0.372604 | Uncertain | 0.818 | 0.302 | 0.125 | -9.347 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.74 | Ambiguous | 0.3 | 1.43 | Ambiguous | 1.09 | Ambiguous | 0.80 | Ambiguous | 0.646 | Likely Pathogenic | -1.72 | Neutral | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.73 | Benign | 0.01 | Affected | 0.0805 | 0.4054 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.773G>C | R258P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R258P is not reported in ClinVar and has no entries in gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only FATHMM predicts a benign outcome. Predictions of uncertain status come from FoldX, Rosetta, and Foldetta. High‑accuracy tools reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta remains inconclusive. Overall, the preponderance of evidence supports a pathogenic classification for R258P, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.295083 | Structured | 0.293667 | Uncertain | 0.894 | 0.260 | 0.250 | -14.293 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.26 | Ambiguous | 0.4 | 0.92 | Ambiguous | 1.09 | Ambiguous | 1.00 | Destabilizing | 0.924 | Likely Pathogenic | -5.83 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.79 | Benign | 0.01 | Affected | 0.2148 | 0.4557 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1129A>G | M377V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377V is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (gnomAD ID 6‑33438034‑A‑G). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable. High‑accuracy assessments confirm the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, while Foldetta remains uncertain. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.675549 | Disordered | 0.431183 | Uncertain | 0.324 | 0.884 | 0.625 | 6-33438034-A-G | -1.507 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.92 | Ambiguous | 0.3 | 1.27 | Ambiguous | 1.10 | Ambiguous | 0.48 | Likely Benign | 0.161 | Likely Benign | -0.31 | Neutral | 0.000 | Benign | 0.000 | Benign | 5.46 | Benign | 0.15 | Tolerated | 4.32 | 12 | 0.4530 | 0.4096 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||
| c.1471A>T | T491S 2D AIThe SynGAP1 missense variant T491S is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. No evidence from FoldX or Rosetta is available to support a stability change. Overall, the preponderance of evidence points to a pathogenic effect for T491S, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | -7.273 | In-Between | 0.924 | Likely Pathogenic | Ambiguous | 0.93 | Ambiguous | 0.7 | 1.27 | Ambiguous | 1.10 | Ambiguous | 1.00 | Destabilizing | 0.704 | Likely Pathogenic | -3.90 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.25 | Pathogenic | 0.19 | Tolerated | 0.3119 | 0.2815 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1472C>G | T491S 2D AIThe SynGAP1 missense variant T491S is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. No evidence from FoldX or Rosetta is available to support a stability change. Overall, the preponderance of evidence points to a pathogenic effect for T491S, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | -7.273 | In-Between | 0.924 | Likely Pathogenic | Ambiguous | 0.93 | Ambiguous | 0.7 | 1.27 | Ambiguous | 1.10 | Ambiguous | 1.00 | Destabilizing | 0.666 | Likely Pathogenic | -3.90 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.25 | Pathogenic | 0.19 | Tolerated | 0.3119 | 0.2815 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1784T>A | L595Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L595Q is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized—predict a pathogenic effect, and the SGM‑Consensus score indicates a likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized returns a pathogenic prediction, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a likely pathogenic result, while Foldetta’s stability analysis is inconclusive. Overall, the majority of computational evidence points to a pathogenic effect, which does not contradict the ClinVar designation of uncertain significance but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.015344 | Structured | 0.128444 | Uncertain | 0.920 | 0.150 | 0.000 | Uncertain | 1 | -15.101 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.79 | Ambiguous | 0.1 | 1.40 | Ambiguous | 1.10 | Ambiguous | 1.99 | Destabilizing | 0.733 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.75 | Benign | 0.00 | Affected | 3.37 | 35 | 0.1074 | 0.1563 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.1850A>G | E617G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617G is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from premPS, SIFT, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | -7.984 | In-Between | 0.777 | Likely Pathogenic | Likely Benign | 0.59 | Ambiguous | 0.2 | 1.60 | Ambiguous | 1.10 | Ambiguous | 0.22 | Likely Benign | 0.701 | Likely Pathogenic | -4.99 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.41 | Pathogenic | 0.18 | Tolerated | 0.2344 | 0.5442 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1900G>T | A634S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A634S 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 FATHMM and AlphaMissense‑Optimized; those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.085092 | Structured | 0.052058 | Uncertain | 0.932 | 0.242 | 0.000 | -9.706 | Likely Pathogenic | 0.434 | Ambiguous | Likely Benign | 0.91 | Ambiguous | 0.1 | 1.28 | Ambiguous | 1.10 | Ambiguous | 0.77 | Ambiguous | 0.506 | Likely Pathogenic | -2.99 | Deleterious | 0.953 | Possibly Damaging | 0.985 | Probably Damaging | 2.67 | Benign | 0.05 | Affected | 0.2607 | 0.4231 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.621G>C | K207N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K207N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicating likely pathogenic, while Foldetta’s stability prediction is unavailable. Overall, the preponderance of evidence points to a pathogenic effect for K207N, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -12.881 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.1 | 1.48 | Ambiguous | 1.10 | Ambiguous | 1.00 | Destabilizing | 0.123 | Likely Benign | -3.54 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.98 | Benign | 0.07 | Tolerated | 0.3184 | 0.2335 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.621G>T | K207N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K207N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions arise from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, and the SGM Consensus (majority vote) also predicts Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence indicates that K207N is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -12.881 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.1 | 1.48 | Ambiguous | 1.10 | Ambiguous | 1.00 | Destabilizing | 0.124 | Likely Benign | -3.54 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.98 | Benign | 0.07 | Tolerated | 0.3184 | 0.2335 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.808G>A | E270K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E270K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FoldX, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give uncertain results: Foldetta (a combined FoldX‑MD/Rosetta stability assessment) and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta remains uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, which is consistent with the lack of ClinVar reporting and gnomAD absence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.382573 | Uncertain | 0.938 | 0.231 | 0.125 | -14.466 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | -0.06 | Likely Benign | 0.2 | 2.26 | Destabilizing | 1.10 | Ambiguous | 0.71 | Ambiguous | 0.530 | Likely Pathogenic | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.68 | Pathogenic | 0.01 | Affected | 0.2296 | 0.4251 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.988G>A | D330N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330N missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious interpretation: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic,” while AlphaMissense‑Optimized and Foldetta yield uncertain results and are treated as unavailable. No folding‑stability methods (FoldX, Rosetta, premPS) provide decisive evidence. Overall, the preponderance of pathogenic predictions strongly suggests that D330N is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -12.993 | Likely Pathogenic | 0.909 | Likely Pathogenic | Ambiguous | 1.61 | Ambiguous | 0.2 | 0.59 | Ambiguous | 1.10 | Ambiguous | 0.59 | Ambiguous | 0.350 | Likely Benign | -3.46 | Deleterious | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 1.01 | Pathogenic | 0.02 | Affected | 0.1252 | 0.4263 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1488G>C | E496D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E496D missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FoldX, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain predictions come from Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a unanimous majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is consistent with the absence of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | -10.552 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.43 | Likely Benign | 0.2 | 1.78 | Ambiguous | 1.11 | Ambiguous | 1.18 | Destabilizing | 0.583 | Likely Pathogenic | -2.78 | Deleterious | 0.996 | Probably Damaging | 0.989 | Probably Damaging | -1.45 | Pathogenic | 0.04 | Affected | 3.37 | 35 | 0.1576 | 0.1912 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||
| c.1488G>T | E496D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E496D is reported in gnomAD (ID 6‑33438520‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions are provided only by FoldX, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—classify the change as pathogenic. Uncertain results come from Rosetta, Foldetta, and AlphaMissense‑Optimized and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | 6-33438520-G-T | 2 | 1.24e-6 | -10.552 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.43 | Likely Benign | 0.2 | 1.78 | Ambiguous | 1.11 | Ambiguous | 1.18 | Destabilizing | 0.583 | Likely Pathogenic | -2.78 | Deleterious | 0.996 | Probably Damaging | 0.989 | Probably Damaging | -1.45 | Pathogenic | 0.04 | Affected | 3.37 | 35 | 0.1576 | 0.1912 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||
| c.1700A>C | E567A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E567A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Four tools (Foldetta, premPS, Rosetta, AlphaMissense‑Optimized) yield uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.021816 | Structured | 0.051008 | Uncertain | 0.916 | 0.234 | 0.000 | -12.854 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.43 | Likely Benign | 0.1 | 1.79 | Ambiguous | 1.11 | Ambiguous | 0.63 | Ambiguous | 0.418 | Likely Benign | -5.74 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.43 | Benign | 0.17 | Tolerated | 0.3170 | 0.5189 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1723C>A | R575S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R575S is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include only SIFT, whereas the majority—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict pathogenicity. FoldX, Rosetta, Foldetta, and premPS give uncertain results, which are treated as unavailable evidence. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R575S, and this assessment does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.021362 | Uncertain | 0.916 | 0.259 | 0.000 | -11.124 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 1.66 | Ambiguous | 0.1 | 0.55 | Ambiguous | 1.11 | Ambiguous | 0.76 | Ambiguous | 0.582 | Likely Pathogenic | -2.71 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.21 | Pathogenic | 0.33 | Tolerated | 0.2669 | 0.2394 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||
| c.1949A>G | N650S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650S lies in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain or inconclusive results come from AlphaMissense‑Optimized, FoldX, Rosetta, Foldetta, and premPS. For high‑accuracy methods, AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta is uncertain. Overall, the majority of available predictions support a pathogenic effect. The variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -11.291 | Likely Pathogenic | 0.916 | Likely Pathogenic | Ambiguous | 0.79 | Ambiguous | 0.2 | 1.43 | Ambiguous | 1.11 | Ambiguous | 0.77 | Ambiguous | 0.395 | Likely Benign | -4.98 | Deleterious | 0.996 | Probably Damaging | 0.606 | Possibly Damaging | 3.06 | Benign | 0.02 | Affected | 0.3791 | 0.5090 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.2023A>T | N675Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N675Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions (six pathogenic vs. four benign) indicate 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. | GAP | 0.129801 | Structured | 0.111024 | Uncertain | 0.513 | 0.333 | 0.000 | -9.981 | Likely Pathogenic | 0.553 | Ambiguous | Likely Benign | 3.02 | Destabilizing | 1.3 | -0.81 | Ambiguous | 1.11 | Ambiguous | 0.19 | Likely Benign | 0.439 | Likely Benign | -5.86 | Deleterious | 1.000 | Probably Damaging | 0.955 | Probably Damaging | 3.38 | Benign | 0.01 | Affected | 0.0603 | 0.6417 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||
| c.2035T>G | F679V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F679V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta provide inconclusive results and are treated as unavailable. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -11.868 | Likely Pathogenic | 0.900 | Likely Pathogenic | Ambiguous | 1.92 | Ambiguous | 0.5 | 0.29 | Likely Benign | 1.11 | Ambiguous | 0.89 | Ambiguous | 0.497 | Likely Benign | -6.86 | Deleterious | 0.993 | Probably Damaging | 0.968 | Probably Damaging | 3.50 | Benign | 0.01 | Affected | 0.1830 | 0.2349 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.2120C>T | A707V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A707V variant is not reported in ClinVar (no ClinVar ID) but is present in gnomAD (variant ID 6‑33441585‑C‑T). Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign classification. Only three tools—Rosetta, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar—predict pathogenicity, while Foldetta reports an uncertain stability change. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM‑Consensus is benign, and Foldetta remains uncertain. Overall, the majority of evidence supports a benign impact for A707V, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.203355 | Structured | 0.371229 | Uncertain | 0.927 | 0.365 | 0.000 | 6-33441585-C-T | 1 | 6.20e-7 | -6.479 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.05 | Likely Benign | 0.0 | 2.17 | Destabilizing | 1.11 | Ambiguous | -0.30 | Likely Benign | 0.212 | Likely Benign | -1.62 | Neutral | 0.991 | Probably Damaging | 0.912 | Probably Damaging | 3.45 | Benign | 1.00 | Tolerated | 3.50 | 9 | 0.0794 | 0.4048 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||
| c.630C>A | H210Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H210Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign calls come from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar) and FATHMM, whereas pathogenic calls are made by premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN, favors a pathogenic outcome (3/4). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote) also predicts pathogenic. Foldetta, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta, is inconclusive and therefore not used as evidence. Overall, the majority of reliable predictors indicate a pathogenic effect for H210Q, and this conclusion does not conflict with any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -12.639 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.26 | Likely Benign | 0.3 | 1.96 | Ambiguous | 1.11 | Ambiguous | 1.20 | Destabilizing | 0.258 | Likely Benign | -6.84 | Deleterious | 0.141 | Benign | 0.064 | Benign | 3.10 | Benign | 0.00 | Affected | 0.1016 | 0.2852 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.630C>G | H210Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar) and FATHMM, whereas pathogenic calls come from premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized. When predictions are grouped, five tools favor a benign effect and six favor a pathogenic effect. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenic, and the Foldetta stability analysis is inconclusive. No evidence from ClinVar contradicts these findings. Therefore, the variant is most likely pathogenic based on the aggregate computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -12.639 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.26 | Likely Benign | 0.3 | 1.96 | Ambiguous | 1.11 | Ambiguous | 1.20 | Destabilizing | 0.258 | Likely Benign | -6.84 | Deleterious | 0.141 | Benign | 0.064 | Benign | 3.10 | Benign | 0.00 | Affected | 0.1016 | 0.2852 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.763G>T | D255Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include premPS and FATHMM, while the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -13.180 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.25 | Ambiguous | 0.2 | 0.96 | Ambiguous | 1.11 | Ambiguous | 0.13 | Likely Benign | 0.832 | Likely Pathogenic | -7.77 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 5.73 | Benign | 0.00 | Affected | 0.0464 | 0.5178 | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||
| c.1075A>C | T359P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T359P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.281712 | Structured | 0.414952 | Uncertain | 0.939 | 0.480 | 0.250 | -6.884 | Likely Benign | 0.319 | Likely Benign | Likely Benign | 0.97 | Ambiguous | 0.1 | 1.27 | Ambiguous | 1.12 | Ambiguous | 0.68 | Ambiguous | 0.248 | Likely Benign | -2.36 | Neutral | 0.627 | Possibly Damaging | 0.091 | Benign | 1.78 | Pathogenic | 0.14 | Tolerated | 0.2352 | 0.5611 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1213C>T | R405C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R405C missense variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438118‑C‑T). Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic outcome. 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 show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the balance 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 | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | Conflicting | 3 | 6-33438118-C-T | 6 | 3.72e-6 | -9.206 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 0.72 | Ambiguous | 0.1 | 1.51 | Ambiguous | 1.12 | Ambiguous | 1.21 | Destabilizing | 0.427 | Likely Benign | -7.27 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.61 | Benign | 0.02 | Affected | 3.38 | 28 | 0.3227 | 0.3964 | -4 | -3 | 7.0 | -53.05 | 221.3 | 82.6 | -0.1 | 0.0 | -0.2 | 0.3 | X | X | Potentially Pathogenic | The guanidinium group of Arg405, located in an anti-parallel β sheet strand of the C2 domain (res. Ala399-Ile411), forms a salt bridge with the carboxylate group of the Glu446 side chain from an opposing α helix (res. Val441-Ser457) in the GAP domain. The positively charged Arg405 side chain also stacks with the aromatic ring of the Phe358 side chain from a loop preceding the β strand (res. Thr359-Thr366), which could assist in maintaining the anti-parallel strand arrangement.In the variant simulations, the thiol-containing side chain of Cys405 is neutral and smaller compared to the arginine side chain. The lack of Arg405-Phe358 stacking affects the loop structure, causing it to assume a β strand form—an effect that could be exacerbated during protein folding. Moreover, the inability of Cys405 to form a salt bridge with Glu446 could affect the tertiary structure assembly, although this is not apparent based on the variant simulations. | ||||||||||||
| c.1657A>G | K553E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K553E missense variant is not reported in ClinVar (status: None) and has no entries in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict pathogenicity. FoldX and Rosetta give uncertain results, and Foldetta also reports an uncertain stability change. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a deleterious effect. Thus, the variant is most likely pathogenic based on current predictions, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.012270 | Structured | 0.006539 | Uncertain | 0.949 | 0.246 | 0.000 | -17.415 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.08 | Ambiguous | 0.3 | 1.15 | Ambiguous | 1.12 | Ambiguous | 1.04 | Destabilizing | 0.828 | Likely Pathogenic | -3.85 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.35 | Pathogenic | 0.12 | Tolerated | 0.2890 | 0.0650 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1933T>C | F645L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F645L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No evidence from FoldX, Rosetta, or premPS is available to alter this view. Overall, the majority of computational evidence points to a pathogenic impact for F645L, 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 | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -10.624 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.12 | Ambiguous | 0.99 | Ambiguous | 0.264 | Likely Benign | -4.24 | Deleterious | 0.116 | Benign | 0.008 | Benign | 3.44 | Benign | 0.03 | Affected | 0.2214 | 0.3873 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1935T>A | F645L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F645L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No evidence from FoldX, Rosetta, or premPS is available to alter this view. Overall, the majority of computational evidence points to a pathogenic impact for F645L, 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 | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -10.624 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.12 | Ambiguous | 0.99 | Ambiguous | 0.159 | Likely Benign | -4.24 | Deleterious | 0.116 | Benign | 0.008 | Benign | 3.44 | Benign | 0.03 | Affected | 0.2214 | 0.3873 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1935T>G | F645L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F645L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess sequence conservation and structural impact fall into two groups: benign predictions are made by REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM; pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. No evidence from FoldX‑MD, Rosetta, or premPS is available to alter this conclusion. Overall, the majority of computational evidence points to a pathogenic impact for F645L, and this assessment is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -10.624 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.12 | Ambiguous | 0.99 | Ambiguous | 0.159 | Likely Benign | -4.24 | Deleterious | 0.116 | Benign | 0.008 | Benign | 3.44 | Benign | 0.03 | Affected | 0.2214 | 0.3873 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.2009T>A | L670Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L670Q is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Predictions that are inconclusive (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also as Likely Benign, while Foldetta remains uncertain. Overall, the majority of available evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.161087 | Structured | 0.090855 | Uncertain | 0.812 | 0.385 | 0.000 | -8.217 | Likely Pathogenic | 0.306 | Likely Benign | Likely Benign | 1.02 | Ambiguous | 0.1 | 1.21 | Ambiguous | 1.12 | Ambiguous | 0.96 | Ambiguous | 0.152 | Likely Benign | -1.12 | Neutral | 1.000 | Probably Damaging | 0.988 | Probably Damaging | 3.40 | Benign | 0.36 | Tolerated | 0.1088 | 0.1303 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.639C>G | I213M 2D AIThe SynGAP1 missense variant I213M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are PROVEAN and FATHMM, while a larger group—REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) return uncertain or inconclusive results and are therefore treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -10.777 | Likely Pathogenic | 0.906 | Likely Pathogenic | Ambiguous | 0.66 | Ambiguous | 0.5 | 1.58 | Ambiguous | 1.12 | Ambiguous | 0.85 | Ambiguous | 0.680 | Likely Pathogenic | -2.31 | Neutral | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.85 | Benign | 0.01 | Affected | 0.0611 | 0.2524 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||
| c.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.783C>A | D261E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The high‑accuracy consensus from AlphaMissense‑Optimized and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) both indicate a benign outcome, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is inconclusive. Overall, the majority of evidence points to a benign impact. This assessment is consistent with the absence of ClinVar annotation and does not contradict any existing database status. Based on the predictions, the variant is most likely benign, and this does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.284882 | Structured | 0.422514 | Uncertain | 0.883 | 0.264 | 0.125 | -2.646 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 1.44 | Ambiguous | 0.8 | 0.79 | Ambiguous | 1.12 | Ambiguous | -0.03 | Likely Benign | 0.377 | Likely Benign | 0.20 | Neutral | 0.994 | Probably Damaging | 0.978 | Probably Damaging | 5.88 | Benign | 1.00 | Tolerated | 0.0963 | 0.4359 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.783C>G | D261E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Protein‑stability calculations from FoldX and Rosetta are uncertain. Overall, the majority of evidence points to a benign impact, which is consistent with the absence of a ClinVar claim and gnomAD observation. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.284882 | Structured | 0.422514 | Uncertain | 0.883 | 0.264 | 0.125 | -2.646 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 1.44 | Ambiguous | 0.8 | 0.79 | Ambiguous | 1.12 | Ambiguous | -0.03 | Likely Benign | 0.377 | Likely Benign | 0.20 | Neutral | 0.994 | Probably Damaging | 0.978 | Probably Damaging | 5.88 | Benign | 1.00 | Tolerated | 0.0963 | 0.4359 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.784A>C | N262H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Rosetta, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. FoldX and Foldetta results are uncertain, providing no clear direction. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.284882 | Structured | 0.399879 | Uncertain | 0.912 | 0.240 | 0.000 | -6.932 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 1.82 | Ambiguous | 0.5 | 0.41 | Likely Benign | 1.12 | Ambiguous | 0.33 | Likely Benign | 0.694 | Likely Pathogenic | -3.44 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 5.81 | Benign | 0.41 | Tolerated | 0.1122 | 0.4860 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.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.1975T>C | S659P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are SGM‑Consensus, Rosetta, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results—FoldX, premPS, and Foldetta—are treated as unavailable. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized reports a benign change, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta’s stability assessment is uncertain. Overall, the balance of evidence leans toward a pathogenic effect, but the presence of a strong benign prediction from AlphaMissense‑Optimized and the lack of ClinVar annotation means the variant’s clinical significance remains uncertain and does not contradict existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | -10.461 | Likely Pathogenic | 0.609 | Likely Pathogenic | Likely Benign | -0.73 | Ambiguous | 0.3 | 2.98 | Destabilizing | 1.13 | Ambiguous | 0.73 | Ambiguous | 0.224 | Likely Benign | -3.26 | Deleterious | 0.932 | Possibly Damaging | 0.245 | Benign | 3.39 | Benign | 0.18 | Tolerated | 0.2207 | 0.5553 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.2186A>C | N729T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729T is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID 6‑33441651‑A‑C). Consensus among the majority of in‑silico predictors is benign: REVEL, premPS, 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, PROVEAN) indicates “Likely Benign”; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. Overall, the evidence strongly supports a benign effect, and this conclusion does not contradict ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | 6-33441651-A-C | 1 | 6.20e-7 | -1.952 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.52 | Ambiguous | 0.3 | 1.73 | Ambiguous | 1.13 | Ambiguous | -0.34 | Likely Benign | 0.052 | Likely Benign | -0.52 | Neutral | 0.123 | Benign | 0.042 | Benign | 3.33 | Benign | 1.00 | Tolerated | 3.59 | 7 | 0.1201 | 0.4805 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||
| c.836G>A | R279Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279Q is reported in gnomAD (ID 6‑33437741‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect are SIFT and AlphaMissense‑Optimized; those that agree on a pathogenic effect are SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of reliable predictors (nine pathogenic vs two benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | 6-33437741-G-A | 6 | 3.72e-6 | -8.730 | Likely Pathogenic | 0.761 | Likely Pathogenic | Likely Benign | 1.37 | Ambiguous | 0.1 | 0.88 | Ambiguous | 1.13 | Ambiguous | 1.35 | Destabilizing | 0.554 | Likely Pathogenic | -2.61 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.94 | Pathogenic | 0.06 | Tolerated | 3.39 | 18 | 0.2680 | 0.1792 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||
| c.973C>A | L325M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and premPS. Two tools give uncertain results: Foldetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. No prediction or folding stability result is missing or inconclusive. Overall, the majority of tools (six pathogenic vs five benign) lean toward pathogenicity, but the high‑accuracy methods and several benign predictions introduce uncertainty. Thus, the variant is most likely pathogenic based on the collective evidence, and this assessment is not contradicted by any ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.352862 | Structured | 0.424577 | Uncertain | 0.955 | 0.436 | 0.000 | -6.725 | Likely Benign | 0.445 | Ambiguous | Likely Benign | 0.22 | Likely Benign | 0.0 | 2.04 | Destabilizing | 1.13 | Ambiguous | 1.05 | Destabilizing | 0.306 | Likely Benign | -0.86 | Neutral | 0.997 | Probably Damaging | 0.939 | Probably Damaging | 1.36 | Pathogenic | 0.01 | Affected | 0.0934 | 0.3942 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1209A>C | K403N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K403N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict a pathogenic impact. Predictions from FoldX, Foldetta, and premPS are uncertain or inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -10.913 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.87 | Ambiguous | 0.1 | 0.41 | Likely Benign | 1.14 | Ambiguous | 0.74 | Ambiguous | 0.201 | Likely Benign | -4.51 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.73 | Benign | 0.05 | Affected | 0.3374 | 0.2492 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1209A>T | K403N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K403N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict a pathogenic impact. Predictions from FoldX, Foldetta, and premPS are uncertain or inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -10.913 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.87 | Ambiguous | 0.1 | 0.41 | Likely Benign | 1.14 | Ambiguous | 0.74 | Ambiguous | 0.201 | Likely Benign | -4.51 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.73 | Benign | 0.05 | Affected | 0.3374 | 0.2492 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1463C>T | T488M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T488M is listed in ClinVar with an uncertain significance (ClinVar ID 2824521.0) and is present in gnomAD (ID 6‑33438495‑C‑T). Prediction tools that indicate a benign effect include premPS and FATHMM, whereas the majority of algorithms predict a pathogenic outcome: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as inconclusive. No other tools provide definitive evidence. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | Uncertain | 1 | 6-33438495-C-T | 2 | 1.24e-6 | -12.459 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.66 | Ambiguous | 0.3 | 1.62 | Ambiguous | 1.14 | Ambiguous | 0.46 | Likely Benign | 0.746 | Likely Pathogenic | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 3.37 | 35 | 0.1027 | 0.4857 | -1 | -1 | 2.6 | 30.09 | ||||||||||||||||||||||
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