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.1840T>C | Y614H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y614H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and Rosetta. Tools with uncertain or inconclusive results (FoldX, Foldetta, premPS) are not considered evidence for either side. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.314870 | Structured | 0.182134 | Uncertain | 0.852 | 0.254 | 0.000 | -9.678 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.17 | Ambiguous | 0.5 | 2.38 | Destabilizing | 1.78 | Ambiguous | 0.91 | Ambiguous | 0.397 | Likely Benign | -4.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.58 | Benign | 0.27 | Tolerated | 0.1948 | 0.0373 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.2089T>G | W697G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 W697G missense change 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. In contrast, a majority of tools predict a pathogenic outcome: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar). AlphaMissense‑Default and ESM1b are uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it receives one benign, one pathogenic, and two uncertain calls. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus remains unavailable. Overall, the preponderance of evidence from multiple independent pathogenicity predictors and the protein‑stability assessment by Foldetta indicates that W697G is most likely pathogenic. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.400169 | Uncertain | 0.945 | 0.297 | 0.000 | -7.429 | In-Between | 0.480 | Ambiguous | Likely Benign | 2.57 | Destabilizing | 0.1 | 2.38 | Destabilizing | 2.48 | Destabilizing | 1.21 | Destabilizing | 0.485 | Likely Benign | -8.93 | Deleterious | 1.000 | Probably Damaging | 0.987 | Probably Damaging | 3.44 | Benign | 0.06 | Tolerated | 0.3965 | 0.1482 | -7 | -2 | 0.5 | -129.16 | ||||||||||||||||||||||||||||||
| c.845G>T | C282F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282F is not listed in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are provided by REVEL and premPS, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic outcome. Taken together, the overwhelming majority of evidence points to a pathogenic impact for C282F. This conclusion is consistent with the absence of a ClinVar entry, which does not contradict the prediction. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | -13.288 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 6.22 | Destabilizing | 1.4 | 2.38 | Destabilizing | 4.30 | Destabilizing | 0.42 | Likely Benign | 0.430 | Likely Benign | -10.11 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.65 | Pathogenic | 0.00 | Affected | 0.1267 | 0.3607 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.1241T>A | M414K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414K 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, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. FoldX and Foldetta provide uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta is unavailable. Based on the overwhelming agreement among the majority of prediction tools and the high‑accuracy methods, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -13.537 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.18 | Ambiguous | 0.1 | 2.39 | Destabilizing | 1.79 | Ambiguous | 1.50 | Destabilizing | 0.503 | Likely Pathogenic | -5.03 | Deleterious | 0.942 | Possibly Damaging | 0.860 | Possibly Damaging | 3.40 | Benign | 0.04 | Affected | 0.1299 | 0.0888 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.601G>T | D201Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D201Y missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, and FATHMM. Those that predict a pathogenic effect comprise SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and Rosetta. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; SGM Consensus predicts likely pathogenic; Foldetta is uncertain. Because the majority of consensus and individual predictors (seven pathogenic vs four benign) lean toward a damaging outcome, the variant is most likely pathogenic. This assessment is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -10.916 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.28 | Likely Benign | 0.2 | 2.39 | Destabilizing | 1.34 | Ambiguous | 0.31 | Likely Benign | 0.334 | Likely Benign | -4.93 | Deleterious | 1.000 | Probably Damaging | 0.960 | Probably Damaging | 4.02 | Benign | 0.02 | Affected | 0.0431 | 0.5371 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.930G>C | E310D 2D  3DClick to see structure in 3D Viewer AISynGAP1 E310D is reported in ClinVar (ID 975473.0) as Pathogenic and is not found in gnomAD. Prediction tools that assess the variant’s effect all converge on a deleterious outcome: REVEL, FoldX (uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, leaving no tool in the benign category. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also reports Pathogenic. The single uncertain result from FoldX is treated as unavailable. Overall, the variant is most likely pathogenic, and this assessment is consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | Likely Pathogenic | 1 | -11.218 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.87 | Ambiguous | 0.5 | 2.39 | Destabilizing | 2.13 | Destabilizing | 1.04 | Destabilizing | 0.666 | Likely Pathogenic | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.19 | Pathogenic | 0.02 | Affected | 3.38 | 19 | 0.1981 | 0.5222 | 3 | 2 | 0.0 | -14.03 | 232.6 | 27.2 | 0.1 | 0.0 | 0.1 | 0.1 | X | Potentially Benign | The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand. Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 potentially plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the carboxylate group of Asp310 can form the same interactions as glutamate; however, due to its one hydrocarbon shorter length, the connections are less stable or less optimal. | ||||||||||||||||
| c.930G>T | E310D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity uniformly favor a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL (Pathogenic), Rosetta (Pathogenic), Foldetta (Pathogenic), premPS (Pathogenic), PROVEAN (Pathogenic), polyPhen‑2 HumDiv (Pathogenic), polyPhen‑2 HumVar (Pathogenic), SIFT (Pathogenic), ESM1b (Pathogenic), FATHMM (Pathogenic), AlphaMissense‑Default (Pathogenic), and AlphaMissense‑Optimized (Pathogenic). No tool predicts a benign outcome; the only inconclusive result is FoldX (Uncertain). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for E310D. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | -11.218 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.87 | Ambiguous | 0.5 | 2.39 | Destabilizing | 2.13 | Destabilizing | 1.04 | Destabilizing | 0.666 | Likely Pathogenic | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.19 | Pathogenic | 0.02 | Affected | 3.38 | 19 | 0.1981 | 0.5222 | 3 | 2 | 0.0 | -14.03 | 232.6 | 27.2 | 0.1 | 0.0 | 0.1 | 0.1 | X | Potentially Benign | The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand. Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 potentially plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the carboxylate group of Asp310 can form the same interactions as glutamate; however, due to its one hydrocarbon shorter length, the connections are less stable or less optimal. | ||||||||||||||||||
| c.932A>C | H311P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign outcome; the remaining predictions are uncertain (FoldX, Foldetta, premPS, AlphaMissense‑Optimized). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the majority of evidence points to a deleterious impact on protein function. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for H311P. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -10.454 | Likely Pathogenic | 0.869 | Likely Pathogenic | Ambiguous | 1.57 | Ambiguous | 0.6 | 2.39 | Destabilizing | 1.98 | Ambiguous | 0.74 | Ambiguous | 0.724 | Likely Pathogenic | -7.76 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.87 | Pathogenic | 0.01 | Affected | 0.2173 | 0.4172 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.1087T>C | Y363H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y363H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, while the majority of other in silico predictors (Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, Foldetta) indicate a pathogenic impact; FoldX and ESM1b are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for Y363H, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.435392 | Uncertain | 0.954 | 0.586 | 0.125 | -7.003 | In-Between | 0.747 | Likely Pathogenic | Likely Benign | 1.75 | Ambiguous | 0.1 | 2.40 | Destabilizing | 2.08 | Destabilizing | 1.04 | Destabilizing | 0.419 | Likely Benign | -4.38 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.56 | Pathogenic | 0.01 | Affected | 0.3267 | 0.2021 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.1315C>G | L439V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L439V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar; premPS is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions (8 benign vs. 5 pathogenic) favor a benign classification, and this consensus does not contradict the absence of ClinVar evidence. Thus, based on current computational predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | -6.340 | Likely Benign | 0.279 | Likely Benign | Likely Benign | 2.34 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.37 | Destabilizing | 0.91 | Ambiguous | 0.121 | Likely Benign | -1.13 | Neutral | 0.976 | Probably Damaging | 0.941 | Probably Damaging | 3.36 | Benign | 0.12 | Tolerated | 0.1272 | 0.2628 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1342G>A | A448T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 A448T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the overwhelming majority of evidence indicates that A448T is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.192 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 3.06 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.73 | Destabilizing | 0.63 | Ambiguous | 0.558 | Likely Pathogenic | -3.95 | Deleterious | 0.996 | Probably Damaging | 0.973 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 0.1187 | 0.5050 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1489T>C | Y497H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497H is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -10.970 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 2.46 | Destabilizing | 0.1 | 2.40 | Destabilizing | 2.43 | Destabilizing | 1.29 | Destabilizing | 0.819 | Likely Pathogenic | -4.94 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.65 | Pathogenic | 0.02 | Affected | 0.1983 | 0.0612 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.1502T>G | I501S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized; all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized indicates a benign change, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. Overall, the preponderance of evidence points to a pathogenic effect for I501S. This conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -9.914 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 3.23 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.82 | Destabilizing | 1.79 | Destabilizing | 0.511 | Likely Pathogenic | -5.14 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.04 | Affected | 0.2370 | 0.0858 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1541T>A | I514N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the overwhelming consensus of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -13.869 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.41 | Destabilizing | 0.3 | 2.41 | Destabilizing | 2.91 | Destabilizing | 2.61 | Destabilizing | 0.582 | Likely Pathogenic | -6.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.82 | Benign | 0.00 | Affected | 0.0770 | 0.0142 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1780T>C | F594L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F594L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX (uncertain), Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only FoldX and Foldetta are inconclusive. In the high‑accuracy subset, AlphaMissense‑Optimized remains pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta is uncertain. No tools predict a benign outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this change. 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 | -11.270 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.50 | Ambiguous | 0.1 | 2.41 | Destabilizing | 1.96 | Ambiguous | 1.56 | Destabilizing | 0.940 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.98 | Pathogenic | 0.03 | Affected | 0.1790 | 0.2439 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1782C>A | F594L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F594L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX (uncertain), Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only FoldX and Foldetta are inconclusive. In the high‑accuracy subset, AlphaMissense‑Optimized remains pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta is uncertain. No tools predict a benign outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this change. 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 | -11.270 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.50 | Ambiguous | 0.1 | 2.41 | Destabilizing | 1.96 | Ambiguous | 1.56 | Destabilizing | 0.893 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.98 | Pathogenic | 0.03 | Affected | 0.1790 | 0.2439 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1782C>G | F594L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F594L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity; SGM‑Consensus also indicates a likely pathogenic outcome. No tool in the dataset predicts a benign effect. Stability‑focused methods give mixed results: FoldX is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain, so these do not provide decisive evidence. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, while Foldetta remains uncertain. Overall, the consensus of available predictions strongly suggests that F594L 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 | 0.009187 | Structured | 0.120166 | Uncertain | 0.946 | 0.147 | 0.000 | -11.270 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.50 | Ambiguous | 0.1 | 2.41 | Destabilizing | 1.96 | Ambiguous | 1.56 | Destabilizing | 0.893 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.98 | Pathogenic | 0.03 | Affected | 0.1790 | 0.2439 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.791T>A | L264Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264Q is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.323473 | Uncertain | 0.939 | 0.264 | 0.000 | Uncertain | 1 | -15.729 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.43 | Destabilizing | 0.1 | 2.41 | Destabilizing | 2.92 | Destabilizing | 2.48 | Destabilizing | 0.678 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.49 | Pathogenic | 0.00 | Affected | 3.38 | 18 | 0.0942 | 0.0558 | -2 | -2 | -7.3 | 14.97 | 254.7 | -7.6 | 0.0 | 0.0 | 0.0 | 0.3 | X | X | X | Potentially Pathogenic | The iso-butyl branched hydrocarbon side chain of Leu264, located at the end of an anti-parallel β sheet strand (res. Arg259-Arg272), packs against multiple hydrophobic residues such as Leu266, Phe314, Leu317, and Leu323 in the WT simulations. In the variant simulations, the hydrophilic carboxamide group of the Gln264 side chain is not suitable for the hydrophobic niche, causing the hydrophobic residues to make room for the swapped residue. Additionally, the carboxamide group of Gln264 forms hydrogen bonds with the backbone amide groups of Arg405 and Lys256 in the β sheet and the carbonyl group of Val350 in an α helical section of a nearby loop (res. Pro359-Phe358). The residue swap disrupts the packing of the C2 domain, which could adversely affect the C2 domain structure during folding. This disruption could potentially weaken the stability of the SynGAP-membrane association. | ||||||||||||||
| c.1813C>G | P605A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic, while premPS remains uncertain. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. No tool predicts a benign outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | -10.085 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 2.58 | Destabilizing | 0.3 | 2.42 | Destabilizing | 2.50 | Destabilizing | 0.91 | Ambiguous | 0.744 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.75 | Pathogenic | 0.00 | Affected | 0.3432 | 0.4607 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.938A>G | E313G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313G is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—all of which classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. Taken together, the overwhelming consensus from both general and high‑accuracy predictors indicates that E313G is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | -14.615 | Likely Pathogenic | 0.912 | Likely Pathogenic | Ambiguous | 2.00 | Destabilizing | 0.5 | 2.42 | Destabilizing | 2.21 | Destabilizing | 0.79 | Ambiguous | 0.750 | Likely Pathogenic | -5.50 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.83 | Pathogenic | 0.01 | Affected | 0.2638 | 0.6680 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.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.1636T>G | C546G 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant C546G is not reported in ClinVar and is present in gnomAD (ID 6‑33438879‑T‑G). Prediction tools that indicate a benign effect include only SIFT, whereas the remaining tools—REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta is inconclusive and therefore not considered evidence. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | 6-33438879-T-G | 1 | 6.20e-7 | -14.026 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 1.55 | Ambiguous | 0.0 | 2.43 | Destabilizing | 1.99 | Ambiguous | 1.53 | Destabilizing | 0.877 | Likely Pathogenic | -9.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.26 | Pathogenic | 0.06 | Tolerated | 3.37 | 35 | 0.3135 | 0.2513 | -3 | -3 | -2.9 | -46.09 | ||||||||||||||||||||||||
| c.1759A>G | R587G 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R587G is not reported in ClinVar and is present in gnomAD (ID 6‑33440811‑A‑G). Prediction tools that agree on a benign effect include SIFT and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) classify the change as pathogenic. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized predicts benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—returns pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence from multiple independent predictors indicates that R587G 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 | 0.054297 | Structured | 0.077330 | Uncertain | 0.862 | 0.216 | 0.000 | 6-33440811-A-G | 2 | 1.24e-6 | -13.780 | Likely Pathogenic | 0.780 | Likely Pathogenic | Likely Benign | 1.55 | Ambiguous | 0.2 | 2.43 | Destabilizing | 1.99 | Ambiguous | 1.55 | Destabilizing | 0.578 | Likely Pathogenic | -6.07 | Deleterious | 1.000 | Probably Damaging | 0.972 | Probably Damaging | -1.28 | Pathogenic | 0.07 | Tolerated | 3.37 | 35 | 0.3183 | 0.3401 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||
| c.889A>G | K297E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome; the only inconclusive result is FoldX, which is listed as “Uncertain” and is treated as unavailable. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective predictions, K297E is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -10.143 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.99 | Ambiguous | 0.4 | 2.43 | Destabilizing | 2.21 | Destabilizing | 1.16 | Destabilizing | 0.507 | Likely Pathogenic | -3.54 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.61 | Pathogenic | 0.02 | Affected | 0.4073 | 0.1547 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.982T>C | Y328H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.411940 | Structured | 0.392519 | Uncertain | 0.916 | 0.497 | 0.000 | -10.885 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 2.08 | Destabilizing | 0.0 | 2.43 | Destabilizing | 2.26 | Destabilizing | 1.35 | Destabilizing | 0.516 | Likely Pathogenic | -4.53 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.54 | Pathogenic | 0.02 | Affected | 0.2572 | 0.0703 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.1267T>C | Y423H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 Y423H 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 REVEL, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and AlphaMissense‑Default. AlphaMissense‑Optimized is reported as uncertain. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and therefore inconclusive, while Foldetta predicts a pathogenic impact. Overall, the majority of evaluated tools (10 pathogenic vs. 4 benign) support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -6.638 | Likely Benign | 0.873 | Likely Pathogenic | Ambiguous | 3.09 | Destabilizing | 0.1 | 2.44 | Destabilizing | 2.77 | Destabilizing | 1.66 | Destabilizing | 0.257 | Likely Benign | -3.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.39 | Benign | 0.61 | Tolerated | 0.1603 | 0.0352 | 0 | 2 | -1.9 | -26.03 | ||||||||||||||||||||||||||||||
| c.1934T>G | F645C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F645C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas the majority of tools predict a pathogenic outcome: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is inconclusive. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, 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 | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -9.182 | Likely Pathogenic | 0.828 | Likely Pathogenic | Ambiguous | 2.25 | Destabilizing | 0.1 | 2.44 | Destabilizing | 2.35 | Destabilizing | 1.38 | Destabilizing | 0.286 | Likely Benign | -5.41 | Deleterious | 0.967 | Probably Damaging | 0.389 | Benign | 3.35 | Benign | 0.01 | Affected | 0.2421 | 0.1372 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.2000T>C | I667T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I667T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.083597 | Uncertain | 0.927 | 0.379 | 0.000 | -11.917 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 3.29 | Destabilizing | 0.1 | 2.44 | Destabilizing | 2.87 | Destabilizing | 2.23 | Destabilizing | 0.676 | Likely Pathogenic | -4.81 | Deleterious | 1.000 | Probably Damaging | 0.985 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | 0.0967 | 0.0608 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.716G>C | R239T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R239T is recorded in gnomAD (ID 6‑33435567‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions arise from REVEL, Rosetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX reports an uncertain effect and is therefore not considered. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Consequently, the variant is most likely pathogenic according to the available computational evidence, and this assessment does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | 6-33435567-G-C | 1 | 6.19e-7 | -14.792 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.96 | Ambiguous | 0.3 | 2.44 | Destabilizing | 2.20 | Destabilizing | 1.21 | Destabilizing | 0.869 | Likely Pathogenic | -5.35 | Deleterious | 0.259 | Benign | 0.064 | Benign | 5.66 | Benign | 0.01 | Affected | 3.40 | 14 | 0.1805 | 0.4414 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||
| c.1343C>G | A448G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448G resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas those that predict pathogenicity are Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; FoldX is inconclusive. High‑accuracy assessments further clarify the impact: AlphaMissense‑Optimized reports a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a pathogenic effect. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.984 | Likely Pathogenic | 0.640 | Likely Pathogenic | Likely Benign | 1.76 | Ambiguous | 0.0 | 2.45 | Destabilizing | 2.11 | Destabilizing | 1.00 | Destabilizing | 0.378 | Likely Benign | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.980 | Probably Damaging | 3.15 | Benign | 0.06 | Tolerated | 0.2135 | 0.2936 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1553A>C | Y518S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y518S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SIFT and FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic”; AlphaMissense‑Optimized is uncertain; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic effect. Taken together, the preponderance of evidence points to a pathogenic effect for Y518S, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | -12.453 | Likely Pathogenic | 0.912 | Likely Pathogenic | Ambiguous | 2.76 | Destabilizing | 0.8 | 2.45 | Destabilizing | 2.61 | Destabilizing | 1.61 | Destabilizing | 0.551 | Likely Pathogenic | -8.38 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.06 | Tolerated | 0.3948 | 0.1059 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.656G>T | C219F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219F is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are premPS and FATHMM, while the remaining 13 tools—including SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized reports pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -14.322 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 7.31 | Destabilizing | 1.9 | 2.45 | Destabilizing | 4.88 | Destabilizing | 0.47 | Likely Benign | 0.814 | Likely Pathogenic | -9.18 | Deleterious | 0.940 | Possibly Damaging | 0.505 | Possibly Damaging | 5.82 | Benign | 0.00 | Affected | 0.0959 | 0.3804 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.1181A>C | K394T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K394T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, Foldetta, and premPS. 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 is also inconclusive. Overall, the balance of evidence (five benign versus three pathogenic predictions) 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 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | -6.487 | Likely Benign | 0.599 | Likely Pathogenic | Likely Benign | 0.50 | Ambiguous | 0.1 | 2.46 | Destabilizing | 1.48 | Ambiguous | 0.57 | Ambiguous | 0.482 | Likely Benign | -3.35 | Deleterious | 0.247 | Benign | 0.166 | Benign | 4.61 | Benign | 0.01 | Affected | 0.2727 | 0.4453 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||
| c.1199T>A | V400E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400E is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | Uncertain | 1 | -13.686 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.70 | Destabilizing | 0.2 | 2.46 | Destabilizing | 3.08 | Destabilizing | 2.29 | Destabilizing | 0.810 | Likely Pathogenic | -4.88 | Deleterious | 0.920 | Possibly Damaging | 0.335 | Benign | 5.31 | Benign | 0.00 | Affected | 3.38 | 27 | 0.1044 | 0.1922 | -2 | -2 | -7.7 | 29.98 | 249.1 | -38.8 | -0.1 | 0.1 | 1.0 | 0.0 | X | X | X | Potentially Pathogenic | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). In the variant simulations, the negatively charged carboxylate group of the Glu400 side chain is not suitable for occupying the hydrophobic niche. Consequently, the side chain escapes the center of the C2 domain and interacts with the backbone amide groups of Leu402 in the same β strand and/or Ile269 and Glu270 in a neighboring β strand (res. Arg259-Arg272). This residue swap disrupts the hydrophobic packing and generally has extensive negative effects on the C2 domain structure. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | ||||||||||||||
| c.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.799T>A | W267R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267R has no ClinVar entry and is not reported in gnomAD. Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic or likely pathogenic scores. Tools that are inconclusive (FoldX and premPS) are noted as uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No benign predictions are present. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -13.868 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.94 | Ambiguous | 0.1 | 2.47 | Destabilizing | 2.21 | Destabilizing | 0.51 | Ambiguous | 0.672 | Likely Pathogenic | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.00 | Pathogenic | 0.01 | Affected | 0.3763 | 0.0571 | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||||||
| c.799T>C | W267R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267R is not reported in ClinVar (ClinVar status: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tools predict a benign outcome. Uncertain predictions are provided by FoldX and premPS. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts Likely Pathogenic; and Foldetta predicts Pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -13.868 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.94 | Ambiguous | 0.1 | 2.47 | Destabilizing | 2.21 | Destabilizing | 0.51 | Ambiguous | 0.672 | Likely Pathogenic | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.00 | Pathogenic | 0.01 | Affected | 0.3763 | 0.0571 | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||||||
| c.950T>A | L317Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L317Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on these predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.106997 | Structured | 0.394031 | Uncertain | 0.874 | 0.240 | 0.125 | -13.424 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.87 | Destabilizing | 0.2 | 2.47 | Destabilizing | 2.67 | Destabilizing | 1.61 | Destabilizing | 0.607 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.75 | Pathogenic | 0.00 | Affected | 0.1252 | 0.1251 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1058T>G | L353R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L353R is not reported in ClinVar and is absent from gnomAD. In silico predictors largely agree on a deleterious effect: benign predictions are limited to REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all classify the variant as pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is uncertain, SGM‑Consensus predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction contradicts the ClinVar status, which is currently unreported. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.137348 | Structured | 0.373584 | Uncertain | 0.926 | 0.315 | 0.000 | -11.213 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 3.60 | Destabilizing | 0.5 | 2.48 | Destabilizing | 3.04 | Destabilizing | 1.91 | Destabilizing | 0.444 | Likely Benign | -4.15 | Deleterious | 0.947 | Possibly Damaging | 0.454 | Possibly Damaging | 1.33 | Pathogenic | 0.01 | Affected | 0.1304 | 0.1145 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1352T>A | L451Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451Q is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: pathogenic predictions are returned by REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -15.426 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.91 | Destabilizing | 0.0 | 2.48 | Destabilizing | 2.70 | Destabilizing | 2.30 | Destabilizing | 0.708 | Likely Pathogenic | -5.79 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.0869 | 0.0558 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.724T>G | W242G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD, so no population frequency data are available. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the single uncertain call from premPS is treated as unavailable. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | -14.319 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.70 | Destabilizing | 0.3 | 2.48 | Destabilizing | 2.59 | Destabilizing | 0.83 | Ambiguous | 0.883 | Likely Pathogenic | -11.80 | Deleterious | 0.900 | Possibly Damaging | 0.452 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | 0.4378 | 0.1851 | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||||||
| c.1577T>C | V526A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V526A is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all agree that the variant is deleterious: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify it as pathogenic or likely pathogenic. No tool predicts a benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized is uncertain, SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Based on the overwhelming consensus of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.023118 | Uncertain | 0.943 | 0.403 | 0.000 | -12.055 | Likely Pathogenic | 0.852 | Likely Pathogenic | Ambiguous | 2.30 | Destabilizing | 0.1 | 2.49 | Destabilizing | 2.40 | Destabilizing | 2.05 | Destabilizing | 0.908 | Likely Pathogenic | -3.93 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.44 | Pathogenic | 0.00 | Affected | 0.2224 | 0.1922 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1757A>G | D586G 2D  3DClick to see structure in 3D Viewer AISynGAP1 D586G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and SIFT, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a unanimous 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 indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -8.497 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | 1.37 | Ambiguous | 0.3 | 2.49 | Destabilizing | 1.93 | Ambiguous | 0.34 | Likely Benign | 0.833 | Likely Pathogenic | -4.67 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.26 | Pathogenic | 0.17 | Tolerated | 0.3334 | 0.5052 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1942T>A | F648I 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant F648I resides in the GAP domain. ClinVar contains no entry for this change, and it is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—report a pathogenic or likely pathogenic outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) also yields a pathogenic prediction. Taken together, the evidence overwhelmingly supports a pathogenic classification for F648I, and this conclusion does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.346782 | Uncertain | 0.943 | 0.339 | 0.000 | -11.912 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.49 | Destabilizing | 0.1 | 2.49 | Destabilizing | 2.49 | Destabilizing | 1.05 | Destabilizing | 0.472 | Likely Benign | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.41 | Benign | 0.04 | Affected | 0.1673 | 0.1955 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.841T>A | Y281N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281N is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions are provided only by SIFT, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized remains inconclusive, SGM‑Consensus is labeled Likely Pathogenic, and Foldetta predicts a destabilizing, pathogenic outcome. Overall, the collective evidence indicates that Y281N is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.337647 | Uncertain | 0.927 | 0.254 | 0.000 | -11.620 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 3.29 | Destabilizing | 0.2 | 2.49 | Destabilizing | 2.89 | Destabilizing | 1.71 | Destabilizing | 0.713 | Likely Pathogenic | -6.20 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.99 | Pathogenic | 0.09 | Tolerated | 0.2494 | 0.1503 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.2066T>A | L689H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -14.659 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.40 | Destabilizing | 0.1 | 2.50 | Destabilizing | 2.95 | Destabilizing | 2.21 | Destabilizing | 0.532 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | 0.1013 | 0.0456 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.1301T>C | V434A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V434A 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 comprise Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b; FoldX and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. Overall, the majority of 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. | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -8.531 | Likely Pathogenic | 0.441 | Ambiguous | Likely Benign | 1.72 | Ambiguous | 0.0 | 2.51 | Destabilizing | 2.12 | Destabilizing | 1.00 | Destabilizing | 0.238 | Likely Benign | -2.51 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.58 | Benign | 0.75 | Tolerated | 0.2338 | 0.2292 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||
| c.1435C>G | R479G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R479G is reported in gnomAD (ID 6-33438467-C-G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise AlphaMissense‑Default, ESM1b, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, Rosetta, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX and Foldetta, which assess protein‑folding stability, returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta as inconclusive. Overall, the majority of computational evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Therefore, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | 6-33438467-C-G | 1 | 6.20e-7 | -8.600 | Likely Pathogenic | 0.624 | Likely Pathogenic | Likely Benign | 0.97 | Ambiguous | 0.0 | 2.51 | Destabilizing | 1.74 | Ambiguous | 0.71 | Ambiguous | 0.228 | Likely Benign | -2.82 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.42 | Tolerated | 3.39 | 32 | 0.2911 | 0.2707 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||
| c.1036G>A | V346M 2D  3DClick to see structure in 3D Viewer AISynGAP1 variant V346M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL and FoldX, whereas the majority of other in silico methods (PolyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, PROVEAN, AlphaMissense‑Optimized, and the SGM‑Consensus score) indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, remains uncertain. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | -10.218 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.29 | Likely Benign | 0.1 | 2.52 | Destabilizing | 1.41 | Ambiguous | 0.67 | Ambiguous | 0.367 | Likely Benign | -2.72 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.48 | Pathogenic | 0.05 | Affected | 0.1050 | 0.4749 | 2 | 1 | -2.3 | 32.06 | |||||||||||||||||||||||||||||
| c.1186G>T | G396C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G396C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar; premPS is uncertain. The high‑accuracy consensus methods give a mixed signal: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the majority of individual predictors and the SGM‑Consensus lean toward a benign interpretation, and the two high‑accuracy tools that are available also favor benign over pathogenic. Therefore, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -5.459 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 2.15 | Destabilizing | 0.7 | 2.52 | Destabilizing | 2.34 | Destabilizing | 0.59 | Ambiguous | 0.411 | Likely Benign | -3.00 | Deleterious | 0.983 | Probably Damaging | 0.533 | Possibly Damaging | 3.89 | Benign | 0.08 | Tolerated | 0.1181 | 0.4541 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.1681T>C | F561L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F561L is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only SIFT, whereas the remaining evaluated algorithms (REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic or likely pathogenic outcome; FoldX is listed as uncertain and is therefore not considered evidence for either side. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists for F561L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024826 | Structured | 0.018013 | Uncertain | 0.903 | 0.196 | 0.000 | -8.947 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.72 | Ambiguous | 0.2 | 2.52 | Destabilizing | 2.12 | Destabilizing | 1.39 | Destabilizing | 0.656 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -0.81 | Pathogenic | 0.32 | Tolerated | 0.1911 | 0.2629 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1683C>A | F561L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F561L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and SIFT, whereas the remaining tools (SGM‑Consensus, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic outcome; FoldX is uncertain and therefore not counted as evidence. 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 also predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024826 | Structured | 0.018013 | Uncertain | 0.903 | 0.196 | 0.000 | -8.947 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.72 | Ambiguous | 0.2 | 2.52 | Destabilizing | 2.12 | Destabilizing | 1.39 | Destabilizing | 0.492 | Likely Benign | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -0.81 | Pathogenic | 0.32 | Tolerated | 0.1911 | 0.2629 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1683C>G | F561L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F561L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and SIFT, whereas the remaining tools (SGM‑Consensus, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic outcome; FoldX is uncertain and therefore not counted as evidence. 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 also predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024826 | Structured | 0.018013 | Uncertain | 0.903 | 0.196 | 0.000 | -8.947 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.72 | Ambiguous | 0.2 | 2.52 | Destabilizing | 2.12 | Destabilizing | 1.39 | Destabilizing | 0.493 | Likely Benign | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -0.81 | Pathogenic | 0.32 | Tolerated | 0.1911 | 0.2629 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1627C>A | L543M 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant L543M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and PROVEAN, whereas pathogenic calls are made by polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Rosetta. Predictions that are uncertain (FoldX, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments give AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of available tools predict a deleterious effect, indicating that the variant is most likely pathogenic. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.020918 | Uncertain | 0.963 | 0.314 | 0.000 | -11.452 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.68 | Ambiguous | 0.2 | 2.53 | Destabilizing | 1.61 | Ambiguous | 0.99 | Ambiguous | 0.382 | Likely Benign | -1.99 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.93 | Pathogenic | 0.01 | Affected | 0.0788 | 0.2172 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1726T>G | C576G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C576G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, FoldX (uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a benign outcome. When high‑accuracy methods are considered, AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) also predicts pathogenicity. No prediction is inconclusive or missing. Consequently, the variant is most likely pathogenic based on the consensus of available computational evidence, and this assessment does not contradict any ClinVar annotation (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.017684 | Uncertain | 0.913 | 0.245 | 0.000 | -14.809 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 1.66 | Ambiguous | 0.0 | 2.53 | Destabilizing | 2.10 | Destabilizing | 1.67 | Destabilizing | 0.586 | Likely Pathogenic | -10.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.38 | Benign | 0.00 | Affected | 0.3269 | 0.2574 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.1751T>G | I584S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I584S missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on pathogenicity include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as pathogenic. No contradictory evidence is present. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not conflict with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.059222 | Structured | 0.046673 | Uncertain | 0.846 | 0.244 | 0.000 | -13.379 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 3.15 | Destabilizing | 0.1 | 2.53 | Destabilizing | 2.84 | Destabilizing | 1.70 | Destabilizing | 0.710 | Likely Pathogenic | -5.54 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.18 | Pathogenic | 0.03 | Affected | 0.2391 | 0.0858 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.2059C>G | R687G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R687G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta indicates a destabilizing, pathogenic effect. AlphaMissense‑Optimized is uncertain and therefore treated as unavailable. Overall, the variant is most likely pathogenic based on the consensus of predictive tools, 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 | 0.054297 | Structured | 0.191060 | Uncertain | 0.914 | 0.259 | 0.000 | -12.900 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 2.94 | Destabilizing | 0.3 | 2.53 | Destabilizing | 2.74 | Destabilizing | 1.27 | Destabilizing | 0.360 | Likely Benign | -6.26 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 3.88 | Benign | 0.01 | Affected | 0.2508 | 0.2119 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.716G>T | R239I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R239I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -19.414 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.32 | Destabilizing | 0.5 | 2.53 | Destabilizing | 3.43 | Destabilizing | 0.83 | Ambiguous | 0.890 | Likely Pathogenic | -7.16 | Deleterious | 0.985 | Probably Damaging | 0.724 | Possibly Damaging | 5.69 | Benign | 0.00 | Affected | 0.1480 | 0.3985 | -2 | -3 | 9.0 | -43.03 | |||||||||||||||||||||||||||||
| c.1271T>C | V424A 2D 3DClick to see structure in 3D Viewer AISynGAP1 V424A is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on benign impact are REVEL and FATHMM, whereas the remaining tools—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as unavailable, SGM‑Consensus as likely pathogenic, and Foldetta as pathogenic. Based on the collective evidence, the variant is most likely pathogenic; this conclusion is not contradicted by the ClinVar status. 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 | -9.665 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 2.31 | Destabilizing | 0.1 | 2.54 | Destabilizing | 2.43 | Destabilizing | 2.10 | Destabilizing | 0.245 | Likely Benign | -3.45 | Deleterious | 0.997 | Probably Damaging | 0.961 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.2105 | 0.1355 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1766T>C | I589T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I589T is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. All available predictions are consistent and conclusive. Based on the unanimous computational evidence, 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 | GAP | 0.018415 | Structured | 0.084536 | Uncertain | 0.927 | 0.214 | 0.000 | -12.128 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.60 | Destabilizing | 0.0 | 2.54 | Destabilizing | 2.57 | Destabilizing | 2.07 | Destabilizing | 0.935 | Likely Pathogenic | -4.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.97 | Pathogenic | 0.02 | Affected | 0.1153 | 0.1231 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.940T>G | F314V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). All available in silico predictors classify the variant as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect, so the benign group is empty. High‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta—each return a pathogenic prediction. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -8.907 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 3.31 | Destabilizing | 0.4 | 2.54 | Destabilizing | 2.93 | Destabilizing | 1.44 | Destabilizing | 0.594 | Likely Pathogenic | -5.90 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.26 | Pathogenic | 0.00 | Affected | 0.2054 | 0.2075 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1205T>A | L402Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.243554 | Structured | 0.431978 | Uncertain | 0.961 | 0.383 | 0.000 | -13.403 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.93 | Destabilizing | 0.0 | 2.55 | Destabilizing | 2.74 | Destabilizing | 2.09 | Destabilizing | 0.523 | Likely Pathogenic | -4.52 | Deleterious | 0.999 | Probably Damaging | 0.957 | Probably Damaging | 3.69 | Benign | 0.00 | Affected | 0.1384 | 0.1173 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1400A>G | D467G 2D AISynGAP1 missense variant D467G is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from premPS, while all other evaluated algorithms—including SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. No prediction is inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -12.973 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.87 | Ambiguous | 0.8 | 2.55 | Destabilizing | 2.21 | Destabilizing | 0.23 | Likely Benign | 0.910 | Likely Pathogenic | -6.81 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | -1.32 | Pathogenic | 0.03 | Affected | 0.3455 | 0.4908 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1691A>G | E564G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E564G is listed in gnomAD (ID 6‑33440743‑A‑G) but has no ClinVar entry. Prediction tools that assess pathogenicity are unanimous: REVEL, FoldX (uncertain), Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic effect, while no tool predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment is not contradicted by ClinVar status, which currently contains no entry for E564G. 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 | 6-33440743-A-G | -15.053 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 1.69 | Ambiguous | 0.1 | 2.55 | Destabilizing | 2.12 | Destabilizing | 0.80 | Ambiguous | 0.735 | Likely Pathogenic | -6.83 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.23 | Pathogenic | 0.04 | Affected | 3.37 | 35 | 0.2749 | 0.4443 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||||||||||
| c.1762C>T | L588F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L588F is reported in gnomAD (variant ID 6‑33440814‑C‑T) but has no ClinVar entry. Across the available in‑silico predictors, every tool examined classifies the substitution as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic or likely pathogenic scores. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Because every available prediction converges on a deleterious effect and there is no ClinVar annotation to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.082229 | Uncertain | 0.887 | 0.214 | 0.000 | 6-33440814-C-T | -14.050 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 2.90 | Destabilizing | 0.2 | 2.55 | Destabilizing | 2.73 | Destabilizing | 1.12 | Destabilizing | 0.736 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.38 | Pathogenic | 0.04 | Affected | 3.38 | 34 | 0.0816 | 0.2007 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||||
| c.1889T>A | I630N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I630N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.036106 | Uncertain | 0.966 | 0.236 | 0.000 | -14.259 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 2.96 | Destabilizing | 0.0 | 2.55 | Destabilizing | 2.76 | Destabilizing | 2.39 | Destabilizing | 0.825 | Likely Pathogenic | -4.86 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | -1.49 | Pathogenic | 0.00 | Affected | 0.0853 | 0.0270 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1945A>G | M649V 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant M649V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. With 8 pathogenic versus 3 benign predictions, the overall evidence favors a deleterious effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.360413 | Uncertain | 0.962 | 0.345 | 0.000 | -9.907 | Likely Pathogenic | 0.887 | Likely Pathogenic | Ambiguous | 2.84 | Destabilizing | 0.3 | 2.55 | Destabilizing | 2.70 | Destabilizing | 1.05 | Destabilizing | 0.370 | Likely Benign | -3.99 | Deleterious | 0.997 | Probably Damaging | 0.735 | Possibly Damaging | 3.40 | Benign | 0.06 | Tolerated | 0.2389 | 0.3121 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||
| c.2087T>A | L696H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L696H is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: all available predictors except FATHMM classify the variant as pathogenic (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized). Only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Taken together, the overwhelming majority of computational evidence supports a pathogenic classification, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | -17.042 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.56 | Destabilizing | 0.0 | 2.55 | Destabilizing | 2.56 | Destabilizing | 2.07 | Destabilizing | 0.569 | Likely Pathogenic | -6.58 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | 0.1009 | 0.0488 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.1045C>A | P349T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P349T is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and the SGM‑Consensus score (which is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools with inconclusive results are AlphaMissense‑Default, FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -9.736 | Likely Pathogenic | 0.420 | Ambiguous | Likely Benign | 1.37 | Ambiguous | 0.1 | 2.56 | Destabilizing | 1.97 | Ambiguous | 0.76 | Ambiguous | 0.246 | Likely Benign | -6.12 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.57 | Pathogenic | 0.07 | Tolerated | 0.1615 | 0.6238 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.2162T>C | I721T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721T is not reported in ClinVar (ClinVar status: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that indicate a benign effect include only REVEL. All other evaluated tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote) yields Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts Pathogenic. No prediction or folding result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | -10.374 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.73 | Destabilizing | 0.0 | 2.56 | Destabilizing | 2.65 | Destabilizing | 2.11 | Destabilizing | 0.417 | Likely Benign | -4.18 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 0.0918 | 0.1019 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.1054A>C | T352P 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant T352P has no ClinVar entry and is not reported in gnomAD. Prediction tools that converge on a benign outcome include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, FATHMM, and Rosetta. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. Overall, the balance of evidence favors a benign interpretation; this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | -3.562 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 1.04 | Ambiguous | 0.1 | 2.57 | Destabilizing | 1.81 | Ambiguous | 0.51 | Ambiguous | 0.159 | Likely Benign | -2.31 | Neutral | 0.627 | Possibly Damaging | 0.196 | Benign | 1.72 | Pathogenic | 0.20 | Tolerated | 0.2244 | 0.5968 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1159G>C | G387R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G387R 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 premPS, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Tools that predict pathogenicity are SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign effect, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are missing or inconclusive. Overall, the majority of evidence (10 pathogenic vs. 4 benign) indicates 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 | 0.642678 | Disordered | 0.422910 | Uncertain | 0.293 | 0.861 | 0.750 | -8.728 | Likely Pathogenic | 0.683 | Likely Pathogenic | Likely Benign | 4.13 | Destabilizing | 2.9 | 2.57 | Destabilizing | 3.35 | Destabilizing | 0.15 | Likely Benign | 0.516 | Likely Pathogenic | -0.54 | Neutral | 0.003 | Benign | 0.004 | Benign | 1.32 | Pathogenic | 0.01 | Affected | 0.1309 | 0.4356 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.617T>A | I206N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I206N is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL and FATHMM, while the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is pathogenic. No prediction or folding result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -15.211 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.98 | Destabilizing | 0.2 | 2.57 | Destabilizing | 2.78 | Destabilizing | 2.04 | Destabilizing | 0.334 | Likely Benign | -5.55 | Deleterious | 0.940 | Possibly Damaging | 0.641 | Possibly Damaging | 3.62 | Benign | 0.00 | Affected | 0.0689 | 0.0340 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1241T>G | M414R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus remains likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the preponderance of evidence indicates that M414R is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -13.404 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.17 | Ambiguous | 0.1 | 2.58 | Destabilizing | 1.88 | Ambiguous | 1.45 | Destabilizing | 0.525 | Likely Pathogenic | -5.20 | Deleterious | 0.972 | Probably Damaging | 0.895 | Possibly Damaging | 3.38 | Benign | 0.03 | Affected | 0.1509 | 0.1037 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||
| c.1681T>G | F561V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F561V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. All available evidence points to a pathogenic impact. Therefore, 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 | 0.024826 | Structured | 0.018013 | Uncertain | 0.903 | 0.196 | 0.000 | -11.371 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 3.11 | Destabilizing | 0.1 | 2.58 | Destabilizing | 2.85 | Destabilizing | 1.48 | Destabilizing | 0.827 | Likely Pathogenic | -6.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.25 | Pathogenic | 0.04 | Affected | 0.1985 | 0.1575 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.838T>C | Y280H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280H is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Among the available in‑silico predictors, none indicate a benign effect; all 14 tools that produced a classification predict pathogenicity: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are inconclusive or missing. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.161087 | Structured | 0.321243 | Uncertain | 0.917 | 0.248 | 0.125 | -9.970 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.01 | Destabilizing | 0.3 | 2.58 | Destabilizing | 2.80 | Destabilizing | 1.95 | Destabilizing | 0.588 | Likely Pathogenic | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.94 | Pathogenic | 0.01 | Affected | 0.2021 | 0.0212 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.1822T>C | F608L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. FoldX and Foldetta report uncertain stability changes, but these are not considered evidence against pathogenicity. When predictions are grouped, no tool predicts a benign outcome; all available evidence supports a harmful effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (derived from the majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta remains inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -12.274 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.86 | Ambiguous | 0.2 | 2.59 | Destabilizing | 1.73 | Ambiguous | 1.24 | Destabilizing | 0.883 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.50 | Pathogenic | 0.01 | Affected | 0.2231 | 0.2874 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1824T>A | F608L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. FoldX and Foldetta report uncertain stability changes, but these are not considered evidence against pathogenicity. When predictions are grouped, no tool predicts a benign outcome; all available evidence supports a harmful effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (derived from the majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta remains inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -12.274 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.86 | Ambiguous | 0.2 | 2.59 | Destabilizing | 1.73 | Ambiguous | 1.24 | Destabilizing | 0.747 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.50 | Pathogenic | 0.01 | Affected | 0.2231 | 0.2874 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1824T>G | F608L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX‑MD (uncertain), Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only FoldX and Foldetta are inconclusive. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it likely pathogenic, and Foldetta reports an uncertain stability change. No tool predicts 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 | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -12.274 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.86 | Ambiguous | 0.2 | 2.59 | Destabilizing | 1.73 | Ambiguous | 1.24 | Destabilizing | 0.747 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.50 | Pathogenic | 0.01 | Affected | 0.2231 | 0.2874 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.746C>A | A249E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249E has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are SIFT and FATHMM. The majority of other in‑silico predictors (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic; FoldX is uncertain and is not counted as evidence for either side. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of benign evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -13.519 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.60 | Ambiguous | 1.2 | 2.59 | Destabilizing | 2.10 | Destabilizing | 1.02 | Destabilizing | 0.818 | Likely Pathogenic | -3.29 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.64 | Benign | 0.09 | Tolerated | 0.0799 | 0.1509 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||
| c.977A>C | H326P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; pathogenic predictions are reported by REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). The only inconclusive result is premPS, which is listed as Uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Pathogenic. Based on the consensus of these predictions, the variant is most likely pathogenic, and this conclusion is consistent with the absence of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.342579 | Structured | 0.418150 | Uncertain | 0.944 | 0.455 | 0.000 | -18.452 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.67 | Destabilizing | 0.3 | 2.59 | Destabilizing | 2.63 | Destabilizing | 0.88 | Ambiguous | 0.711 | Likely Pathogenic | -8.73 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.92 | Pathogenic | 0.03 | Affected | 0.2383 | 0.4492 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.1085G>T | W362L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W362L is not reported in ClinVar and is absent from gnomAD. All tools except premPS predict pathogenic, leaving no benign predictions. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains uncertain. High‑accuracy methods corroborate this assessment: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.430310 | Uncertain | 0.957 | 0.552 | 0.125 | -12.748 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 2.16 | Destabilizing | 0.1 | 2.60 | Destabilizing | 2.38 | Destabilizing | 0.71 | Ambiguous | 0.523 | Likely Pathogenic | -11.95 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 0.2701 | 0.2452 | -2 | -2 | 4.7 | -73.05 | |||||||||||||||||||||||||||||
| c.1049T>A | V350E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign effect include REVEL and SIFT, whereas a majority of tools predict pathogenicity: premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, Foldetta, and Rosetta. Two tools give inconclusive results: FoldX (Uncertain) and AlphaMissense‑Optimized (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for V350E. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -15.975 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 1.73 | Ambiguous | 0.2 | 2.61 | Destabilizing | 2.17 | Destabilizing | 1.93 | Destabilizing | 0.304 | Likely Benign | -4.67 | Deleterious | 0.976 | Probably Damaging | 0.559 | Possibly Damaging | 1.61 | Pathogenic | 0.08 | Tolerated | 0.1078 | 0.1568 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.1699G>A | E567K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E567K is not reported in ClinVar (no entry) and is absent from gnomAD. Prediction tools cluster into two groups: benign calls come from REVEL, FoldX, SIFT, and FATHMM, while pathogenic calls arise from Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (likely pathogenic). High‑accuracy methods reinforce the pathogenic assessment: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. PremPS is likewise inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by ClinVar status or gnomAD presence. 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 | -15.568 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | -0.18 | Likely Benign | 0.0 | 2.61 | Destabilizing | 1.22 | Ambiguous | 0.65 | Ambiguous | 0.380 | Likely Benign | -3.75 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.45 | Benign | 0.16 | Tolerated | 0.2115 | 0.5552 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.2057G>A | G686D 2D  AIThe SynGAP1 missense variant G686D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists 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 | -14.109 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.00 | Destabilizing | 1.7 | 2.61 | Destabilizing | 2.31 | Destabilizing | 1.05 | Destabilizing | 0.563 | Likely Pathogenic | -6.28 | Deleterious | 1.000 | Probably Damaging | 0.967 | Probably Damaging | 3.40 | Benign | 0.00 | Affected | 0.1720 | 0.2196 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.2107C>G | L703V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Because the variant is not present in ClinVar or gnomAD, there is no existing clinical classification to contradict. Overall, the majority of predictions and the two high‑accuracy benign assessments suggest the variant is most likely benign, although the Foldetta result indicates a potential pathogenic effect that warrants further functional investigation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -10.086 | Likely Pathogenic | 0.301 | Likely Benign | Likely Benign | 2.32 | Destabilizing | 0.1 | 2.61 | Destabilizing | 2.47 | Destabilizing | 1.07 | Destabilizing | 0.080 | Likely Benign | -2.22 | Neutral | 0.789 | Possibly Damaging | 0.352 | Benign | 3.19 | Benign | 0.00 | Affected | 0.1383 | 0.2621 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.871T>C | Y291H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291H is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from REVEL, while all other evaluated algorithms (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a likely pathogenic verdict; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.383842 | Uncertain | 0.912 | 0.251 | 0.000 | -8.749 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 2.13 | Destabilizing | 0.2 | 2.61 | Destabilizing | 2.37 | Destabilizing | 1.56 | Destabilizing | 0.355 | Likely Benign | -4.04 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.77 | Pathogenic | 0.02 | Affected | 0.2403 | 0.0499 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.1094T>C | V365A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by REVEL and polyPhen‑2 HumVar, whereas the remaining tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. High‑accuracy assessments are consistent with a deleterious outcome: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a pathogenic effect. Taken together, the majority of evidence supports a pathogenic classification for V365A, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | -8.954 | Likely Pathogenic | 0.867 | Likely Pathogenic | Ambiguous | 2.61 | Destabilizing | 0.1 | 2.62 | Destabilizing | 2.62 | Destabilizing | 2.10 | Destabilizing | 0.297 | Likely Benign | -3.18 | Deleterious | 0.622 | Possibly Damaging | 0.235 | Benign | 1.67 | Pathogenic | 0.01 | Affected | 0.2682 | 0.2962 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1148G>A | G383E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383E is not 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), and FATHMM. Tools that predict a pathogenic effect are FoldX, Rosetta, SIFT, ESM1b, AlphaMissense‑Default, and the protein‑folding stability method Foldetta. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (pathogenic), FATHMM (benign), and PROVEAN (benign), is inconclusive (tie). Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a pathogenic effect. Overall, the majority of predictions (seven pathogenic vs. six benign) indicate 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. | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | -9.535 | Likely Pathogenic | 0.570 | Likely Pathogenic | Likely Benign | 4.09 | Destabilizing | 2.4 | 2.62 | Destabilizing | 3.36 | Destabilizing | 0.39 | Likely Benign | 0.308 | Likely Benign | -0.78 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.10 | Benign | 0.01 | Affected | 0.1582 | 0.3741 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.1316T>G | L439R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L439R 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 limited to FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic or likely pathogenic impact; FoldX is uncertain and is treated as unavailable. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | -12.870 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 1.90 | Ambiguous | 0.5 | 2.62 | Destabilizing | 2.26 | Destabilizing | 1.40 | Destabilizing | 0.554 | Likely Pathogenic | -5.25 | Deleterious | 0.996 | Probably Damaging | 0.983 | Probably Damaging | 3.22 | Benign | 0.01 | Affected | 0.1217 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1427T>G | F476C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476C is catalogued in gnomAD (ID 6‑33438459‑T‑G) but has no ClinVar entry. Functional prediction tools split in two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, seven tools predict pathogenicity versus six predicting benign, with no ClinVar evidence to contradict this assessment. Thus, the variant is most likely pathogenic based on the current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | 6-33438459-T-G | -9.270 | Likely Pathogenic | 0.745 | Likely Pathogenic | Likely Benign | 2.05 | Destabilizing | 0.1 | 2.62 | Destabilizing | 2.34 | Destabilizing | -0.30 | Likely Benign | 0.280 | Likely Benign | 2.69 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.46 | Benign | 0.83 | Tolerated | 3.40 | 22 | 0.2051 | 0.1251 | -2 | -4 | -0.3 | -44.04 | |||||||||||||||||||||||||||
| c.1493T>C | M498T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: all but one (polyPhen‑2 HumVar) predict pathogenicity, while polyPhen‑2 HumVar alone predicts benign. Uncertain predictions (ESM1b and AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy methods reinforce the pathogenic view: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. AlphaMissense‑Optimized remains inconclusive. Overall, the preponderance of evidence indicates that M498T is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -7.477 | In-Between | 0.869 | Likely Pathogenic | Ambiguous | 2.46 | Destabilizing | 0.1 | 2.62 | Destabilizing | 2.54 | Destabilizing | 1.41 | Destabilizing | 0.672 | Likely Pathogenic | -3.80 | Deleterious | 0.803 | Possibly Damaging | 0.343 | Benign | -1.19 | Pathogenic | 0.02 | Affected | 0.1925 | 0.1630 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||
| c.1532G>A | G511E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -12.263 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.17 | Destabilizing | 0.2 | 2.62 | Destabilizing | 2.40 | Destabilizing | 1.15 | Destabilizing | 0.479 | Likely Benign | -7.69 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.24 | Benign | 0.02 | Affected | 0.1882 | 0.4240 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||
| c.1641T>G | C547W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547W is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic, while premPS remains uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenic. Taken together, the overwhelming consensus from both general and high‑accuracy predictors is that C547W is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | -15.788 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 11.03 | Destabilizing | 0.3 | 2.63 | Destabilizing | 6.83 | Destabilizing | 0.54 | Ambiguous | 0.764 | Likely Pathogenic | -10.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.34 | Pathogenic | 0.01 | Affected | 0.1854 | 0.2750 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.2041G>T | G681C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G681C is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all classify it as pathogenic, while only FATHMM predicts a benign outcome. Uncertain calls come from FoldX, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, Foldetta (combining FoldX‑MD and Rosetta) is pathogenic, and AlphaMissense‑Optimized remains inconclusive. Overall, the evidence strongly favors a pathogenic interpretation, 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 | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | -12.374 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 1.89 | Ambiguous | 1.3 | 2.63 | Destabilizing | 2.26 | Destabilizing | 0.66 | Ambiguous | 0.554 | Likely Pathogenic | -8.98 | Deleterious | 1.000 | Probably Damaging | 0.959 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 0.1194 | 0.3886 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.2152C>T | L718F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L718F lies in the GAP domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools cluster into two groups: benign predictions are made only by REVEL, whereas the remaining tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity; premPS is uncertain and is not counted as evidence. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the overwhelming consensus of these predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.438417 | Uncertain | 0.966 | 0.385 | 0.000 | -11.302 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 3.87 | Destabilizing | 0.2 | 2.64 | Destabilizing | 3.26 | Destabilizing | 0.78 | Ambiguous | 0.347 | Likely Benign | -3.73 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.32 | Pathogenic | 0.00 | Affected | 0.0590 | 0.2979 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.602A>G | D201G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201G missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence favors a pathogenic interpretation, with no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -7.744 | In-Between | 0.603 | Likely Pathogenic | Likely Benign | 0.71 | Ambiguous | 0.0 | 2.64 | Destabilizing | 1.68 | Ambiguous | 0.24 | Likely Benign | 0.289 | Likely Benign | -3.03 | Deleterious | 0.996 | Probably Damaging | 0.877 | Possibly Damaging | 4.09 | Benign | 0.39 | Tolerated | 0.3268 | 0.5047 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||
| c.941T>G | F314C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. All available evidence points to a damaging effect. Consequently, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -12.458 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.37 | Destabilizing | 0.3 | 2.64 | Destabilizing | 3.01 | Destabilizing | 2.49 | Destabilizing | 0.674 | Likely Pathogenic | -6.89 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.13 | Pathogenic | 0.00 | Affected | 0.2401 | 0.1075 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1832T>A | M611K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 M611K variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. The majority of other in silico predictors (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) indicate a pathogenic effect; FoldX is uncertain and therefore not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -13.021 | Likely Pathogenic | 0.630 | Likely Pathogenic | Likely Benign | 1.86 | Ambiguous | 0.6 | 2.65 | Destabilizing | 2.26 | Destabilizing | 1.65 | Destabilizing | 0.665 | Likely Pathogenic | -4.10 | Deleterious | 0.250 | Benign | 0.120 | Benign | -1.26 | Pathogenic | 0.03 | Affected | 0.1193 | 0.0688 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.1907T>G | F636C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F636C is reported in gnomAD (ID 6‑33440959‑T‑G) but has no ClinVar entry. Prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Only FATHMM predicts a benign outcome; FoldX is uncertain and therefore not counted as evidence. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | 6-33440959-T-G | 3 | 1.86e-6 | -13.287 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 1.74 | Ambiguous | 0.1 | 2.65 | Destabilizing | 2.20 | Destabilizing | 1.22 | Destabilizing | 0.612 | Likely Pathogenic | -7.67 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.40 | Benign | 0.04 | Affected | 3.37 | 34 | 0.2301 | 0.0830 | -2 | -4 | -0.3 | -44.04 | ||||||||||||||||||||||||
| c.1393C>G | L465V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and SIFT, while the remaining tools—FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default—indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports likely pathogenic; and Foldetta, which combines FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Overall, the majority of evidence points to a pathogenic impact, which is consistent with the ClinVar uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | Uncertain | 1 | -9.893 | Likely Pathogenic | 0.838 | Likely Pathogenic | Ambiguous | 2.46 | Destabilizing | 0.1 | 2.66 | Destabilizing | 2.56 | Destabilizing | 1.21 | Destabilizing | 0.276 | Likely Benign | -2.98 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.44 | Pathogenic | 0.10 | Tolerated | 3.37 | 34 | 0.1493 | 0.3378 | 2 | 1 | 0.4 | -14.03 | 204.3 | 30.9 | 0.0 | 0.0 | -0.4 | 0.6 | X | Potentially Benign | The iso-butyl side chain of Leu465, located in the middle of an α helix (res. Ala461–Phe476), packs with hydrophobic residues (e.g., Phe464, Met468, Tyr497, Ile494) in an inter-helix space formed with two other α helices (res. Ala461–Phe476 and res. Thr488-Gly502). In the variant simulations, the iso-propyl side chain of Val465 is equally sized and similarly hydrophobic as the original side chain of Leu465. Hence, the mutation does not exert any negative effects on the protein structure based on the variant simulations. | ||||||||||||||||
| c.1406C>T | A469V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 A469V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect comprise FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and Foldetta; premPS and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts pathogenic. With seven tools supporting pathogenicity versus four supporting benignity, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -8.858 | Likely Pathogenic | 0.459 | Ambiguous | Likely Benign | 2.30 | Destabilizing | 0.4 | 2.66 | Destabilizing | 2.48 | Destabilizing | -0.77 | Ambiguous | 0.426 | Likely Benign | 0.26 | Neutral | 0.997 | Probably Damaging | 0.976 | Probably Damaging | -1.20 | Pathogenic | 0.60 | Tolerated | 0.0827 | 0.5421 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.1801G>A | A601T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A601T 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 are FATHMM and AlphaMissense‑Optimized, whereas the remaining pathogenic‑predicting tools—SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently flag the variant as deleterious. Two tools, FoldX and premPS, return uncertain results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. Taken together, 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 entry for this variant. 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 | -10.635 | Likely Pathogenic | 0.662 | Likely Pathogenic | Likely Benign | 1.55 | Ambiguous | 0.1 | 2.66 | Destabilizing | 2.11 | Destabilizing | 0.76 | Ambiguous | 0.642 | Likely Pathogenic | -3.98 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 2.57 | Benign | 0.00 | Affected | 0.1564 | 0.5554 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1907T>C | F636S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F636S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining 13 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) all predict a pathogenic impact. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or folding‑stability result is missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | -14.290 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.08 | Destabilizing | 0.1 | 2.66 | Destabilizing | 2.37 | Destabilizing | 1.51 | Destabilizing | 0.559 | Likely Pathogenic | -7.50 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.41 | Benign | 0.03 | Affected | 0.3877 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.2084T>G | L695R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L695R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all classify the variant as pathogenic. AlphaMissense‑Optimized returns an uncertain result. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also pathogenic. Overall, the evidence overwhelmingly indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.373419 | Uncertain | 0.942 | 0.258 | 0.000 | -15.582 | Likely Pathogenic | 0.873 | Likely Pathogenic | Ambiguous | 2.05 | Destabilizing | 0.1 | 2.66 | Destabilizing | 2.36 | Destabilizing | 1.57 | Destabilizing | 0.605 | Likely Pathogenic | -5.92 | Deleterious | 0.993 | Probably Damaging | 0.588 | Possibly Damaging | 3.17 | Benign | 0.00 | Affected | 0.1220 | 0.0530 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.637A>T | I213F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I213F missense variant is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; FoldX and premPS are uncertain and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain and thus not considered. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -12.212 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.96 | Ambiguous | 0.7 | 2.66 | Destabilizing | 1.81 | Ambiguous | 0.73 | Ambiguous | 0.815 | Likely Pathogenic | -3.30 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.79 | Benign | 0.01 | Affected | 0.0473 | 0.2560 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.881C>A | T294N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T294N is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy methods reinforce this assessment: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status (no report). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.316932 | Uncertain | 0.919 | 0.267 | 0.125 | -14.925 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.74 | Destabilizing | 0.2 | 2.66 | Destabilizing | 2.70 | Destabilizing | 1.56 | Destabilizing | 0.630 | Likely Pathogenic | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -0.18 | Pathogenic | 0.01 | Affected | 0.1040 | 0.3239 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.1409T>A | M470K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M470K is not reported in ClinVar (status: None) and is absent from gnomAD. Prediction tools cluster into two groups: the single benign call comes from SIFT, while all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—label the change as pathogenic or likely pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports pathogenic. Thus, the variant is most likely pathogenic based on the consensus of available predictions, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -14.327 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.77 | Destabilizing | 0.1 | 2.67 | Destabilizing | 2.72 | Destabilizing | 1.55 | Destabilizing | 0.823 | Likely Pathogenic | -5.42 | Deleterious | 0.923 | Possibly Damaging | 0.922 | Probably Damaging | -1.06 | Pathogenic | 0.20 | Tolerated | 0.1157 | 0.0656 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.742C>G | R248G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R248G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | -13.413 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.23 | Destabilizing | 0.7 | 2.67 | Destabilizing | 2.45 | Destabilizing | 1.33 | Destabilizing | 0.770 | Likely Pathogenic | -6.07 | Deleterious | 0.958 | Probably Damaging | 0.502 | Possibly Damaging | 5.70 | Benign | 0.00 | Affected | 0.3011 | 0.3385 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.758A>C | N253T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253T is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default) predict a pathogenic outcome. High‑accuracy methods give a consistent pathogenic signal: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta) also predicts pathogenic. AlphaMissense‑Optimized is uncertain and is treated as unavailable. Overall, the preponderance 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 | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -11.656 | Likely Pathogenic | 0.929 | Likely Pathogenic | Ambiguous | 1.96 | Ambiguous | 0.3 | 2.67 | Destabilizing | 2.32 | Destabilizing | 0.16 | Likely Benign | 0.739 | Likely Pathogenic | -5.01 | Deleterious | 0.993 | Probably Damaging | 0.971 | Probably Damaging | 5.54 | Benign | 0.06 | Tolerated | 0.1640 | 0.8665 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.812C>A | A271D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271D is listed in ClinVar as Pathogenic (ClinVar ID 2019732.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.413873 | Uncertain | 0.939 | 0.220 | 0.125 | Pathogenic | 1 | -18.590 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.71 | Destabilizing | 0.4 | 2.67 | Destabilizing | 3.69 | Destabilizing | 1.59 | Destabilizing | 0.706 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.62 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.1565 | 0.1541 | 0 | -2 | -5.3 | 44.01 | 226.2 | -63.4 | 0.0 | 0.0 | 0.9 | 0.1 | X | X | X | X | Potentially Pathogenic | The methyl group of Ala271, located near the end of an anti-parallel β sheet strand (res. Arg259-Arg272), packs against multiple hydrophobic residues such as Val400, Val306, and Leu274 in the WT simulations. In the variant simulations, the carboxylate group of Asp271 is not suitable for the hydrophobic niche, causing the hydrophobic residues to make room for the swapped residue. Additionally, the carboxylate group of the Asp271 side chain forms hydrogen bonds with the backbone amide groups of Arg272 and Ala399 in the β sheet, or even forms a salt bridge with the amino group of the Lys394 side chain. This directly affects the integrity of the anti-parallel β sheet at the end. In short, the residue swap disrupts the C2 domain packing during folding, which could weaken the stability of the SynGAP-membrane association. | |||||||||||||
| c.1357C>G | H453D 2D  3DClick to see structure in 3D Viewer AISynGAP1 H453D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are made by FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods reinforce a pathogenic interpretation: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenicity. premPS remains uncertain. Overall, the majority of evidence points to a pathogenic effect for H453D, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -15.256 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 3.33 | Destabilizing | 0.0 | 2.68 | Destabilizing | 3.01 | Destabilizing | 0.97 | Ambiguous | 0.443 | Likely Benign | -8.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.48 | Benign | 0.09 | Tolerated | 0.2225 | 0.1815 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.1409T>C | M470T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M470T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or folding‑stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | Uncertain | 1 | -8.104 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 3.19 | Destabilizing | 0.1 | 2.68 | Destabilizing | 2.94 | Destabilizing | 1.49 | Destabilizing | 0.763 | Likely Pathogenic | -5.30 | Deleterious | 0.996 | Probably Damaging | 0.985 | Probably Damaging | -1.08 | Pathogenic | 0.24 | Tolerated | 3.37 | 34 | 0.1782 | 0.1950 | -1 | -1 | -2.6 | -30.09 | 213.8 | 46.5 | 0.0 | 0.0 | -0.2 | 0.2 | X | X | Potentially Pathogenic | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558, Cys576, Trp572) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, the Met470 side chain also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the hydroxyl group of the Thr470 side chain forms an H-bond with the backbone carbonyl group of Ser466 in the α helix, potentially lowering its structural integrity. Importantly, the hydroxyl group of Thr470 also forms an H-bond with the guanidinium group of Arg575, which helps it form a more permanent salt bridge with Asp467. | |||||||||||||||
| c.1537T>G | F513V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -10.675 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 3.54 | Destabilizing | 0.4 | 2.68 | Destabilizing | 3.11 | Destabilizing | 1.13 | Destabilizing | 0.799 | Likely Pathogenic | -6.70 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.21 | Pathogenic | 0.44 | Tolerated | 0.1656 | 0.1583 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1552T>G | Y518D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y518D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | -12.247 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 3.92 | Destabilizing | 0.9 | 2.68 | Destabilizing | 3.30 | Destabilizing | 1.36 | Destabilizing | 0.619 | Likely Pathogenic | -9.41 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.03 | Affected | 0.3682 | 0.0212 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.2153T>A | L718H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L718H is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools cluster into two groups: the single benign predictor REVEL, and a consensus of pathogenic predictions from FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are inconclusive or missing. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.438417 | Uncertain | 0.966 | 0.385 | 0.000 | -14.923 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.84 | Destabilizing | 0.1 | 2.68 | Destabilizing | 3.26 | Destabilizing | 2.69 | Destabilizing | 0.460 | Likely Benign | -6.64 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 0.1020 | 0.0526 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.617T>C | I206T 2D AIThe SynGAP1 I206T missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give consistent results: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions or stability results are missing or inconclusive. Based on the overall evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not currently listed. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -10.812 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 2.43 | Destabilizing | 0.5 | 2.68 | Destabilizing | 2.56 | Destabilizing | 1.94 | Destabilizing | 0.252 | Likely Benign | -3.78 | Deleterious | 0.421 | Benign | 0.156 | Benign | 3.65 | Benign | 0.00 | Affected | 0.0830 | 0.0669 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.670A>C | T224P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T224P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are SIFT and FATHMM, while the remaining tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b) all predict a pathogenic impact; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -11.812 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 3.63 | Destabilizing | 0.4 | 2.68 | Destabilizing | 3.16 | Destabilizing | 0.57 | Ambiguous | 0.765 | Likely Pathogenic | -3.65 | Deleterious | 0.971 | Probably Damaging | 0.543 | Possibly Damaging | 5.56 | Benign | 0.23 | Tolerated | 0.2355 | 0.6063 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.974T>A | L325Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—return pathogenic or likely pathogenic calls. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.352862 | Structured | 0.424577 | Uncertain | 0.955 | 0.436 | 0.000 | -17.005 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.23 | Destabilizing | 0.0 | 2.68 | Destabilizing | 2.96 | Destabilizing | 2.02 | Destabilizing | 0.547 | Likely Pathogenic | -3.97 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 1.33 | Pathogenic | 0.00 | Affected | 0.1235 | 0.1405 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1844C>G | P615R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P615R is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar or gnomAD evidence to the contrary, the variant is most likely pathogenic. 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 | -15.628 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.62 | Destabilizing | 0.5 | 2.69 | Destabilizing | 2.66 | Destabilizing | 1.14 | Destabilizing | 0.871 | Likely Pathogenic | -8.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 0.1463 | 0.2603 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1024T>G | Y342D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y342D is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and SIFT, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict it to be pathogenic. FoldX reports an uncertain effect, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta is pathogenic. Based on the preponderance of pathogenic predictions and the absence of benign evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.366687 | Structured | 0.408200 | Uncertain | 0.866 | 0.487 | 0.250 | -10.940 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 1.60 | Ambiguous | 0.1 | 2.70 | Destabilizing | 2.15 | Destabilizing | 0.13 | Likely Benign | 0.668 | Likely Pathogenic | -7.19 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.71 | Pathogenic | 0.07 | Tolerated | 0.3925 | 0.0862 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1796G>T | C599F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C599F is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic or likely pathogenic. Only premPS predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding‑stability result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009865 | Structured | 0.151725 | Uncertain | 0.960 | 0.151 | 0.000 | -13.969 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 3.72 | Destabilizing | 1.3 | 2.70 | Destabilizing | 3.21 | Destabilizing | -0.42 | Likely Benign | 0.902 | Likely Pathogenic | -10.95 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.47 | Pathogenic | 0.00 | Affected | 0.1319 | 0.3073 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.1877T>C | I626T 2D AISynGAP1 missense variant I626T is listed in ClinVar with an uncertain significance (ClinVar ID 3359331.0) and is not reported in gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions are returned by REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a benign outcome, while AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the consensus of the majority of tools points to a pathogenic effect, contradicting the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.109221 | Structured | 0.040732 | Uncertain | 0.970 | 0.223 | 0.000 | Uncertain | 1 | -10.420 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 2.94 | Destabilizing | 0.1 | 2.70 | Destabilizing | 2.82 | Destabilizing | 2.23 | Destabilizing | 0.640 | Likely Pathogenic | -4.18 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.04 | Benign | 0.00 | Affected | 0.1000 | 0.0840 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||
| c.1702G>A | V568M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V568M is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, whereas the remaining tools—REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus—predict a 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. With the majority of evidence pointing to pathogenicity and no ClinVar annotation to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024826 | Structured | 0.053503 | Uncertain | 0.937 | 0.257 | 0.000 | -10.361 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.06 | Likely Benign | 0.3 | 2.71 | Destabilizing | 1.39 | Ambiguous | 0.66 | Ambiguous | 0.811 | Likely Pathogenic | -2.79 | Deleterious | 0.997 | Probably Damaging | 0.924 | Probably Damaging | -1.42 | Pathogenic | 0.00 | Affected | 0.0697 | 0.3124 | 2 | 1 | -2.3 | 32.06 | |||||||||||||||||||||||||||||
| c.842A>G | Y281C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized indicates a benign outcome, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. Consequently, the variant is most likely pathogenic based on the overwhelming majority of predictions, and this assessment does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.337647 | Uncertain | 0.927 | 0.254 | 0.000 | -8.528 | Likely Pathogenic | 0.752 | Likely Pathogenic | Likely Benign | 3.00 | Destabilizing | 0.1 | 2.71 | Destabilizing | 2.86 | Destabilizing | 1.48 | Destabilizing | 0.615 | Likely Pathogenic | -5.55 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.99 | Pathogenic | 0.05 | Affected | 0.2949 | 0.2176 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.1340T>C | V447A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V447A missense variant is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta both predict pathogenicity. No predictions are missing or inconclusive. Based on the overall distribution of predictions, 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 | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | -9.852 | Likely Pathogenic | 0.692 | Likely Pathogenic | Likely Benign | 2.18 | Destabilizing | 0.0 | 2.72 | Destabilizing | 2.45 | Destabilizing | 1.56 | Destabilizing | 0.266 | Likely Benign | -2.84 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.37 | Benign | 0.15 | Tolerated | 0.2456 | 0.2124 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.719A>G | D240G 2D AIThe SynGAP1 missense variant D240G is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Benign predictions are provided by premPS and FATHMM, whereas pathogenic predictions are made by REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. FoldX‑MD is inconclusive, and AlphaMissense‑Optimized is uncertain. High‑accuracy methods show that AlphaMissense‑Optimized is inconclusive, SGM Consensus predicts pathogenic, and Foldetta predicts pathogenic. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | Uncertain | 1 | -12.825 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 1.85 | Ambiguous | 0.1 | 2.72 | Destabilizing | 2.29 | Destabilizing | 0.24 | Likely Benign | 0.912 | Likely Pathogenic | -6.19 | Deleterious | 0.993 | Probably Damaging | 0.984 | Probably Damaging | 5.79 | Benign | 0.01 | Affected | 0.3474 | 0.4989 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||
| c.1025A>G | Y342C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y342C is listed in ClinVar as Benign (ClinVar ID 1213078.0) and is observed in gnomAD (ID 6‑33437930‑A‑G). Across general prediction tools, benign calls are made by REVEL and AlphaMissense‑Optimized, whereas pathogenic calls are made by FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by premPS and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized predicting Benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting Pathogenic. Overall, the majority of predictions support a pathogenic effect, contradicting the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.366687 | Structured | 0.408200 | Uncertain | 0.866 | 0.487 | 0.250 | Benign/Likely benign | 2 | 6-33437930-A-G | 21 | 1.30e-5 | -7.596 | In-Between | 0.682 | Likely Pathogenic | Likely Benign | 2.48 | Destabilizing | 0.1 | 2.73 | Destabilizing | 2.61 | Destabilizing | 0.92 | Ambiguous | 0.404 | Likely Benign | -6.67 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.72 | Pathogenic | 0.02 | Affected | 3.37 | 25 | 0.2836 | 0.2870 | 0 | -2 | 3.8 | -60.04 | 242.4 | 62.8 | 0.1 | 0.0 | -0.1 | 0.2 | Potentially Pathogenic | The phenol ring of Tyr342, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), faces outward in the C2 domain. This phenol ring contributes to a triple tyrosine stack (Tyr342, Tyr328, and Tyr281) that links together three anti-parallel β sheet strands. Additionally, it shields Gly344 from the solvent, reducing its exposure and providing stability for the β-sandwich. This motif also contributes to a twist formation in the β sheet.In the variant simulations, the Cys342 side chain cannot participate in the stack formation. Instead, its thiol group forms a hydrogen bond with the backbone carbonyl group of Leu327. Although these changes in surface interactions could weaken the characteristic twist that strengthens the β sheet fold, no major structural effects are observed in the variant simulations. The residue swap could also affect the SynGAP-membrane association; however, this phenomenon cannot be addressed using solvent-only simulations. Notably, the thiol group of cysteine is not a particularly strong hydrogen-bonding partner, which could mitigate the negative effects of the residue swap. | ||||||||||||||
| c.1037T>C | V346A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346A is reported in gnomAD (6‑33437942‑T‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect are limited to REVEL, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) uniformly predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | 6-33437942-T-C | 1 | 6.20e-7 | -8.556 | Likely Pathogenic | 0.856 | Likely Pathogenic | Ambiguous | 2.72 | Destabilizing | 0.2 | 2.73 | Destabilizing | 2.73 | Destabilizing | 1.92 | Destabilizing | 0.477 | Likely Benign | -3.68 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.70 | Pathogenic | 0.01 | Affected | 3.37 | 25 | 0.3341 | 0.2967 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||
| c.1814C>T | P605L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605L 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. All other evaluated tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, AlphaMissense‑Default, AlphaMissense‑Optimized, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, indicates a pathogenic effect. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | -12.114 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.65 | Destabilizing | 1.1 | 2.74 | Destabilizing | 2.70 | Destabilizing | -0.10 | Likely Benign | 0.814 | Likely Pathogenic | -9.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.69 | Pathogenic | 0.00 | Affected | 0.2232 | 0.6158 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.2161A>T | I721F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic impact, while premPS remains uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | -12.559 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 4.61 | Destabilizing | 0.1 | 2.74 | Destabilizing | 3.68 | Destabilizing | 0.66 | Ambiguous | 0.295 | Likely Benign | -3.74 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 0.0420 | 0.2931 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.848A>G | E283G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E283G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the single uncertain call from premPS is treated as unavailable. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.358602 | Uncertain | 0.950 | 0.249 | 0.000 | -13.937 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.13 | Destabilizing | 0.1 | 2.74 | Destabilizing | 2.94 | Destabilizing | 0.55 | Ambiguous | 0.559 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.63 | Pathogenic | 0.01 | Affected | 0.3123 | 0.4842 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.904T>C | S302P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302P is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only Rosetta predicts a pathogenic outcome, while FoldX and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also supports a benign classification. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains inconclusive. Overall, the preponderance of evidence points to a benign impact for S302P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -2.485 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 1.19 | Ambiguous | 0.4 | 2.74 | Destabilizing | 1.97 | Ambiguous | 0.14 | Likely Benign | 0.101 | Likely Benign | -0.89 | Neutral | 0.157 | Benign | 0.153 | Benign | 4.11 | Benign | 0.20 | Tolerated | 0.2522 | 0.6243 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1409T>G | M470R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M470R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only SIFT, whereas all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -13.161 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.75 | Destabilizing | 0.1 | 2.75 | Destabilizing | 2.75 | Destabilizing | 1.57 | Destabilizing | 0.823 | Likely Pathogenic | -5.47 | Deleterious | 0.963 | Probably Damaging | 0.943 | Probably Damaging | -1.19 | Pathogenic | 0.17 | Tolerated | 0.1399 | 0.0757 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||
| c.1495A>G | R499G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499G is listed in gnomAD (variant ID 6‑33438527‑A‑G) but has no ClinVar entry. Prediction tools that assess the variant’s effect on protein function overwhelmingly indicate a deleterious outcome: REVEL, FoldX‑MD (Rosetta component), Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify it as pathogenic. Only FoldX (overall) and AlphaMissense‑Optimized report uncertain results, which are treated as unavailable evidence. No tool predicts a benign effect. High‑accuracy assessments specifically show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as pathogenic. Taken together, the preponderance of evidence supports a pathogenic classification for R499G, and this conclusion is not contradicted by any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | 6-33438527-A-G | 3 | 1.86e-6 | -9.960 | Likely Pathogenic | 0.789 | Likely Pathogenic | Ambiguous | 1.55 | Ambiguous | 0.1 | 2.75 | Destabilizing | 2.15 | Destabilizing | 1.41 | Destabilizing | 0.681 | Likely Pathogenic | -4.50 | Deleterious | 0.958 | Probably Damaging | 0.769 | Possibly Damaging | -1.47 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2888 | 0.1798 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||
| c.1233C>G | I411M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411M is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two consensus groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are supported by SGM‑Consensus, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX and AlphaMissense‑Optimized yield uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta also predicts pathogenicity. 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 | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | -10.969 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 1.30 | Ambiguous | 0.2 | 2.76 | Destabilizing | 2.03 | Destabilizing | 1.21 | Destabilizing | 0.344 | Likely Benign | -2.73 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.31 | Benign | 0.00 | Affected | 0.0677 | 0.2848 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.797T>G | L266R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect, so the benign‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -17.131 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.97 | Destabilizing | 0.2 | 2.76 | Destabilizing | 3.37 | Destabilizing | 2.04 | Destabilizing | 0.574 | Likely Pathogenic | -5.32 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.1059 | 0.0558 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1772C>A | A591D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A591D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining evaluated algorithms (AlphaMissense‑Default, ESM1b, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, premPS, FoldX‑MD, Rosetta, Foldetta, and the SGM Consensus) uniformly predict a pathogenic or likely pathogenic outcome; FoldX‑MD is uncertain but does not counter the overall trend. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of benign evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.018787 | Structured | 0.093848 | Uncertain | 0.882 | 0.185 | 0.000 | -14.747 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.55 | Ambiguous | 0.2 | 2.77 | Destabilizing | 2.16 | Destabilizing | 1.40 | Destabilizing | 0.414 | Likely Benign | -5.02 | Deleterious | 0.919 | Possibly Damaging | 0.495 | Possibly Damaging | 3.42 | Benign | 0.00 | Affected | 0.1550 | 0.1741 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.737T>G | L246R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L246R missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -13.849 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.94 | Destabilizing | 0.8 | 2.77 | Destabilizing | 3.36 | Destabilizing | 1.72 | Destabilizing | 0.925 | Likely Pathogenic | -5.43 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.67 | Benign | 0.00 | Affected | 0.1266 | 0.0600 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2098C>A | L700M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L700M is not 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, and AlphaMissense‑Optimized. Only Rosetta predicts a pathogenic outcome, while Foldetta’s stability assessment is uncertain. The high‑accuracy consensus (SGM Consensus) is derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, all of which are benign, yielding a “Likely Benign” classification. AlphaMissense‑Optimized also predicts benign, whereas Foldetta remains inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.113710 | Structured | 0.416255 | Uncertain | 0.927 | 0.331 | 0.000 | -4.617 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.11 | Likely Benign | 0.0 | 2.79 | Destabilizing | 1.45 | Ambiguous | 0.35 | Likely Benign | 0.039 | Likely Benign | -0.32 | Neutral | 0.211 | Benign | 0.081 | Benign | 3.29 | Benign | 0.08 | Tolerated | 0.0733 | 0.2397 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1141G>A | G381R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381R is not reported in ClinVar and is present in gnomAD (ID 6‑33438046‑G‑A). Prediction tools that classify it as benign include premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized indicates a benign outcome, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the majority of evidence points to a pathogenic impact for G381R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.724957 | Disordered | 0.431692 | Uncertain | 0.301 | 0.951 | 0.750 | 6-33438046-G-A | -8.990 | Likely Pathogenic | 0.652 | Likely Pathogenic | Likely Benign | 5.60 | Destabilizing | 0.9 | 2.80 | Destabilizing | 4.20 | Destabilizing | 0.20 | Likely Benign | 0.589 | Likely Pathogenic | -0.82 | Neutral | 0.985 | Probably Damaging | 0.795 | Possibly Damaging | 1.32 | Pathogenic | 0.08 | Tolerated | 4.32 | 9 | 0.1339 | 0.3945 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||
| c.1141G>C | G381R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G381R is catalogued in gnomAD (ID 6‑33438046‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from SGM‑Consensus, REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized reports a benign outcome, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the majority of evidence indicates a pathogenic impact for G381R, and this conclusion is not contradicted by ClinVar status, which currently lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.724957 | Disordered | 0.431692 | Uncertain | 0.301 | 0.951 | 0.750 | 6-33438046-G-C | 2 | 1.25e-6 | -8.990 | Likely Pathogenic | 0.652 | Likely Pathogenic | Likely Benign | 5.60 | Destabilizing | 0.9 | 2.80 | Destabilizing | 4.20 | Destabilizing | 0.20 | Likely Benign | 0.589 | Likely Pathogenic | -0.82 | Neutral | 0.985 | Probably Damaging | 0.795 | Possibly Damaging | 1.32 | Pathogenic | 0.08 | Tolerated | 4.32 | 9 | 0.1339 | 0.3945 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||
| c.1249T>C | Y417H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417H is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for Y417H. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -11.447 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.22 | Destabilizing | 0.1 | 2.80 | Destabilizing | 3.01 | Destabilizing | 1.54 | Destabilizing | 0.513 | Likely Pathogenic | -4.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.97 | Benign | 0.00 | Affected | 0.2596 | 0.0668 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.1796G>A | C599Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C599Y is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that indicate a benign effect include only premPS, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, and this assessment 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 | 0.009865 | Structured | 0.151725 | Uncertain | 0.960 | 0.151 | 0.000 | -13.563 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 4.00 | Destabilizing | 1.4 | 2.80 | Destabilizing | 3.40 | Destabilizing | -0.29 | Likely Benign | 0.905 | Likely Pathogenic | -10.95 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.49 | Pathogenic | 0.00 | Affected | 0.1092 | 0.2555 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1916T>G | F639C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F639C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, and ESM1b all indicate pathogenicity, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. No predictions are missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -12.532 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 4.02 | Destabilizing | 0.2 | 2.80 | Destabilizing | 3.41 | Destabilizing | 1.38 | Destabilizing | 0.615 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.935 | Probably Damaging | 3.05 | Benign | 0.01 | Affected | 0.2451 | 0.0783 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1942T>G | F648V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F648V is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include SIFT and FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and the SGM‑Consensus—predict it to be pathogenic. High‑accuracy methods give consistent results: AlphaMissense‑Optimized indicates pathogenicity; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a destabilizing, pathogenic effect. No prediction is missing or inconclusive. Overall, the evidence overwhelmingly supports a pathogenic classification, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.346782 | Uncertain | 0.943 | 0.339 | 0.000 | -11.574 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 3.11 | Destabilizing | 0.1 | 2.80 | Destabilizing | 2.96 | Destabilizing | 1.14 | Destabilizing | 0.514 | Likely Pathogenic | -6.98 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 3.49 | Benign | 0.06 | Tolerated | 0.1848 | 0.1983 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1969T>G | W657G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W657G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. In contrast, the majority of other in silico predictors (AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FoldX, Rosetta, premPS, Foldetta) all classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No predictions are missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status 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 | 0.030611 | Structured | 0.208729 | Uncertain | 0.941 | 0.245 | 0.000 | -12.559 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 3.04 | Destabilizing | 0.2 | 2.80 | Destabilizing | 2.92 | Destabilizing | 1.28 | Destabilizing | 0.389 | Likely Benign | -11.16 | Deleterious | 0.999 | Probably Damaging | 0.941 | Probably Damaging | 3.46 | Benign | 0.15 | Tolerated | 0.4470 | 0.0885 | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||||||
| c.629A>C | H210P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -14.634 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 2.26 | Destabilizing | 0.5 | 2.80 | Destabilizing | 2.53 | Destabilizing | 1.00 | Destabilizing | 0.512 | Likely Pathogenic | -8.55 | Deleterious | 0.989 | Probably Damaging | 0.795 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.1805 | 0.3175 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.1762C>G | L588V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L588V 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 the remaining 13 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Taken together, the overwhelming majority of evidence points to a pathogenic effect for L588V. This conclusion is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Thus, the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.082229 | Uncertain | 0.887 | 0.214 | 0.000 | -10.374 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 3.61 | Destabilizing | 0.4 | 2.81 | Destabilizing | 3.21 | Destabilizing | 1.24 | Destabilizing | 0.533 | Likely Pathogenic | -2.99 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.28 | Pathogenic | 0.08 | Tolerated | 0.1422 | 0.2228 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.638T>A | I213N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I213N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining evaluated algorithms—SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; FoldX is uncertain and is treated as unavailable. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -15.069 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.71 | Ambiguous | 0.8 | 2.81 | Destabilizing | 2.26 | Destabilizing | 1.85 | Destabilizing | 0.862 | Likely Pathogenic | -5.81 | Deleterious | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.83 | Benign | 0.00 | Affected | 0.0750 | 0.0412 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.692T>G | F231C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231C is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -13.315 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.26 | Destabilizing | 0.3 | 2.82 | Destabilizing | 2.54 | Destabilizing | 2.04 | Destabilizing | 0.937 | Likely Pathogenic | -6.89 | Deleterious | 0.992 | Probably Damaging | 0.707 | Possibly Damaging | 5.49 | Benign | 0.00 | Affected | 0.2527 | 0.1612 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1361T>C | I454T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -9.045 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.20 | Destabilizing | 0.0 | 2.83 | Destabilizing | 3.02 | Destabilizing | 2.02 | Destabilizing | 0.502 | Likely Pathogenic | -4.74 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.0877 | 0.0708 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.1396T>C | S466P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S466P is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the only inconclusive result is from premPS (Uncertain). High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts Pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -13.107 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.67 | Destabilizing | 0.2 | 2.83 | Destabilizing | 2.75 | Destabilizing | 0.95 | Ambiguous | 0.811 | Likely Pathogenic | -3.02 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | -1.55 | Pathogenic | 0.04 | Affected | 0.1617 | 0.4915 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.844T>G | C282G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The high‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; SGM‑Consensus is pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among pathogenic predictors and the high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | -15.830 | Likely Pathogenic | 0.837 | Likely Pathogenic | Ambiguous | 2.60 | Destabilizing | 0.1 | 2.83 | Destabilizing | 2.72 | Destabilizing | 1.60 | Destabilizing | 0.482 | Likely Benign | -11.03 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.64 | Pathogenic | 0.04 | Affected | 0.3229 | 0.2238 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.2000T>A | I667N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I667N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.083597 | Uncertain | 0.927 | 0.379 | 0.000 | -15.730 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 2.89 | Destabilizing | 0.2 | 2.84 | Destabilizing | 2.87 | Destabilizing | 2.56 | Destabilizing | 0.572 | Likely Pathogenic | -6.73 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.95 | Benign | 0.00 | Affected | 0.0841 | 0.0470 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.656G>A | C219Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219Y is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized returns a pathogenic prediction; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Based on the preponderance of evidence, the variant is most likely pathogenic, a conclusion that does not contradict its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | Uncertain | 1 | -14.797 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 8.98 | Destabilizing | 2.0 | 2.84 | Destabilizing | 5.91 | Destabilizing | 0.55 | Ambiguous | 0.812 | Likely Pathogenic | -9.09 | Deleterious | 0.990 | Probably Damaging | 0.758 | Possibly Damaging | 5.81 | Benign | 0.00 | Affected | 0.0772 | 0.3285 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||
| c.1087T>A | Y363N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y363N is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify Y363N 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 (majority vote) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.435392 | Uncertain | 0.954 | 0.586 | 0.125 | -12.121 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 2.06 | Destabilizing | 0.1 | 2.85 | Destabilizing | 2.46 | Destabilizing | 1.45 | Destabilizing | 0.477 | Likely Benign | -8.04 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.55 | Pathogenic | 0.01 | Affected | 0.3117 | 0.2021 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1516C>A | L506I 2D  AIThe SynGAP1 missense variant L506I is not reported in ClinVar and is absent from gnomAD. Consensus from standard in‑silico predictors shows a split: benign calls come from REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Uncertain results are reported by FoldX, premPS, and AlphaMissense‑Default. High‑accuracy assessments give a pathogenic verdict from Foldetta (a combined FoldX‑MD/Rosetta stability analysis) and from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). AlphaMissense‑Optimized, however, predicts benign. Overall, the majority of reliable tools and the high‑accuracy methods favor a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | -10.386 | Likely Pathogenic | 0.501 | Ambiguous | Likely Benign | 1.73 | Ambiguous | 1.0 | 2.85 | Destabilizing | 2.29 | Destabilizing | 0.98 | Ambiguous | 0.365 | Likely Benign | -1.99 | Neutral | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 1.65 | Pathogenic | 0.01 | Affected | 0.0745 | 0.2033 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.2051A>C | D684A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: pathogenic calls are made by REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while only premPS and FATHMM predict a benign outcome. High‑accuracy assessments reinforce the pathogenic interpretation: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No evidence is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -14.873 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.34 | Destabilizing | 1.1 | 2.85 | Destabilizing | 3.10 | Destabilizing | 0.28 | Likely Benign | 0.547 | Likely Pathogenic | -7.98 | Deleterious | 0.994 | Probably Damaging | 0.758 | Possibly Damaging | 3.42 | Benign | 0.01 | Affected | 0.3477 | 0.5423 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.835C>G | R279G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote) which labels it “Likely Pathogenic.” AlphaMissense‑Optimized is uncertain, providing no definitive evidence. High‑accuracy assessments further support pathogenicity: the SGM‑Consensus remains “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the overwhelming majority of predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | -9.941 | Likely Pathogenic | 0.920 | Likely Pathogenic | Ambiguous | 3.10 | Destabilizing | 0.7 | 2.85 | Destabilizing | 2.98 | Destabilizing | 1.11 | Destabilizing | 0.442 | Likely Benign | -5.37 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.92 | Pathogenic | 0.02 | Affected | 0.2961 | 0.2209 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1306G>A | E436K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E436K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining evaluated algorithms (REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) uniformly predict a pathogenic impact; FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E436K, which does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | Uncertain | 1 | -13.869 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.56 | Ambiguous | 0.1 | 2.86 | Destabilizing | 1.71 | Ambiguous | 0.82 | Ambiguous | 0.829 | Likely Pathogenic | -3.77 | Deleterious | 0.994 | Probably Damaging | 0.951 | Probably Damaging | 4.71 | Benign | 0.02 | Affected | 3.37 | 29 | 0.2332 | 0.5995 | 0 | 1 | -0.4 | -0.94 | 186.8 | 39.8 | 0.0 | 0.0 | -0.2 | 0.0 | X | X | X | Potentially Pathogenic | The carboxylate group of Glu436, located on the α helix (res. Met414-Glu436), forms a salt bridge with the amino group of the Lys444 side chain on an opposing α helix (res. Val441-Ser457). The backbone carbonyl of Glu436 also H-bonds with the Lys444 side chain, which helps keep the ends of the two α helices tightly connected. In contrast, in the variant simulations, the salt bridge formation with Lys444 is not possible. Instead, the repelled Lys436 side chain rotates outward, causing a change in the α helix backbone H-bonding: the amide group of Lys444 H-bonds with the carbonyl of Ala433 instead of the carbonyl of Cys432. | ||||||||||||||
| c.1415A>G | E472G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472G is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic or likely pathogenic. Only premPS predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -15.239 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.06 | Destabilizing | 0.2 | 2.86 | Destabilizing | 2.96 | Destabilizing | 0.24 | Likely Benign | 0.744 | Likely Pathogenic | -6.83 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.30 | Pathogenic | 0.00 | Affected | 0.3343 | 0.4950 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1493T>A | M498K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498K is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign calls come only from polyPhen‑2 HumDiv and HumVar, whereas the remaining 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict pathogenicity. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a destabilizing, pathogenic effect. Taken together, the overwhelming majority of evidence indicates that M498K is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -11.622 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 2.82 | Destabilizing | 0.1 | 2.86 | Destabilizing | 2.84 | Destabilizing | 1.79 | Destabilizing | 0.867 | Likely Pathogenic | -4.53 | Deleterious | 0.287 | Benign | 0.120 | Benign | -1.37 | Pathogenic | 0.00 | Affected | 0.1281 | 0.0656 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.1025A>C | Y342S 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant Y342S is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of algorithms predict a pathogenic impact: FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and the Foldetta stability assessment (combining FoldX‑MD and Rosetta). Uncertain results come from premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy methods specifically give AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as pathogenic. Overall, the preponderance of evidence points to a pathogenic effect, which contradicts the ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.366687 | Structured | 0.408200 | Uncertain | 0.866 | 0.487 | 0.250 | Uncertain | 2 | -7.996 | In-Between | 0.925 | Likely Pathogenic | Ambiguous | 3.03 | Destabilizing | 0.1 | 2.87 | Destabilizing | 2.95 | Destabilizing | 0.93 | Ambiguous | 0.407 | Likely Benign | -6.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.75 | Pathogenic | 0.04 | Affected | 3.37 | 25 | 0.4617 | 0.2637 | -3 | -2 | 0.5 | -76.10 | 200.1 | 77.8 | 0.0 | 0.0 | -0.2 | 0.1 | Potentially Pathogenic | The phenol ring of Tyr342, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), faces outward in the C2 domain. In the WT simulations, the phenol ring of Tyr342 contributes to a triple tyrosine stack (Tyr342, Tyr328, and Tyr281) that links together three anti-parallel β sheet strands. Additionally, it shields Gly344 from the solvent, reducing its exposure and providing stability for the β-sandwich. This motif also contributes to a twist formation in the β sheet.In the variant simulations, the Ser342 side chain cannot participate in the stack formation. Instead, the hydroxyl group of the Ser342 side chain forms a hydrogen bond with the imidazole ring of His326 in a neighboring β strand (res. Ala322-Asp330). This disrupts the formation of a hydrogen bond between His326 and the carboxylate group of the Glu283 side chain from another β strand (res. Arg279-Cys285). Although these changes in surface interactions could weaken the characteristic twist that strengthens the β sheet fold, no major structural effects are observed in the variant simulations. The residue swap could also affect the SynGAP-membrane association, as the hydroxyl group of Ser342 could form hydrogen bonds with membrane-facing loop residues. However, this phenomenon cannot be addressed using solvent-only simulations. | |||||||||||||||||
| c.1114G>A | G372R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Default. Two tools, FoldX and ESM1b, returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta predicting pathogenic. Overall, the majority of predictions (seven pathogenic vs. five benign) and the consensus of high‑accuracy methods indicate a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -7.344 | In-Between | 0.617 | Likely Pathogenic | Likely Benign | 1.49 | Ambiguous | 0.3 | 2.87 | Destabilizing | 2.18 | Destabilizing | 0.20 | Likely Benign | 0.572 | Likely Pathogenic | -0.61 | Neutral | 0.001 | Benign | 0.001 | Benign | -0.74 | Pathogenic | 0.02 | Affected | 0.1323 | 0.4313 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1114G>C | G372R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Default. Two tools (FoldX and ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. Overall, the majority of predictions (seven pathogenic vs five benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -7.344 | In-Between | 0.617 | Likely Pathogenic | Likely Benign | 1.49 | Ambiguous | 0.3 | 2.87 | Destabilizing | 2.18 | Destabilizing | 0.20 | Likely Benign | 0.572 | Likely Pathogenic | -0.61 | Neutral | 0.001 | Benign | 0.001 | Benign | -0.74 | Pathogenic | 0.02 | Affected | 0.1323 | 0.4313 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1216T>A | Y406N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y406N is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also indicates pathogenicity. Taken together, the preponderance of evidence points to a pathogenic effect for Y406N, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -13.206 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 2.90 | Destabilizing | 0.1 | 2.88 | Destabilizing | 2.89 | Destabilizing | 1.58 | Destabilizing | 0.288 | Likely Benign | -7.11 | Deleterious | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 3.78 | Benign | 0.02 | Affected | 0.2532 | 0.1071 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1513T>C | Y505H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505H is listed in ClinVar as Pathogenic (ClinVar ID 3064218.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. High‑accuracy consensus methods reinforce this view: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also Pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among predictive tools, the variant is most likely pathogenic, consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | Likely Pathogenic | 1 | -11.383 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 2.91 | Destabilizing | 0.1 | 2.88 | Destabilizing | 2.90 | Destabilizing | 1.60 | Destabilizing | 0.646 | Likely Pathogenic | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.64 | Benign | 0.00 | Affected | 3.37 | 35 | 0.2148 | 0.0612 | 2 | 0 | -1.9 | -26.03 | |||||||||||||||||||||||||
| c.1024T>A | Y342N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y342N has no ClinVar entry (ClinVar status: None) and is not reported in gnomAD (gnomAD ID: None). Prediction tools that assess the variant’s effect are overwhelmingly in agreement that it is deleterious: SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Taken together, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.366687 | Structured | 0.408200 | Uncertain | 0.866 | 0.487 | 0.250 | -9.685 | Likely Pathogenic | 0.940 | Likely Pathogenic | Ambiguous | 1.76 | Ambiguous | 0.1 | 2.89 | Destabilizing | 2.33 | Destabilizing | 1.02 | Destabilizing | 0.554 | Likely Pathogenic | -6.65 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.71 | Pathogenic | 0.03 | Affected | 0.2189 | 0.0862 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1390T>G | F464V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F464V variant is listed in ClinVar with an “Uncertain” status (ClinVar ID 1716596.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective predictions, the variant is most likely pathogenic, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | Uncertain | 1 | -12.254 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.61 | Destabilizing | 0.1 | 2.89 | Destabilizing | 3.25 | Destabilizing | 1.40 | Destabilizing | 0.592 | Likely Pathogenic | -6.96 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 3.36 | Benign | 0.04 | Affected | 3.37 | 34 | 0.1587 | 0.2219 | -1 | -1 | 1.4 | -48.04 | 210.1 | 40.5 | -0.1 | 0.0 | -0.9 | 0.3 | X | Potentially Pathogenic | The phenyl ring of Phe464, located in the middle of an α helix (res. Ala461–Phe476), packs against hydrophobic residues (e.g., Met468, Leu451, Leu455, and Tyr428) in the inter-helix space formed with two other α helices (res. Asn440-Lys460 and res. Pro413-Glu436). The iso-propyl side chain of Val464 is similarly hydrophobic but considerably smaller than the original phenyl ring of Phe464. To compensate for the size difference, neighboring residues need to fill in the gap in the variant simulations.The phenolic side chain of Tyr428, located at the middle bend of an α helix (res. Glu436-Pro413), assumes a new position in the inter-helix space or rotates inward next to the third α helix (res. Asn440-Lys460) when the stable H-bond between Tyr428 and Asp467 seen in the WT simulations breaks. The residue swap also leads to the loss of the methionine-aromatic interaction between the Met468 and Phe464 side chains, which could weaken the integrity of the parent α helix (res. Ala461-Phe476). Although the simulations likely underestimate the full adverse effect of the introduced mutation during folding, the two opposing α helices (res. Ala461–Phe476 and res. Glu436-Pro413) move substantially closer to each other in the variant simulations. | ||||||||||||||||
| c.988G>T | D330Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D330Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and premPS, whereas the remaining tools—including SGM‑Consensus, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; FoldX is uncertain and therefore not counted. High‑accuracy methods all support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is pathogenic. Taken together, the overwhelming majority of evidence indicates that D330Y is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -14.200 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 1.98 | Ambiguous | 0.6 | 2.90 | Destabilizing | 2.44 | Destabilizing | 0.35 | Likely Benign | 0.472 | Likely Benign | -6.47 | Deleterious | 0.998 | Probably Damaging | 0.948 | Probably Damaging | 0.89 | Pathogenic | 0.00 | Affected | 0.0539 | 0.4689 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1115G>A | G372E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are REVEL, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while Foldetta predicts pathogenic. The SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split and is treated as unavailable. Overall, the majority of evidence (seven benign vs. five pathogenic) supports a benign classification. This conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -6.682 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 1.58 | Ambiguous | 0.4 | 2.91 | Destabilizing | 2.25 | Destabilizing | 0.34 | Likely Benign | 0.566 | Likely Pathogenic | -0.81 | Neutral | 0.001 | Benign | 0.001 | Benign | -0.74 | Pathogenic | 0.08 | Tolerated | 0.1606 | 0.4103 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.1115G>T | G372V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372V is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (variant ID 6-33438020-G-T). Functional prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are REVEL, FoldX, Rosetta, FATHMM, and Foldetta. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, while Foldetta (combining FoldX‑MD and Rosetta stability outputs) indicates a pathogenic effect. Overall, the majority of predictions support a benign classification, and there is no conflict with ClinVar status because the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | 6-33438020-G-T | -5.898 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 2.81 | Destabilizing | 0.3 | 2.91 | Destabilizing | 2.86 | Destabilizing | 0.02 | Likely Benign | 0.535 | Likely Pathogenic | -0.92 | Neutral | 0.003 | Benign | 0.000 | Benign | -0.74 | Pathogenic | 0.06 | Tolerated | 3.52 | 18 | 0.1663 | 0.4198 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||
| c.2074C>G | L692V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. All other evaluated tools—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized indicates benign, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as pathogenic, and Foldetta also predicts pathogenic. No predictions are missing or inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | -11.441 | Likely Pathogenic | 0.733 | Likely Pathogenic | Likely Benign | 3.29 | Destabilizing | 0.1 | 2.91 | Destabilizing | 3.10 | Destabilizing | 1.57 | Destabilizing | 0.286 | Likely Benign | -2.99 | Deleterious | 0.978 | Probably Damaging | 0.606 | Possibly Damaging | 3.12 | Benign | 0.01 | Affected | 0.1395 | 0.2460 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.845G>A | C282Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282Y resides in the C2 domain. ClinVar has no entry for this variant, and it is not listed in gnomAD. Prediction tools that indicate a benign effect are REVEL and premPS. All other evaluated algorithms—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | -13.438 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 8.50 | Destabilizing | 1.1 | 2.91 | Destabilizing | 5.71 | Destabilizing | 0.41 | Likely Benign | 0.419 | Likely Benign | -10.11 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.63 | Pathogenic | 0.00 | Affected | 0.1069 | 0.3089 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.934T>C | F312L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” The only tool with an inconclusive result is FoldX, which is listed as “Uncertain.” No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -9.891 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.16 | Ambiguous | 0.3 | 2.91 | Destabilizing | 2.04 | Destabilizing | 1.27 | Destabilizing | 0.852 | Likely Pathogenic | -5.52 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.32 | Pathogenic | 0.05 | Affected | 0.2149 | 0.3813 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.936C>A | F312L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” The only tool with an inconclusive result is FoldX, which is listed as “Uncertain.” No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -9.891 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.16 | Ambiguous | 0.3 | 2.91 | Destabilizing | 2.04 | Destabilizing | 1.27 | Destabilizing | 0.615 | Likely Pathogenic | -5.52 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.32 | Pathogenic | 0.05 | Affected | 0.2149 | 0.3813 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.936C>G | F312L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” The only tool with an inconclusive result is FoldX, which is listed as “Uncertain.” No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -9.891 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.16 | Ambiguous | 0.3 | 2.91 | Destabilizing | 2.04 | Destabilizing | 1.27 | Destabilizing | 0.615 | Likely Pathogenic | -5.52 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.32 | Pathogenic | 0.05 | Affected | 0.2149 | 0.3813 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1135T>C | S379P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, Rosetta, and Foldetta; FoldX is uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the majority of evidence—including the high‑accuracy benign predictions—suggests that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.433206 | Uncertain | 0.327 | 0.931 | 0.625 | -5.007 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 1.10 | Ambiguous | 0.8 | 2.92 | Destabilizing | 2.01 | Destabilizing | 0.17 | Likely Benign | 0.430 | Likely Benign | -0.41 | Neutral | 0.808 | Possibly Damaging | 0.212 | Benign | 3.83 | Benign | 0.10 | Tolerated | 0.3035 | 0.6594 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.717A>C | R239S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 R239S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -13.418 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.67 | Destabilizing | 0.1 | 2.94 | Destabilizing | 3.31 | Destabilizing | 1.26 | Destabilizing | 0.813 | Likely Pathogenic | -5.31 | Deleterious | 0.900 | Possibly Damaging | 0.376 | Benign | 5.64 | Benign | 0.02 | Affected | 0.3160 | 0.3788 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||
| c.717A>T | R239S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -13.418 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.67 | Destabilizing | 0.1 | 2.94 | Destabilizing | 3.31 | Destabilizing | 1.26 | Destabilizing | 0.813 | Likely Pathogenic | -5.31 | Deleterious | 0.900 | Possibly Damaging | 0.376 | Benign | 5.64 | Benign | 0.02 | Affected | 0.3160 | 0.3788 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||
| c.2050G>C | D684H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684H is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are inconclusive or missing. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | Uncertain | 1 | -14.194 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.36 | Destabilizing | 1.0 | 2.95 | Destabilizing | 3.16 | Destabilizing | 0.55 | Ambiguous | 0.613 | Likely Pathogenic | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.972 | Probably Damaging | 3.36 | Benign | 0.00 | Affected | 3.42 | 17 | 0.1344 | 0.6618 | -1 | 1 | 0.3 | 22.05 | |||||||||||||||||||||||||
| c.2054T>C | L685S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any existing 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 | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -12.303 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.08 | Destabilizing | 0.2 | 2.95 | Destabilizing | 3.02 | Destabilizing | 1.24 | Destabilizing | 0.520 | Likely Pathogenic | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.27 | Benign | 0.01 | Affected | 0.2844 | 0.0505 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||
| c.638T>G | I213S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -12.858 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.00 | Destabilizing | 1.1 | 2.95 | Destabilizing | 2.48 | Destabilizing | 1.53 | Destabilizing | 0.879 | Likely Pathogenic | -4.88 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.83 | Benign | 0.00 | Affected | 0.2290 | 0.0800 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1360A>T | I454F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. All other evaluated algorithms—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. premPS is uncertain and does not influence the overall assessment. Based on the preponderance of pathogenic predictions and the absence of benign evidence, the variant is most likely pathogenic, with no ClinVar status to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -12.468 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 4.15 | Destabilizing | 0.7 | 2.96 | Destabilizing | 3.56 | Destabilizing | 0.70 | Ambiguous | 0.464 | Likely Benign | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.973 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 0.0422 | 0.2560 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1874T>A | L625H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L625H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | -14.264 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.85 | Destabilizing | 0.3 | 2.96 | Destabilizing | 2.91 | Destabilizing | 2.02 | Destabilizing | 0.738 | Likely Pathogenic | -6.87 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | 0.0954 | 0.0541 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.782A>G | D261G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261G is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include premPS and FATHMM, while the remaining tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Based on the aggregate predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.284882 | Structured | 0.422514 | Uncertain | 0.883 | 0.264 | 0.125 | -10.847 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 2.81 | Destabilizing | 0.5 | 2.96 | Destabilizing | 2.89 | Destabilizing | 0.21 | Likely Benign | 0.850 | Likely Pathogenic | -4.77 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 5.81 | Benign | 0.02 | Affected | 0.2924 | 0.4562 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1898T>A | L633Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L633Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.045407 | Uncertain | 0.952 | 0.252 | 0.000 | -14.303 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 2.98 | Destabilizing | 0.1 | 2.97 | Destabilizing | 2.98 | Destabilizing | 2.23 | Destabilizing | 0.712 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.69 | Benign | 0.00 | Affected | 0.1333 | 0.0876 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.811G>C | A271P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (integrating FoldX‑MD and Rosetta outputs) also reports a pathogenic effect. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.413873 | Uncertain | 0.939 | 0.220 | 0.125 | -14.699 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.06 | Destabilizing | 0.2 | 2.97 | Destabilizing | 3.52 | Destabilizing | 1.15 | Destabilizing | 0.680 | Likely Pathogenic | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.62 | Pathogenic | 0.01 | Affected | 0.1705 | 0.3267 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.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.665T>C | V222A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V222A missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -10.248 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.89 | Destabilizing | 0.3 | 2.98 | Destabilizing | 2.94 | Destabilizing | 2.06 | Destabilizing | 0.894 | Likely Pathogenic | -3.50 | Deleterious | 0.984 | Probably Damaging | 0.956 | Probably Damaging | 5.26 | Benign | 0.04 | Affected | 0.2386 | 0.2081 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1079A>G | E360G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360G is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: premPS is the only tool that predicts a benign outcome, whereas all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized returns a pathogenic prediction; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic effect. Taken together, the overwhelming majority of evidence points to a pathogenic impact for E360G, and this conclusion is consistent with the absence of a ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.421183 | Uncertain | 0.955 | 0.498 | 0.250 | -13.972 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 2.55 | Destabilizing | 0.1 | 2.99 | Destabilizing | 2.77 | Destabilizing | 0.31 | Likely Benign | 0.569 | Likely Pathogenic | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.986 | Probably Damaging | 1.68 | Pathogenic | 0.04 | Affected | 0.2993 | 0.6935 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1283A>G | Y428C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y428C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are REVEL and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus—consistently predict a pathogenic impact. High‑accuracy assessments show the SGM‑Consensus result as “Likely Pathogenic,” Foldetta predicts a destabilizing, pathogenic effect, while AlphaMissense‑Optimized is uncertain. No prediction or stability result is missing; the only inconclusive outcome is the AlphaMissense‑Optimized score. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | -11.312 | Likely Pathogenic | 0.852 | Likely Pathogenic | Ambiguous | 2.82 | Destabilizing | 0.0 | 2.99 | Destabilizing | 2.91 | Destabilizing | 2.02 | Destabilizing | 0.454 | Likely Benign | -8.59 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.3322 | 0.2220 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.1639T>G | C547G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict pathogenic. No tool predicts a benign outcome. AlphaMissense‑Optimized is uncertain, providing no definitive direction. High‑accuracy assessments further support a harmful impact: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a pathogenic effect. Taken together, the evidence overwhelmingly points to a pathogenic classification for this variant, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | -14.182 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | 2.21 | Destabilizing | 0.0 | 2.99 | Destabilizing | 2.60 | Destabilizing | 1.83 | Destabilizing | 0.902 | Likely Pathogenic | -11.60 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.30 | Pathogenic | 0.05 | Affected | 0.3201 | 0.2502 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.1145G>C | G382A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G382A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the majority of predictions lean toward a benign effect, and this consensus does not contradict any ClinVar status (none available). Thus, based on the available computational evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.429690 | Uncertain | 0.315 | 0.951 | 0.750 | -6.323 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 2.90 | Destabilizing | 0.6 | 3.00 | Destabilizing | 2.95 | Destabilizing | -0.03 | Likely Benign | 0.495 | Likely Benign | -0.59 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 1.33 | Pathogenic | 0.12 | Tolerated | 0.4048 | 0.4576 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1529T>A | I510N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510N is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic impact. Based on the uniform predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -12.784 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 3.09 | Destabilizing | 0.1 | 3.00 | Destabilizing | 3.05 | Destabilizing | 2.08 | Destabilizing | 0.925 | Likely Pathogenic | -5.62 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.45 | Pathogenic | 0.00 | Affected | 0.0761 | 0.0270 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.653T>C | F218S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218S has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar, SIFT, and FATHMM, whereas the remaining tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -8.882 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.35 | Destabilizing | 0.1 | 3.00 | Destabilizing | 2.68 | Destabilizing | 1.22 | Destabilizing | 0.731 | Likely Pathogenic | -4.62 | Deleterious | 0.808 | Possibly Damaging | 0.225 | Benign | 5.80 | Benign | 0.07 | Tolerated | 0.3802 | 0.0454 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.917T>C | V306A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas the remaining tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome; ESM1b is uncertain and therefore not counted. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and a pathogenic prediction from Foldetta. Taken together, the preponderance of evidence indicates that V306A is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.363090 | Structured | 0.315026 | Uncertain | 0.896 | 0.287 | 0.125 | -7.924 | In-Between | 0.599 | Likely Pathogenic | Likely Benign | 2.76 | Destabilizing | 0.1 | 3.00 | Destabilizing | 2.88 | Destabilizing | 2.25 | Destabilizing | 0.300 | Likely Benign | -2.94 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.77 | Pathogenic | 0.05 | Affected | 0.2687 | 0.1989 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.896G>C | R299P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299P is not reported in ClinVar or gnomAD, indicating no publicly available frequency data. Prediction tools cluster into benign and pathogenic groups: benign predictions include REVEL and AlphaMissense‑Optimized, while pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, SIFT, FATHMM, and AlphaMissense‑Default; ESM1b is uncertain. The SGM‑Consensus label is Likely Pathogenic. High‑accuracy tools give a clear signal: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta also predicts pathogenic. Overall, the predictions strongly favor a pathogenic interpretation, with no ClinVar status to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | -7.662 | In-Between | 0.722 | Likely Pathogenic | Likely Benign | 4.10 | Destabilizing | 0.2 | 3.01 | Destabilizing | 3.56 | Destabilizing | 1.19 | Destabilizing | 0.295 | Likely Benign | -4.09 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.68 | Pathogenic | 0.02 | Affected | 0.2072 | 0.5379 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.2069C>A | S690Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus confirms a Likely Pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Based on the preponderance of pathogenic predictions and the absence of benign consensus, the variant is most likely pathogenic, with no contradiction to 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 | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | -14.051 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 11.45 | Destabilizing | 3.1 | 3.02 | Destabilizing | 7.24 | Destabilizing | 0.16 | Likely Benign | 0.381 | Likely Benign | -5.76 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.39 | Benign | 0.00 | Affected | 0.0512 | 0.4643 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.842A>C | Y281S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools cluster into two groups: the single benign prediction comes from SIFT, while the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict pathogenicity. High‑accuracy assessments further support a deleterious effect: 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 Pathogenic. With the overwhelming majority of evidence indicating pathogenicity and no ClinVar annotation to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.337647 | Uncertain | 0.927 | 0.254 | 0.000 | -9.541 | Likely Pathogenic | 0.847 | Likely Pathogenic | Ambiguous | 3.24 | Destabilizing | 0.3 | 3.02 | Destabilizing | 3.13 | Destabilizing | 1.59 | Destabilizing | 0.642 | Likely Pathogenic | -5.68 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.02 | Pathogenic | 0.12 | Tolerated | 0.4203 | 0.2543 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.1087T>G | Y363D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y363D 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 none; all evaluated algorithms predict a deleterious impact. Pathogenic predictions come from SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions or stability results are missing or inconclusive. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.435392 | Uncertain | 0.954 | 0.586 | 0.125 | -13.840 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.86 | Destabilizing | 0.2 | 3.03 | Destabilizing | 2.95 | Destabilizing | 1.73 | Destabilizing | 0.635 | Likely Pathogenic | -8.94 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.54 | Pathogenic | 0.00 | Affected | 0.4720 | 0.1853 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1211C>A | A404E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -13.639 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.16 | Destabilizing | 0.1 | 3.04 | Destabilizing | 2.60 | Destabilizing | 1.51 | Destabilizing | 0.163 | Likely Benign | -2.77 | Deleterious | 0.179 | Benign | 0.033 | Benign | 4.02 | Benign | 0.02 | Affected | 0.1423 | 0.2383 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||
| c.1823T>G | F608C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608C is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classifies the change as pathogenic; no tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic effect. Because all evidence points to a deleterious impact and there is no ClinVar entry to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -14.409 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 2.46 | Destabilizing | 0.2 | 3.04 | Destabilizing | 2.75 | Destabilizing | 1.77 | Destabilizing | 0.920 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.67 | Pathogenic | 0.00 | Affected | 0.2738 | 0.1050 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1937T>A | L646Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L646Q lies in the GAP domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect are REVEL, FATHMM, and AlphaMissense‑Optimized. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Taken together, the overwhelming majority of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -12.735 | Likely Pathogenic | 0.752 | Likely Pathogenic | Likely Benign | 3.23 | Destabilizing | 0.1 | 3.04 | Destabilizing | 3.14 | Destabilizing | 2.12 | Destabilizing | 0.462 | Likely Benign | -2.78 | Deleterious | 0.994 | Probably Damaging | 0.790 | Possibly Damaging | 3.17 | Benign | 0.00 | Affected | 0.2090 | 0.1963 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.629A>G | H210R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 H210R missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and FoldX, whereas a majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The high‑accuracy AlphaMissense‑Optimized result is pathogenic; the SGM Consensus, based on the same set of predictors, is also pathogenic; Foldetta’s stability assessment is uncertain and therefore not considered evidence. Overall, the balance of evidence points to a pathogenic effect for H210R. This prediction does not contradict the ClinVar “Uncertain” classification, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | Uncertain | 1 | -14.254 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.4 | 3.05 | Destabilizing | 1.73 | Ambiguous | 1.12 | Destabilizing | 0.431 | Likely Benign | -6.74 | Deleterious | 0.808 | Possibly Damaging | 0.452 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.1427 | 0.1982 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||
| c.1793T>G | L598R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L598R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.007259 | Structured | 0.147872 | Uncertain | 0.953 | 0.154 | 0.000 | -17.392 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.70 | Destabilizing | 0.5 | 3.06 | Destabilizing | 2.88 | Destabilizing | 2.23 | Destabilizing | 0.682 | Likely Pathogenic | -5.87 | Deleterious | 0.999 | Probably Damaging | 0.973 | Probably Damaging | 3.10 | Benign | 0.00 | Affected | 0.1297 | 0.0679 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1835A>C | Q612P 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q612P is listed in ClinVar (ID 3660462.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, PolyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, PROVEAN, and the SGM Consensus score (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The high‑accuracy AlphaMissense‑Optimized predicts benign, whereas the SGM Consensus predicts likely pathogenic; Foldetta, a folding‑stability method combining FoldX‑MD and Rosetta outputs, returns an uncertain result and is therefore not factored into the consensus. Overall, the majority of evidence supports a pathogenic effect, which contrasts with the ClinVar uncertain classification. Thus, based on current predictions, the variant is most likely pathogenic, contradicting the ClinVar status. 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 | Uncertain | 1 | -9.684 | Likely Pathogenic | 0.673 | Likely Pathogenic | Likely Benign | -0.19 | Likely Benign | 0.3 | 3.06 | Destabilizing | 1.44 | Ambiguous | 0.56 | Ambiguous | 0.671 | Likely Pathogenic | -5.84 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.31 | Pathogenic | 0.19 | Tolerated | 0.2252 | 0.4050 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||
| c.2044T>G | Y682D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y682D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic effect. With no ClinVar assertion to oppose these findings, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -15.094 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 2.81 | Destabilizing | 0.4 | 3.06 | Destabilizing | 2.94 | Destabilizing | 0.96 | Ambiguous | 0.639 | Likely Pathogenic | -9.60 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.32 | Benign | 0.01 | Affected | 0.4191 | 0.0760 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.851T>A | L284H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L284H is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a pathogenic impact. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.094817 | Structured | 0.371601 | Uncertain | 0.950 | 0.255 | 0.000 | -16.581 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.26 | Destabilizing | 0.1 | 3.06 | Destabilizing | 3.16 | Destabilizing | 2.57 | Destabilizing | 0.772 | Likely Pathogenic | -6.22 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.65 | Pathogenic | 0.00 | Affected | 0.0954 | 0.0726 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.1163G>A | G388D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G388D is reported in gnomAD (variant ID 6-33438068‑G‑A) but has no entry in ClinVar. Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, and AlphaMissense‑Optimized; pathogenic predictions arise from SGM‑Consensus, REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments reinforce this split: AlphaMissense‑Optimized indicates 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, integrating FoldX‑MD and Rosetta outputs, also predicts a pathogenic impact on protein stability. Taken together, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic effect for G388D, 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 | 0.736850 | Disordered | 0.420316 | Uncertain | 0.319 | 0.827 | 0.750 | 6-33438068-G-A | -8.416 | Likely Pathogenic | 0.574 | Likely Pathogenic | Likely Benign | 5.56 | Destabilizing | 7.3 | 3.08 | Destabilizing | 4.32 | Destabilizing | 0.42 | Likely Benign | 0.618 | Likely Pathogenic | -0.67 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 1.32 | Pathogenic | 0.04 | Affected | 4.32 | 3 | 0.1923 | 0.1624 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||
| c.1607T>C | L536S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L536S is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. The only inconclusive result is from FoldX, which is listed as uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | -12.996 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 1.45 | Ambiguous | 0.3 | 3.08 | Destabilizing | 2.27 | Destabilizing | 1.51 | Destabilizing | 0.909 | Likely Pathogenic | -5.78 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.47 | Pathogenic | 0.00 | Affected | 0.2849 | 0.0577 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||
| c.1916T>C | F639S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F639S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -11.511 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 4.92 | Destabilizing | 0.3 | 3.08 | Destabilizing | 4.00 | Destabilizing | 1.87 | Destabilizing | 0.561 | Likely Pathogenic | -7.97 | Deleterious | 0.965 | Probably Damaging | 0.457 | Possibly Damaging | 3.12 | Benign | 0.04 | Affected | 0.3813 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1426T>A | F476I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F476I has no ClinVar entry and is not reported in gnomAD. Functional prediction tools fall into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, and FATHMM; pathogenic predictions come from FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—remains inconclusive and is treated as unavailable. With seven tools indicating pathogenicity versus five indicating benign, and two high‑accuracy tools supporting pathogenicity, the evidence points to a likely pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no record for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -12.617 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 3.90 | Destabilizing | 0.1 | 3.09 | Destabilizing | 3.50 | Destabilizing | 0.39 | Likely Benign | 0.239 | Likely Benign | -1.23 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 3.50 | Benign | 0.37 | Tolerated | 0.1383 | 0.2202 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||
| c.1526C>A | A509D 2D AIThe SynGAP1 missense variant A509D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Pathogenic” verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a pathogenic effect. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -17.026 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 4.02 | Destabilizing | 1.6 | 3.09 | Destabilizing | 3.56 | Destabilizing | 1.36 | Destabilizing | 0.915 | Likely Pathogenic | -4.94 | Deleterious | 0.963 | Probably Damaging | 0.844 | Possibly Damaging | -1.40 | Pathogenic | 0.00 | Affected | 0.1610 | 0.1360 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1096A>C | T366P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366P is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors leans toward a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign) all classify the substitution as tolerated. In contrast, polyPhen‑2 HumDiv, FATHMM, Rosetta, and the Foldetta stability analysis predict a damaging or pathogenic outcome. FoldX reports an uncertain effect and is therefore not considered evidence. High‑accuracy tools give mixed results: AlphaMissense‑Optimized and the SGM‑Consensus both indicate benign, whereas Foldetta predicts pathogenic. Overall, the majority of predictors (8 benign vs. 4 pathogenic) support a benign classification, and this is consistent with the lack of ClinVar evidence. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | -6.483 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 1.75 | Ambiguous | 0.5 | 3.10 | Destabilizing | 2.43 | Destabilizing | 0.47 | Likely Benign | 0.150 | Likely Benign | -2.49 | Neutral | 0.627 | Possibly Damaging | 0.139 | Benign | 1.70 | Pathogenic | 0.24 | Tolerated | 0.2250 | 0.6251 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1403T>C | M468T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468T is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database. Prediction tools that are available all converge on a pathogenic interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool reports a benign outcome. High‑accuracy assessments are consistent: AlphaMissense‑Optimized is “Uncertain,” SGM Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. **Based on the aggregate predictions, the variant is most likely pathogenic, which does not contradict the ClinVar “Uncertain” classification.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | Uncertain | 2 | 6-33438435-T-C | 1 | 6.20e-7 | -12.399 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 3.47 | Destabilizing | 0.1 | 3.10 | Destabilizing | 3.29 | Destabilizing | 1.84 | Destabilizing | 0.801 | Likely Pathogenic | -3.85 | Deleterious | 0.994 | Probably Damaging | 0.985 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 3.37 | 31 | 0.2094 | 0.1950 | -1 | -1 | -2.6 | -30.09 | 214.6 | 47.1 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | The thioether group of Met468, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Phe464, Leu465, Leu489) in an inter-helix space formed by two other α helices (res. Ala461–Phe476, res. Thr488–Gly502). In the variant simulations, the hydrophilic side chain of Thr468 does not pack favorably in the hydrophobic niche, and the methionine-aromatic stacking is lost. Although the hydroxyl group of Thr468 forms an H-bond with the backbone carbonyl group of Phe464, the integrity of the α helix is not affected in the simulations. No large-scale structural changes are observed during the variant simulations; however, due to the importance of hydrophobic packing, the effects could be more pronounced during protein folding. | |||||||||||||
| c.934T>A | F312I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312I is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect, so the benign group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -12.000 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.09 | Destabilizing | 0.3 | 3.10 | Destabilizing | 2.60 | Destabilizing | 1.72 | Destabilizing | 0.872 | Likely Pathogenic | -5.52 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.23 | Pathogenic | 0.01 | Affected | 0.1997 | 0.2842 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1199T>C | V400A 2D 3DClick to see structure in 3D Viewer AISynGAP1 V400A is not reported in ClinVar and is absent from gnomAD. Consensus from standard predictors shows a split: benign calls from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls come from FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT and AlphaMissense‑Default. Two high‑accuracy tools give a clear signal: AlphaMissense‑Optimized is uncertain, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta also predicts pathogenic. With most evidence pointing to deleterious effects, the variant is most likely pathogenic, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | -7.564 | In-Between | 0.871 | Likely Pathogenic | Ambiguous | 3.14 | Destabilizing | 0.1 | 3.12 | Destabilizing | 3.13 | Destabilizing | 2.29 | Destabilizing | 0.479 | Likely Benign | -3.12 | Deleterious | 0.435 | Benign | 0.049 | Benign | 5.32 | Benign | 0.01 | Affected | 0.3291 | 0.2767 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||
| c.1043T>C | V348A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further highlight the discrepancy: AlphaMissense‑Optimized predicts a benign effect, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies the variant as pathogenic. Taken together, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict ClinVar status, which currently has no entry for V348A. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -9.993 | Likely Pathogenic | 0.767 | Likely Pathogenic | Likely Benign | 2.46 | Destabilizing | 0.1 | 3.13 | Destabilizing | 2.80 | Destabilizing | 2.23 | Destabilizing | 0.175 | Likely Benign | -3.42 | Deleterious | 0.622 | Possibly Damaging | 0.152 | Benign | 1.59 | Pathogenic | 0.14 | Tolerated | 0.3223 | 0.2437 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1766T>A | I589N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I589N is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. All available predictions are consistent and conclusive. Based on the unanimous computational evidence, 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 | GAP | 0.018415 | Structured | 0.084536 | Uncertain | 0.927 | 0.214 | 0.000 | -15.539 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.72 | Destabilizing | 0.2 | 3.13 | Destabilizing | 3.43 | Destabilizing | 2.69 | Destabilizing | 0.930 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.99 | Pathogenic | 0.00 | Affected | 0.0968 | 0.0742 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.821T>G | L274R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274R is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. All available predictions and stability analyses are concordant and indicate a likely pathogenic impact. Thus, based on the current computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.066181 | Structured | 0.377483 | Uncertain | 0.866 | 0.195 | 0.250 | -17.691 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.61 | Destabilizing | 0.8 | 3.15 | Destabilizing | 3.38 | Destabilizing | 1.56 | Destabilizing | 0.807 | Likely Pathogenic | -5.45 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.00 | Pathogenic | 0.00 | Affected | 0.1404 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1124G>C | G375A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G375A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the majority of evidence points to a benign effect; this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | -5.986 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 2.52 | Destabilizing | 1.0 | 3.16 | Destabilizing | 2.84 | Destabilizing | -0.09 | Likely Benign | 0.419 | Likely Benign | -0.61 | Neutral | 0.020 | Benign | 0.008 | Benign | 1.33 | Pathogenic | 0.27 | Tolerated | 0.3991 | 0.5242 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1717C>G | R573G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R573G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while no tool predicts a benign outcome. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Based on the uniform predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar annotation exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.032433 | Uncertain | 0.934 | 0.235 | 0.000 | -15.387 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.71 | Destabilizing | 0.7 | 3.16 | Destabilizing | 3.44 | Destabilizing | 1.37 | Destabilizing | 0.744 | Likely Pathogenic | -6.01 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.45 | Pathogenic | 0.01 | Affected | 0.2931 | 0.2166 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1840T>A | Y614N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y614N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas the majority of other in silico predictors (Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact; FoldX is inconclusive and is 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, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Taken together, the preponderance of evidence points to a pathogenic effect for Y614N, 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 | 0.314870 | Structured | 0.182134 | Uncertain | 0.852 | 0.254 | 0.000 | -13.004 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 1.32 | Ambiguous | 0.5 | 3.16 | Destabilizing | 2.24 | Destabilizing | 1.58 | Destabilizing | 0.471 | Likely Benign | -8.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.42 | Benign | 0.06 | Tolerated | 0.1944 | 0.0573 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.2098C>G | L700V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L700V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, protein‑stability methods predict a deleterious impact: FoldX and Rosetta both score the variant as pathogenic, and the combined Foldetta analysis (FoldX‑MD + Rosetta) also reports a pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, while Foldetta remains pathogenic. Overall, the majority of predictions support a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.113710 | Structured | 0.416255 | Uncertain | 0.927 | 0.331 | 0.000 | -3.703 | Likely Benign | 0.192 | Likely Benign | Likely Benign | 2.52 | Destabilizing | 0.0 | 3.16 | Destabilizing | 2.84 | Destabilizing | 0.13 | Likely Benign | 0.056 | Likely Benign | 0.37 | Neutral | 0.003 | Benign | 0.005 | Benign | 3.46 | Benign | 0.76 | Tolerated | 0.1424 | 0.2460 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.895C>G | R299G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized indicates a benign change, but the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. With the majority of evidence pointing to a damaging effect, the variant is most likely pathogenic. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | -8.354 | Likely Pathogenic | 0.629 | Likely Pathogenic | Likely Benign | 3.58 | Destabilizing | 0.2 | 3.16 | Destabilizing | 3.37 | Destabilizing | 1.37 | Destabilizing | 0.248 | Likely Benign | -3.84 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.79 | Pathogenic | 0.02 | Affected | 0.3361 | 0.4150 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1141G>T | G381W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381W is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438046‑G‑T). Prediction tools that agree on a benign effect include premPS, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. 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 (combining FoldX‑MD and Rosetta outputs) a pathogenic call. No prediction or folding result is missing or inconclusive. Overall, the majority of tools and the high‑accuracy methods indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.724957 | Disordered | 0.431692 | Uncertain | 0.301 | 0.951 | 0.750 | 6-33438046-G-T | 1 | 6.24e-7 | -10.173 | Likely Pathogenic | 0.438 | Ambiguous | Likely Benign | 8.81 | Destabilizing | 2.0 | 3.17 | Destabilizing | 5.99 | Destabilizing | 0.02 | Likely Benign | 0.576 | Likely Pathogenic | -1.04 | Neutral | 0.996 | Probably Damaging | 0.920 | Probably Damaging | 1.31 | Pathogenic | 0.01 | Affected | 4.32 | 9 | 0.0993 | 0.4000 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||||
| c.1991T>G | L664W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: benign calls are made only by REVEL and FATHMM, whereas the remaining 13 predictors—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | -17.438 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 7.81 | Destabilizing | 0.5 | 3.17 | Destabilizing | 5.49 | Destabilizing | 1.57 | Destabilizing | 0.479 | Likely Benign | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.984 | Probably Damaging | 2.84 | Benign | 0.00 | Affected | 0.0543 | 0.2272 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.803T>A | I268N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -13.664 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.48 | Destabilizing | 0.1 | 3.17 | Destabilizing | 3.33 | Destabilizing | 2.21 | Destabilizing | 0.812 | Likely Pathogenic | -6.26 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | 0.0708 | 0.0142 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.749T>G | V250G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V250G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default, while only FATHMM predicts a benign outcome. Uncertain results are reported by FoldX and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, AlphaMissense‑Optimized remains uncertain, and Foldetta is pathogenic. Taken together, the overwhelming majority of evidence indicates a pathogenic effect. This conclusion is consistent with the absence of a ClinVar classification; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -11.255 | Likely Pathogenic | 0.917 | Likely Pathogenic | Ambiguous | 1.65 | Ambiguous | 0.3 | 3.18 | Destabilizing | 2.42 | Destabilizing | 2.08 | Destabilizing | 0.900 | Likely Pathogenic | -5.90 | Deleterious | 0.879 | Possibly Damaging | 0.997 | Probably Damaging | 5.75 | Benign | 0.00 | Affected | 0.1884 | 0.1996 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.970C>G | R324G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R324G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. With the majority of evidence pointing to deleterious impact and two of the three high‑accuracy methods supporting pathogenicity, the variant is most likely pathogenic. This conclusion does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.257454 | Structured | 0.426893 | Uncertain | 0.954 | 0.397 | 0.000 | -12.266 | Likely Pathogenic | 0.708 | Likely Pathogenic | Likely Benign | 2.99 | Destabilizing | 0.1 | 3.18 | Destabilizing | 3.09 | Destabilizing | 1.27 | Destabilizing | 0.496 | Likely Benign | -2.64 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.84 | Pathogenic | 0.39 | Tolerated | 0.3546 | 0.4135 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.803T>C | I268T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268T is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on pathogenicity include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a destabilizing, pathogenic effect. All available predictions are concordant and point to a deleterious impact. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -10.753 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.44 | Destabilizing | 0.1 | 3.19 | Destabilizing | 3.32 | Destabilizing | 1.93 | Destabilizing | 0.828 | Likely Pathogenic | -4.24 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.0882 | 0.0638 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.1523A>G | D508G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508G missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. FoldX‑MD is inconclusive and is treated as unavailable. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM Consensus, and a pathogenic prediction from Foldetta. Overall, the majority of evidence, including the high‑accuracy tools, supports a pathogenic effect. This conclusion does not contradict ClinVar, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -8.478 | Likely Pathogenic | 0.622 | Likely Pathogenic | Likely Benign | 0.87 | Ambiguous | 0.2 | 3.20 | Destabilizing | 2.04 | Destabilizing | 0.13 | Likely Benign | 0.368 | Likely Benign | -6.61 | Deleterious | 0.997 | Probably Damaging | 0.933 | Probably Damaging | 3.30 | Benign | 0.07 | Tolerated | 0.3821 | 0.4528 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.800G>C | W267S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267S is not listed in ClinVar and has no allele in gnomAD. Functional prediction tools largely agree on a deleterious effect: SIFT is the sole benign predictor, whereas the remaining 12 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all report pathogenicity; premPS is uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction is missing or inconclusive. 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 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -12.833 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.42 | Destabilizing | 0.3 | 3.20 | Destabilizing | 3.31 | Destabilizing | 0.87 | Ambiguous | 0.593 | Likely Pathogenic | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.03 | Pathogenic | 0.09 | Tolerated | 0.3809 | 0.1415 | -2 | -3 | 0.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1768A>C | S590R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590R is not reported in ClinVar (status: None) and has no entries in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (likely pathogenic), REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are inconclusive or missing. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -18.228 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.69 | Ambiguous | 0.6 | 3.21 | Destabilizing | 2.45 | Destabilizing | 1.28 | Destabilizing | 0.640 | Likely Pathogenic | -4.88 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.11 | Benign | 0.01 | Affected | 0.0983 | 0.3388 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1770C>A | S590R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, Rosetta, and Foldetta) all predict a pathogenic impact; FoldX is uncertain and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). 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 | -18.228 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.69 | Ambiguous | 0.6 | 3.21 | Destabilizing | 2.45 | Destabilizing | 1.28 | Destabilizing | 0.391 | Likely Benign | -4.88 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.11 | Benign | 0.01 | Affected | 0.0983 | 0.3388 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1770C>G | S590R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, Rosetta, and Foldetta) all predict a pathogenic impact; FoldX is uncertain and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). 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 | -18.228 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.69 | Ambiguous | 0.6 | 3.21 | Destabilizing | 2.45 | Destabilizing | 1.28 | Destabilizing | 0.389 | Likely Benign | -4.88 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.11 | Benign | 0.01 | Affected | 0.0983 | 0.3388 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1841A>G | Y614C 2D AIThe SynGAP1 missense variant Y614C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.314870 | Structured | 0.182134 | Uncertain | 0.852 | 0.254 | 0.000 | -11.716 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.56 | Ambiguous | 0.7 | 3.21 | Destabilizing | 2.39 | Destabilizing | 1.76 | Destabilizing | 0.539 | Likely Pathogenic | -8.83 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.41 | Benign | 0.02 | Affected | 0.3081 | 0.1679 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.1954T>G | F652V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F652V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, whereas only FATHMM predicts a benign outcome. The high‑accuracy subset confirms this trend: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -11.576 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 2.66 | Destabilizing | 0.1 | 3.21 | Destabilizing | 2.94 | Destabilizing | 1.49 | Destabilizing | 0.595 | Likely Pathogenic | -6.71 | Deleterious | 0.995 | Probably Damaging | 0.885 | Possibly Damaging | 3.05 | Benign | 0.00 | Affected | 0.1656 | 0.1783 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.2162T>A | I721N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | -14.905 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.82 | Destabilizing | 0.0 | 3.21 | Destabilizing | 3.02 | Destabilizing | 2.10 | Destabilizing | 0.425 | Likely Benign | -6.30 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.19 | Pathogenic | 0.00 | Affected | 0.0737 | 0.0340 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1160G>A | G387D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G387D is reported in gnomAD (6‑33438065‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. With two of the three high‑accuracy methods indicating pathogenicity and a majority of general predictors leaning toward pathogenic, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.642678 | Disordered | 0.422910 | Uncertain | 0.293 | 0.861 | 0.750 | 6-33438065-G-A | 2 | 1.24e-6 | -8.625 | Likely Pathogenic | 0.612 | Likely Pathogenic | Likely Benign | 3.57 | Destabilizing | 2.3 | 3.22 | Destabilizing | 3.40 | Destabilizing | 0.39 | Likely Benign | 0.459 | Likely Benign | -0.37 | Neutral | 0.069 | Benign | 0.041 | Benign | 1.32 | Pathogenic | 0.02 | Affected | 4.32 | 3 | 0.2145 | 0.2035 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||
| c.1217A>G | Y406C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y406C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: FoldX, Rosetta, 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, also indicates a likely pathogenic outcome, and the Foldetta stability assessment (combining FoldX‑MD and Rosetta) predicts a destabilizing, pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while both SGM‑Consensus and Foldetta are pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for Y406C, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -9.954 | Likely Pathogenic | 0.810 | Likely Pathogenic | Ambiguous | 2.47 | Destabilizing | 0.2 | 3.22 | Destabilizing | 2.85 | Destabilizing | 1.27 | Destabilizing | 0.229 | Likely Benign | -6.72 | Deleterious | 0.998 | Probably Damaging | 0.851 | Possibly Damaging | 3.78 | Benign | 0.01 | Affected | 0.3026 | 0.2861 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.1414G>A | E472K 2D AIThe SynGAP1 missense variant E472K is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the only inconclusive result is from premPS, which is listed as uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -15.214 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.01 | Destabilizing | 1.2 | 3.23 | Destabilizing | 2.62 | Destabilizing | 0.78 | Ambiguous | 0.670 | Likely Pathogenic | -3.95 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | 2.33 | Pathogenic | 0.03 | Affected | 0.3077 | 0.5651 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1943T>C | F648S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F648S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: benign calls are limited to SIFT and FATHMM, whereas the remaining 12 predictors—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, both polyPhen‑2 versions, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also indicates a pathogenic effect. No prediction is inconclusive or missing. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.346782 | Uncertain | 0.943 | 0.339 | 0.000 | -10.356 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.36 | Destabilizing | 0.0 | 3.23 | Destabilizing | 3.30 | Destabilizing | 1.35 | Destabilizing | 0.604 | Likely Pathogenic | -7.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.48 | Benign | 0.06 | Tolerated | 0.3680 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1841A>C | Y614S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y614S is not reported in ClinVar and is present in gnomAD (ID 6‑33440893‑A‑C). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas the majority of algorithms—AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 (HumDiv and HumVar), premPS, Rosetta, Foldetta, and the SGM Consensus—indicate pathogenicity; FoldX remains uncertain. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Overall, the preponderance of evidence points to a pathogenic classification, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.314870 | Structured | 0.182134 | Uncertain | 0.852 | 0.254 | 0.000 | 6-33440893-A-C | 1 | 6.20e-7 | -12.709 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.74 | Ambiguous | 0.4 | 3.25 | Destabilizing | 2.50 | Destabilizing | 2.05 | Destabilizing | 0.482 | Likely Benign | -8.83 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.48 | Benign | 0.09 | Tolerated | 3.37 | 35 | 0.4155 | 0.1220 | -2 | -3 | 0.5 | -76.10 | ||||||||||||||||||||||||
| c.2096T>G | V699G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V699G has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FATHMM and AlphaMissense‑Optimized, while the remaining tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b) uniformly predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta also predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.069024 | Structured | 0.432975 | Uncertain | 0.935 | 0.315 | 0.000 | -11.912 | Likely Pathogenic | 0.481 | Ambiguous | Likely Benign | 2.22 | Destabilizing | 0.0 | 3.25 | Destabilizing | 2.74 | Destabilizing | 1.77 | Destabilizing | 0.514 | Likely Pathogenic | -5.11 | Deleterious | 0.972 | Probably Damaging | 0.999 | Probably Damaging | 3.37 | Benign | 0.01 | Affected | 0.1830 | 0.2240 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1034T>C | L345P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L345P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.354989 | Uncertain | 0.936 | 0.478 | 0.125 | -10.994 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.33 | Destabilizing | 0.2 | 3.26 | Destabilizing | 3.30 | Destabilizing | 1.27 | Destabilizing | 0.335 | Likely Benign | -4.80 | Deleterious | 0.998 | Probably Damaging | 0.889 | Possibly Damaging | 1.70 | Pathogenic | 0.02 | Affected | 0.3581 | 0.1342 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1213C>G | R405G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R405G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | -11.836 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 3.22 | Destabilizing | 0.5 | 3.26 | Destabilizing | 3.24 | Destabilizing | 1.38 | Destabilizing | 0.419 | Likely Benign | -6.35 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.63 | Benign | 0.01 | Affected | 0.3381 | 0.4139 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1958T>A | L653Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L653Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.335213 | Uncertain | 0.963 | 0.332 | 0.000 | -14.347 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 2.71 | Destabilizing | 0.1 | 3.26 | Destabilizing | 2.99 | Destabilizing | 1.98 | Destabilizing | 0.614 | Likely Pathogenic | -5.65 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.09 | Benign | 0.01 | Affected | 0.1195 | 0.1363 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1300G>T | V434F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434F is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that indicate a benign effect include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; SGM‑Consensus predicts pathogenic; Foldetta predicts pathogenic. All predictions are available and none are inconclusive. Based on the overall distribution of predictions, 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 | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -12.553 | Likely Pathogenic | 0.672 | Likely Pathogenic | Likely Benign | 3.64 | Destabilizing | 0.1 | 3.27 | Destabilizing | 3.46 | Destabilizing | 0.27 | Likely Benign | 0.417 | Likely Benign | -3.93 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.44 | Benign | 0.04 | Affected | 0.0596 | 0.3391 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||
| c.1516C>G | L506V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM Consensus) all indicate a pathogenic impact. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy tools’ results, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | -10.220 | Likely Pathogenic | 0.512 | Ambiguous | Likely Benign | 2.61 | Destabilizing | 0.2 | 3.27 | Destabilizing | 2.94 | Destabilizing | 1.36 | Destabilizing | 0.420 | Likely Benign | -2.98 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 1.62 | Pathogenic | 0.04 | Affected | 0.1126 | 0.1660 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1615C>G | H539D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H539D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the only inconclusive result is FoldX, which is listed as uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is consistent with the absence of any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.031398 | Uncertain | 0.948 | 0.360 | 0.000 | -16.450 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 1.22 | Ambiguous | 0.2 | 3.27 | Destabilizing | 2.25 | Destabilizing | 1.08 | Destabilizing | 0.889 | Likely Pathogenic | -8.05 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.25 | Pathogenic | 0.02 | Affected | 0.2008 | 0.0708 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.2075T>A | L692Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692Q is listed in ClinVar as Pathogenic (ClinVar ID 2714634.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | Pathogenic | 1 | -13.873 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.24 | Destabilizing | 0.1 | 3.27 | Destabilizing | 3.26 | Destabilizing | 2.76 | Destabilizing | 0.596 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 3.42 | 17 | 0.1079 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.1868T>G | L623R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L623R is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a pathogenic impact. Thus, the variant is most likely pathogenic, with no contradiction to 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 | 0.175930 | Structured | 0.060667 | Uncertain | 0.962 | 0.211 | 0.000 | -13.718 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.08 | Destabilizing | 1.4 | 3.28 | Destabilizing | 3.68 | Destabilizing | 2.31 | Destabilizing | 0.795 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.55 | Pathogenic | 0.00 | Affected | 0.1327 | 0.0615 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.968T>A | L323Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L323Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—return pathogenic or likely pathogenic calls. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.268042 | Structured | 0.428564 | Uncertain | 0.956 | 0.369 | 0.000 | -14.487 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.19 | Destabilizing | 0.2 | 3.28 | Destabilizing | 3.24 | Destabilizing | 1.85 | Destabilizing | 0.728 | Likely Pathogenic | -4.54 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 0.59 | Pathogenic | 0.00 | Affected | 0.0915 | 0.0758 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1795T>C | C599R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C599R is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a deleterious effect: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, PROVEAN, ESM1b, FATHMM, premPS, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic, while FoldX reports an uncertain outcome. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009865 | Structured | 0.151725 | Uncertain | 0.960 | 0.151 | 0.000 | -15.968 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.3 | 3.29 | Destabilizing | 2.15 | Destabilizing | 1.54 | Destabilizing | 0.909 | Likely Pathogenic | -11.95 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | 0.1519 | 0.1566 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.1403T>A | M468K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468K is listed in ClinVar (ID 642691.0) as Pathogenic and is not reported in gnomAD. All available in silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | Likely Pathogenic | 1 | -16.982 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 3.21 | Destabilizing | 0.1 | 3.30 | Destabilizing | 3.26 | Destabilizing | 2.57 | Destabilizing | 0.828 | Likely Pathogenic | -4.61 | Deleterious | 0.878 | Possibly Damaging | 0.922 | Probably Damaging | -1.34 | Pathogenic | 0.04 | Affected | 3.37 | 31 | 0.1576 | 0.0456 | 0 | -1 | -5.8 | -3.02 | 188.7 | 69.3 | 0.0 | 0.0 | -0.1 | 0.2 | X | X | Potentially Pathogenic | The thioether group of Met468, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Phe464, Leu465, Leu489) in an inter-helix space formed by two other α helices (res. Ala461–Phe476, res. Thr488–Gly502). In the variant simulations, the positively charged side chain of Lys468 rotates outward to escape the hydrophobic niche, forming an H-bond with the hydroxyl group of the Ser471 side chain and a salt bridge with the carboxylate group of the Glu472 side chain. This residue swap also disrupts the methionine-aromatic stacking with the phenyl ring of the Phe464 side chain. Although no large-scale structural changes are observed during the variant simulations, the importance of hydrophobic packing suggests that the effects could be more pronounced during protein folding. | |||||||||||||||
| c.883A>C | T295P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX and AlphaMissense‑Optimized, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome. High‑accuracy assessments further show that AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it as likely pathogenic, and Foldetta reports an uncertain stability change. With the majority of evidence pointing to deleterious effects, the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -9.941 | Likely Pathogenic | 0.688 | Likely Pathogenic | Likely Benign | 0.26 | Likely Benign | 0.2 | 3.30 | Destabilizing | 1.78 | Ambiguous | 0.60 | Ambiguous | 0.531 | Likely Pathogenic | -4.65 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.90 | Pathogenic | 0.02 | Affected | 0.2442 | 0.5327 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1987T>G | F663V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all indicate pathogenicity, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. No predictions are missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -14.196 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 3.04 | Destabilizing | 0.1 | 3.31 | Destabilizing | 3.18 | Destabilizing | 1.75 | Destabilizing | 0.655 | Likely Pathogenic | -6.98 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 3.02 | Benign | 0.00 | Affected | 0.1844 | 0.1983 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.818A>T | E273V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E273V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL and premPS. The majority of tools predict a pathogenic impact: Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, SGM‑Consensus (Likely Pathogenic), and Foldetta. Two tools give inconclusive results: AlphaMissense‑Optimized (Uncertain) and FoldX (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as Pathogenic. Overall, the consensus of pathogenic‑predicting tools outweighs the benign predictions, indicating that E273V is most likely pathogenic; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.071867 | Structured | 0.398918 | Uncertain | 0.863 | 0.196 | 0.125 | -11.671 | Likely Pathogenic | 0.814 | Likely Pathogenic | Ambiguous | 1.93 | Ambiguous | 0.3 | 3.31 | Destabilizing | 2.62 | Destabilizing | 0.17 | Likely Benign | 0.361 | Likely Benign | -4.66 | Deleterious | 0.984 | Probably Damaging | 0.825 | Possibly Damaging | 1.70 | Pathogenic | 0.01 | Affected | 0.0811 | 0.3813 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1797C>G | C599W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C599W is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009865 | Structured | 0.151725 | Uncertain | 0.960 | 0.151 | 0.000 | -17.500 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.85 | Destabilizing | 0.6 | 3.32 | Destabilizing | 3.59 | Destabilizing | 0.16 | Likely Benign | 0.715 | Likely Pathogenic | -10.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.52 | Pathogenic | 0.00 | Affected | 0.1500 | 0.2363 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1301T>A | V434D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign are SIFT and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and ESM1b—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized returns a pathogenic score; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among pathogenic predictors and the corroborating high‑accuracy 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 | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -14.765 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 3.26 | Destabilizing | 0.0 | 3.33 | Destabilizing | 3.30 | Destabilizing | 1.78 | Destabilizing | 0.592 | Likely Pathogenic | -5.18 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.38 | Benign | 0.13 | Tolerated | 0.1307 | 0.0741 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||
| c.1805T>A | I602N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I602N is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a damaging impact. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -16.033 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 2.94 | Destabilizing | 0.2 | 3.34 | Destabilizing | 3.14 | Destabilizing | 2.31 | Destabilizing | 0.880 | Likely Pathogenic | -6.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -2.01 | Pathogenic | 0.00 | Affected | 0.0718 | 0.0700 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1813C>T | P605S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All evaluated in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, which contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | Uncertain | 1 | -10.830 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 3.40 | Destabilizing | 0.1 | 3.34 | Destabilizing | 3.37 | Destabilizing | 1.00 | Destabilizing | 0.718 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.70 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.3397 | 0.4676 | 1 | -1 | 0.8 | -10.04 | 213.8 | -15.4 | -0.3 | 0.2 | 0.2 | 0.1 | X | X | Potentially Pathogenic | Pro605 is located in a short turn between an α helix (res. Glu582-Met603) and a short α helical section (res. Ser606-Phe608). The pyrrolidine side chain of Pro605 packs hydrophobically with nearby hydrophobic residues (e.g., Ile514, Leu623, Leu610) in the inter-helix space. Additionally, proline lacks a free backbone amide group, which breaks the α helix and facilitates the turn in the WT structure.In the variant simulations, the hydroxyl side chain of Ser605 forms hydrogen bonds with the backbone carbonyl groups of Ala601 and Ile602. Importantly, the helix end is more stable than with Pro605 in the WT. Indeed, proline is a more effective secondary structure breaker compared to serine.Thus, the residue swap could have a more profound effect on the actual folding process, for example, by preventing the bending at the α helix end, than what the simulations suggest. Moreover, due to its location at the GAP-Ras interface, the residue swap could affect the GAP-Ras association. | |||||||||||||||
| c.749T>A | V250E 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V250E is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, whereas the remaining 12 tools (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the change as pathogenic. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. No prediction or stability result is inconclusive. Consequently, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -15.723 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 1.85 | Ambiguous | 0.1 | 3.34 | Destabilizing | 2.60 | Destabilizing | 2.01 | Destabilizing | 0.906 | Likely Pathogenic | -5.13 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.74 | Benign | 0.00 | Affected | 0.0787 | 0.1564 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.1258T>G | F420V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic outcome: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts Pathogenic; the SGM‑Consensus itself is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts Pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy tool consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -11.849 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 3.42 | Destabilizing | 0.1 | 3.35 | Destabilizing | 3.39 | Destabilizing | 1.58 | Destabilizing | 0.402 | Likely Benign | -6.41 | Deleterious | 0.495 | Possibly Damaging | 0.191 | Benign | 3.16 | Benign | 0.01 | Affected | 0.2038 | 0.2022 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1943T>G | F648C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F648C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a deleterious effect: all evaluated algorithms except FATHMM predict pathogenicity, while FATHMM alone predicts benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a pathogenic effect. In summary, the overwhelming consensus from both general and high‑accuracy predictors is that F648C is pathogenic. This conclusion is consistent with the absence of any 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 | 0.051831 | Structured | 0.346782 | Uncertain | 0.943 | 0.339 | 0.000 | -10.547 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.28 | Destabilizing | 0.1 | 3.35 | Destabilizing | 3.32 | Destabilizing | 1.22 | Destabilizing | 0.621 | Likely Pathogenic | -7.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.40 | Benign | 0.03 | Affected | 0.2283 | 0.0783 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1147G>A | G383R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383R is not 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, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that agree on a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, Foldetta predicts a pathogenic outcome, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs. two benign). Overall, the majority of predictions lean toward pathogenicity, and this does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | -9.067 | Likely Pathogenic | 0.660 | Likely Pathogenic | Likely Benign | 4.03 | Destabilizing | 2.3 | 3.36 | Destabilizing | 3.70 | Destabilizing | 0.29 | Likely Benign | 0.449 | Likely Benign | -0.84 | Neutral | 0.498 | Possibly Damaging | 0.119 | Benign | 4.10 | Benign | 0.00 | Affected | 0.1295 | 0.3741 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1147G>C | G383R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383R is not 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, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that agree on a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, Foldetta predicts a pathogenic outcome, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs. two benign). Overall, the majority of predictions lean toward pathogenicity, and this does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | -9.067 | Likely Pathogenic | 0.660 | Likely Pathogenic | Likely Benign | 4.03 | Destabilizing | 2.3 | 3.36 | Destabilizing | 3.70 | Destabilizing | 0.29 | Likely Benign | 0.440 | Likely Benign | -0.84 | Neutral | 0.498 | Possibly Damaging | 0.119 | Benign | 4.10 | Benign | 0.00 | Affected | 0.1295 | 0.3741 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.941T>C | F314S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314S (located in the C2 domain) is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Thus, the variant is most likely pathogenic based on predictions, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -14.371 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.51 | Destabilizing | 0.4 | 3.36 | Destabilizing | 3.94 | Destabilizing | 2.59 | Destabilizing | 0.735 | Likely Pathogenic | -6.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.15 | Pathogenic | 0.00 | Affected | 0.4113 | 0.0600 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1355T>A | V452D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V452D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -15.793 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.92 | Destabilizing | 0.1 | 3.37 | Destabilizing | 3.65 | Destabilizing | 2.52 | Destabilizing | 0.630 | Likely Pathogenic | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.16 | Benign | 0.00 | Affected | 0.1320 | 0.0610 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||
| c.1355T>G | V452G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V452G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. AlphaMissense‑Optimized is uncertain, providing no definitive direction. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. AlphaMissense‑Optimized remains uncertain. Overall, the preponderance of evidence indicates that V452G is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -13.410 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 3.70 | Destabilizing | 0.1 | 3.37 | Destabilizing | 3.54 | Destabilizing | 2.46 | Destabilizing | 0.570 | Likely Pathogenic | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.17 | Benign | 0.00 | Affected | 0.1948 | 0.2567 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1715G>C | W572S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W572S is listed in ClinVar as Pathogenic (ClinVar ID 1069317.0) and is not reported in gnomAD. All available in silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Therefore, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.150080 | Structured | 0.039626 | Uncertain | 0.935 | 0.256 | 0.000 | Pathogenic | 1 | -17.461 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.78 | Destabilizing | 0.2 | 3.37 | Destabilizing | 4.58 | Destabilizing | 1.79 | Destabilizing | 0.775 | Likely Pathogenic | -12.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.24 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.3958 | 0.0857 | -2 | -3 | 0.1 | -99.14 | 235.1 | 76.6 | 0.0 | 0.0 | -0.4 | 0.1 | X | Potentially Pathogenic | The introduced residue Ser572, located in an α-helix (res. Arg563-Glu578), is considerably smaller than the tryptophan it replaced. The indole ring of the Trp572 side chain lies in a hydrophobic inter-helix space, where it makes extensive hydrophobic interactions with nearby residues such as Met470, Phe569, Leu588, and Ile589. In the variant simulations, all these favorable packing interactions are completely removed, as the introduced residue Ser572 is too hydrophilic or small to fill the hydrophobic niche occupied by the indole ring. Moreover, the hydroxyl group of Ser572 forms hydrogen bonds with the carbonyl groups of Glu567 and Val568 within the same α-helix, potentially lowering its integrity. Overall, the residue swap is highly likely to cause critical protein folding problems that are underestimated based on the effects seen in the variant simulations. | ||||||||||||||||
| c.791T>G | L264R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264R is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.323473 | Uncertain | 0.939 | 0.264 | 0.000 | -16.976 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.25 | Destabilizing | 0.3 | 3.37 | Destabilizing | 3.81 | Destabilizing | 2.28 | Destabilizing | 0.742 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.49 | Pathogenic | 0.00 | Affected | 0.1132 | 0.0558 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.871T>A | Y291N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291N is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy methods corroborate this: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic effect. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.383842 | Uncertain | 0.912 | 0.251 | 0.000 | -13.599 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.82 | Destabilizing | 0.6 | 3.37 | Destabilizing | 3.10 | Destabilizing | 2.16 | Destabilizing | 0.533 | Likely Pathogenic | -7.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.76 | Pathogenic | 0.01 | Affected | 0.2255 | 0.0499 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1136C>T | S379L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379L is listed in ClinVar as Benign (ClinVar ID 1360860.0) and is present in gnomAD (ID 6‑33438041‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are Rosetta and SIFT. Foldetta and premPS are inconclusive 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 supports a benign impact, which is consistent with the ClinVar classification; there is no contradiction with the reported ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.433206 | Uncertain | 0.327 | 0.931 | 0.625 | Benign | 1 | 6-33438041-C-T | 8 | 4.05e-5 | -5.641 | Likely Benign | 0.173 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.2 | 3.38 | Destabilizing | 1.89 | Ambiguous | -0.52 | Ambiguous | 0.469 | Likely Benign | -0.85 | Neutral | 0.015 | Benign | 0.002 | Benign | 3.83 | Benign | 0.04 | Affected | 4.32 | 11 | 0.1891 | 0.5644 | -3 | -2 | 4.6 | 26.08 | 251.9 | -48.1 | 0.6 | 1.1 | 0.0 | 0.5 | Uncertain | Ser379 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 leucine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Leu379 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.599T>C | L200S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L200S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Those that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2). High‑accuracy methods give a pathogenic signal from Foldetta (protein‑folding stability analysis) while AlphaMissense‑Optimized is uncertain and thus not considered evidence. Overall, the majority of available predictions (10 pathogenic vs 4 benign) indicate a pathogenic impact. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | -10.755 | Likely Pathogenic | 0.807 | Likely Pathogenic | Ambiguous | 2.72 | Destabilizing | 0.1 | 3.38 | Destabilizing | 3.05 | Destabilizing | 1.43 | Destabilizing | 0.141 | Likely Benign | -1.96 | Neutral | 0.970 | Probably Damaging | 0.683 | Possibly Damaging | 4.05 | Benign | 0.06 | Tolerated | 0.3279 | 0.0575 | -3 | -2 | -4.6 | -26.08 | ||||||||||||||||||||||||||||||
| c.1778T>G | L593R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L593R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009728 | Structured | 0.110534 | Uncertain | 0.941 | 0.151 | 0.000 | -16.139 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.27 | Destabilizing | 0.3 | 3.39 | Destabilizing | 3.83 | Destabilizing | 2.11 | Destabilizing | 0.740 | Likely Pathogenic | -5.87 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | 0.1440 | 0.0615 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.616A>T | I206F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I206F missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and polyPhen‑2 HumVar. Those that predict a pathogenic effect comprise SGM‑Consensus, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. Predictions that are uncertain or inconclusive are FoldX and premPS. High‑accuracy methods all support a deleterious outcome: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -12.669 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 1.82 | Ambiguous | 0.4 | 3.39 | Destabilizing | 2.61 | Destabilizing | 0.70 | Ambiguous | 0.133 | Likely Benign | -3.40 | Deleterious | 0.838 | Possibly Damaging | 0.368 | Benign | 3.64 | Benign | 0.01 | Affected | 0.0428 | 0.2721 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1028T>A | V343D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V343D is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, PROVEAN, ESM1b, FATHMM, premPS, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. Rosetta and Foldetta, which evaluate protein‑folding stability, also predict a pathogenic outcome, while FoldX remains uncertain. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta is pathogenic. Consequently, 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 | C2 | 0.291804 | Structured | 0.383911 | Uncertain | 0.882 | 0.497 | 0.250 | -15.523 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.57 | Ambiguous | 0.2 | 3.40 | Destabilizing | 2.49 | Destabilizing | 1.73 | Destabilizing | 0.530 | Likely Pathogenic | -5.62 | Deleterious | 0.996 | Probably Damaging | 0.930 | Probably Damaging | 1.59 | Pathogenic | 0.00 | Affected | 0.1781 | 0.2261 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||
| c.1418T>G | V473G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473G has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the remaining eleven tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) votes pathogenic, and Foldetta also predicts pathogenic. No predictions are missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective evidence, and this conclusion does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -14.782 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 3.45 | Destabilizing | 0.0 | 3.40 | Destabilizing | 3.43 | Destabilizing | 2.69 | Destabilizing | 0.683 | Likely Pathogenic | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | 0.1885 | 0.2567 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1481T>G | I494R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I494R is listed in ClinVar as Pathogenic (ClinVar ID 1685460.0) and is not reported in gnomAD. Prediction tools that assess functional impact all converge on a pathogenic outcome: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | Likely Pathogenic | 1 | -15.758 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 6.71 | Destabilizing | 0.3 | 3.40 | Destabilizing | 5.06 | Destabilizing | 2.19 | Destabilizing | 0.911 | Likely Pathogenic | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.957 | Probably Damaging | -1.41 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.1180 | 0.0870 | -2 | -3 | -9.0 | 43.03 | 273.9 | -59.8 | 0.0 | 0.0 | 0.0 | 0.1 | X | X | X | X | Potentially Pathogenic | The sec-butyl side chain of Ile494, located in an α-helix (res. Leu489-Glu519), packs against hydrophobic residues (e.g., Phe484, Leu465, Trp572, Ala493, Met468) in an inter-helix space (res. Leu489-Glu519 and res. Ala461-Phe476). In the variant simulations, the bulkier and positively charged residue, Arg494, weakens the integrity of the opposing helix. Additionally, the bulkier Arg494 stacks with Phe484, causing the α-helices to move farther apart to accommodate it. This mutation could have substantial negative effects due to the fundamental role of hydrophobic packing, which is disrupted by Arg494 during protein folding. | |||||||||||||
| c.1828C>T | L610F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L610F is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—all of which classify the variant as pathogenic. No tools predict a benign outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Based on the consensus of these predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.209504 | Uncertain | 0.888 | 0.253 | 0.000 | -13.244 | Likely Pathogenic | 0.808 | Likely Pathogenic | Ambiguous | 6.24 | Destabilizing | 1.1 | 3.40 | Destabilizing | 4.82 | Destabilizing | 0.68 | Ambiguous | 0.782 | Likely Pathogenic | -3.92 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | -1.52 | Pathogenic | 0.01 | Affected | 0.0834 | 0.2816 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1954T>A | F652I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F652I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No prediction or stability assessment is missing or inconclusive. Based on the consensus of the available tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -12.085 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 2.15 | Destabilizing | 0.1 | 3.40 | Destabilizing | 2.78 | Destabilizing | 1.40 | Destabilizing | 0.574 | Likely Pathogenic | -5.71 | Deleterious | 0.996 | Probably Damaging | 0.776 | Possibly Damaging | 3.06 | Benign | 0.00 | Affected | 0.1553 | 0.1955 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1853A>C | Q618P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM Consensus, ESM1b, FATHMM, PROVEAN, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as uncertain. Overall, the majority of predictions lean toward a benign effect, though a subset of high‑confidence tools suggest pathogenicity. The variant’s status is not contradicted by ClinVar, which has no entry for this change. Based on the collective evidence, Q618P is most likely benign, albeit with some conflicting pathogenic signals from high‑accuracy predictors. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -8.273 | Likely Pathogenic | 0.248 | Likely Benign | Likely Benign | -0.11 | Likely Benign | 0.1 | 3.41 | Destabilizing | 1.65 | Ambiguous | 0.23 | Likely Benign | 0.449 | Likely Benign | -3.32 | Deleterious | 0.261 | Benign | 0.246 | Benign | -1.35 | Pathogenic | 0.08 | Tolerated | 0.1990 | 0.4011 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.715A>G | R239G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239G missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining twelve tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -12.133 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 4.05 | Destabilizing | 0.1 | 3.41 | Destabilizing | 3.73 | Destabilizing | 1.33 | Destabilizing | 0.912 | Likely Pathogenic | -6.26 | Deleterious | 0.982 | Probably Damaging | 0.533 | Possibly Damaging | 5.62 | Benign | 0.02 | Affected | 0.3415 | 0.3154 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1283A>C | Y428S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y428S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM. All other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact, while AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus indicates “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Based on the overwhelming majority of predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | -10.936 | Likely Pathogenic | 0.928 | Likely Pathogenic | Ambiguous | 3.00 | Destabilizing | 0.0 | 3.42 | Destabilizing | 3.21 | Destabilizing | 2.00 | Destabilizing | 0.505 | Likely Pathogenic | -8.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.45 | Benign | 0.03 | Affected | 0.4623 | 0.2352 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.1364T>A | L455Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455Q is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -13.075 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.84 | Destabilizing | 0.0 | 3.42 | Destabilizing | 3.13 | Destabilizing | 2.24 | Destabilizing | 0.655 | Likely Pathogenic | -5.66 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | 0.0871 | 0.0958 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.713A>G | E238G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E238G is reported in gnomAD (variant ID 6‑33435564‑A‑G) but has no entry in ClinVar. Functional prediction tools largely agree on a deleterious effect: the benign‑predicting tool FATHMM is the only one that classifies it as benign, whereas the pathogenic‑predicting tools (REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Pathogenic” call) all predict a harmful impact. Predictions of uncertain status (FoldX, premPS) are treated as unavailable. High‑accuracy assessments reinforce the pathogenic view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among high‑confidence tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | 6-33435564-A-G | 1 | 6.19e-7 | -12.582 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.09 | Ambiguous | 0.2 | 3.42 | Destabilizing | 2.26 | Destabilizing | 0.87 | Ambiguous | 0.889 | Likely Pathogenic | -6.35 | Deleterious | 0.970 | Probably Damaging | 0.607 | Possibly Damaging | 5.39 | Benign | 0.00 | Affected | 3.40 | 14 | 0.3137 | 0.4833 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||||||||
| c.874G>A | A292T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely converge on a deleterious effect: only REVEL classifies it as benign, whereas FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a destabilizing, pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -11.039 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 2.16 | Destabilizing | 0.7 | 3.42 | Destabilizing | 2.79 | Destabilizing | 1.08 | Destabilizing | 0.457 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.68 | Pathogenic | 0.01 | Affected | 0.1691 | 0.7377 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1082A>C | Q361P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q361P is listed in ClinVar as Pathogenic (ClinVar ID 3235087.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and premPS. All other evaluated algorithms—FoldX, Rosetta, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy methods specifically give a pathogenic verdict: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. Based on the overwhelming agreement of these predictions, the variant is most likely pathogenic, which is consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.305330 | Structured | 0.427593 | Uncertain | 0.945 | 0.534 | 0.250 | Likely Pathogenic | 1 | -13.280 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 3.12 | Destabilizing | 0.0 | 3.45 | Destabilizing | 3.29 | Destabilizing | 0.38 | Likely Benign | 0.482 | Likely Benign | -3.03 | Deleterious | 0.996 | Probably Damaging | 0.979 | Probably Damaging | 1.63 | Pathogenic | 0.05 | Affected | 3.37 | 25 | 0.1986 | 0.5151 | -1 | 0 | 1.9 | -31.01 | |||||||||||||||||||||||||
| c.1946T>C | M649T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M649T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.360413 | Uncertain | 0.962 | 0.345 | 0.000 | -11.916 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 3.19 | Destabilizing | 0.2 | 3.45 | Destabilizing | 3.32 | Destabilizing | 1.92 | Destabilizing | 0.531 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.779 | Possibly Damaging | 3.35 | Benign | 0.00 | Affected | 0.1732 | 0.1615 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||
| c.667A>C | T223P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T223P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as Uncertain. No other high‑accuracy tools provide a definitive prediction. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | -13.707 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.42 | Likely Benign | 0.3 | 3.45 | Destabilizing | 1.94 | Ambiguous | 0.67 | Ambiguous | 0.898 | Likely Pathogenic | -4.54 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 5.72 | Benign | 0.01 | Affected | 0.1464 | 0.3728 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.665T>A | V222E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V222E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is consistent with the lack of ClinVar reporting (i.e., no contradictory evidence). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -18.017 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.04 | Destabilizing | 0.2 | 3.46 | Destabilizing | 3.75 | Destabilizing | 1.64 | Destabilizing | 0.960 | Likely Pathogenic | -5.20 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.20 | Benign | 0.00 | Affected | 0.0833 | 0.1495 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.934T>G | F312V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312V is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the change as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -12.206 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 2.13 | Destabilizing | 0.1 | 3.46 | Destabilizing | 2.80 | Destabilizing | 1.80 | Destabilizing | 0.877 | Likely Pathogenic | -6.43 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.25 | Pathogenic | 0.00 | Affected | 0.1998 | 0.2810 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1148G>C | G383A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as pathogenic. Thus, the majority of evidence points to a benign impact, with only a minority of high‑accuracy tools suggesting pathogenicity. The variant is most likely benign based on the overall predictions, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | -6.205 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 3.17 | Destabilizing | 1.2 | 3.47 | Destabilizing | 3.32 | Destabilizing | 0.04 | Likely Benign | 0.178 | Likely Benign | -0.64 | Neutral | 0.055 | Benign | 0.037 | Benign | 4.20 | Benign | 0.11 | Tolerated | 0.3880 | 0.4361 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1517T>A | L506H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506H is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | -12.999 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 4.45 | Destabilizing | 0.3 | 3.47 | Destabilizing | 3.96 | Destabilizing | 2.18 | Destabilizing | 0.758 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.54 | Pathogenic | 0.00 | Affected | 0.0919 | 0.0488 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.1628T>A | L543Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L543Q is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.020918 | Uncertain | 0.963 | 0.314 | 0.000 | -14.851 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.03 | Destabilizing | 0.2 | 3.48 | Destabilizing | 3.26 | Destabilizing | 2.25 | Destabilizing | 0.746 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.89 | Pathogenic | 0.00 | Affected | 0.0983 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1670C>A | S557Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S557Y is not reported in ClinVar and has no gnomAD entry. Prediction tools largely agree on a deleterious effect: all except premPS (which predicts benign) return pathogenic or likely pathogenic. The high‑accuracy methods reinforce this: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No tool indicates a benign outcome. Consequently, the variant is most likely pathogenic according to the available computational evidence, and this assessment does not conflict with ClinVar status, which currently contains no entry for S557Y. 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 | -13.792 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 18.89 | Destabilizing | 1.1 | 3.48 | Destabilizing | 11.19 | Destabilizing | -0.20 | Likely Benign | 0.965 | Likely Pathogenic | -5.45 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.77 | Pathogenic | 0.00 | Affected | 0.1157 | 0.6087 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.1700A>G | E567G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E567G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign impact include REVEL, SIFT, and FATHMM, whereas those that agree on pathogenic impact include AlphaMissense‑Default, ESM1b, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, Rosetta, and Foldetta. Predictions that are inconclusive are FoldX, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Taken together, 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 | 0.021816 | Structured | 0.051008 | Uncertain | 0.916 | 0.234 | 0.000 | -13.402 | Likely Pathogenic | 0.912 | Likely Pathogenic | Ambiguous | 1.47 | Ambiguous | 0.0 | 3.48 | Destabilizing | 2.48 | Destabilizing | 0.75 | Ambiguous | 0.456 | Likely Benign | -6.67 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.40 | Benign | 0.07 | Tolerated | 0.2586 | 0.4715 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.710C>A | A237D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237D is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining tools—SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict pathogenicity. Two tools, FoldX and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support a deleterious impact: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenicity, AlphaMissense‑Optimized is uncertain, and Foldetta predicts a destabilizing, pathogenic effect. Overall, the evidence overwhelmingly indicates that the variant is pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -8.880 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 1.23 | Ambiguous | 0.4 | 3.49 | Destabilizing | 2.36 | Destabilizing | 1.20 | Destabilizing | 0.769 | Likely Pathogenic | -3.97 | Deleterious | 0.969 | Probably Damaging | 0.704 | Possibly Damaging | 5.88 | Benign | 0.05 | Affected | 0.1419 | 0.2302 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1271T>A | V424D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V424D is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy tools reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No prediction is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -15.531 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.60 | Destabilizing | 0.1 | 3.50 | Destabilizing | 3.55 | Destabilizing | 2.13 | Destabilizing | 0.615 | Likely Pathogenic | -5.87 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 0.1536 | 0.0845 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||
| c.872A>G | Y291C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291C is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.383842 | Uncertain | 0.912 | 0.251 | 0.000 | Uncertain | 1 | -8.997 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 2.90 | Destabilizing | 0.4 | 3.51 | Destabilizing | 3.21 | Destabilizing | 1.35 | Destabilizing | 0.505 | Likely Pathogenic | -7.37 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.76 | Pathogenic | 0.01 | Affected | 3.38 | 23 | 0.3053 | 0.2527 | 0 | -2 | 3.8 | -60.04 | 205.2 | 66.1 | 0.1 | 0.0 | -0.4 | 0.4 | X | X | Potentially Pathogenic | The phenol group of the Tyr291 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), packs against hydrophobic residues of the C2 and PH domains (e.g., Leu317, Leu286, Leu284, Pro208, Val209). The phenol ring of Tyr291 also forms favorable Met-aromatic stacking with the methyl group of Met289. In the variant simulation, the thiol group of the Cys291 side chain is not as suitable for the hydrophobic inter-domain space as the phenol ring of Tyr291. Consequently, the structural unity of the PH domain is weakened and ultimately unfolds in the second simulation. Moreover, the residue swap might result in severe detrimental effects on the C2 domain structure and the C2-PH domain tertiary structure assembly during folding. | |||||||||||||||
| c.1070A>C | H357P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H357P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Two tools give uncertain results: Foldetta (protein‑folding stability) and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect. Thus, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.203355 | Structured | 0.399052 | Uncertain | 0.861 | 0.413 | 0.250 | -7.953 | In-Between | 0.267 | Likely Benign | Likely Benign | 0.17 | Likely Benign | 0.9 | 3.52 | Destabilizing | 1.85 | Ambiguous | -0.06 | Likely Benign | 0.197 | Likely Benign | -2.70 | Deleterious | 0.936 | Possibly Damaging | 0.469 | Possibly Damaging | 4.18 | Benign | 0.17 | Tolerated | 0.2433 | 0.4468 | 0 | -2 | 1.6 | -40.02 | ||||||||||||||||||||||||||||||
| c.1234T>G | L412V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L412V is 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 remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -11.726 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 3.65 | Destabilizing | 0.0 | 3.52 | Destabilizing | 3.59 | Destabilizing | 1.54 | Destabilizing | 0.231 | Likely Benign | -2.76 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.25 | Benign | 0.01 | Affected | 0.1275 | 0.3378 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1979T>G | M660R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M660R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction is inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.134270 | Uncertain | 0.944 | 0.289 | 0.000 | -15.985 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.95 | Destabilizing | 0.2 | 3.52 | Destabilizing | 3.24 | Destabilizing | 1.96 | Destabilizing | 0.588 | Likely Pathogenic | -5.99 | Deleterious | 0.976 | Probably Damaging | 0.464 | Possibly Damaging | 3.34 | Benign | 0.00 | Affected | 0.1612 | 0.0957 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||
| c.1451T>G | F484C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -14.988 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.01 | Destabilizing | 0.0 | 3.54 | Destabilizing | 3.78 | Destabilizing | 2.07 | Destabilizing | 0.675 | Likely Pathogenic | -7.73 | Deleterious | 1.000 | Probably Damaging | 0.969 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 0.2449 | 0.0902 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1136C>G | S379W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438041‑C‑G). Prediction tools that indicate a benign effect include premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus as benign. Because the majority of conventional tools favor pathogenicity while the high‑accuracy subset is split, the overall evidence leans toward a pathogenic effect. This conclusion does not contradict the ClinVar uncertain status, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.433206 | Uncertain | 0.327 | 0.931 | 0.625 | Uncertain | 1 | 6-33438041-C-G | -8.898 | Likely Pathogenic | 0.388 | Ambiguous | Likely Benign | 4.32 | Destabilizing | 3.4 | 3.56 | Destabilizing | 3.94 | Destabilizing | 0.16 | Likely Benign | 0.520 | Likely Pathogenic | -1.02 | Neutral | 0.998 | Probably Damaging | 0.844 | Possibly Damaging | 3.82 | Benign | 0.01 | Affected | 4.32 | 11 | 0.1196 | 0.6070 | -2 | -3 | -0.1 | 99.14 | 271.3 | -75.7 | 1.4 | 1.0 | 0.6 | 0.5 | Uncertain | Ser379 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, Trp379 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.1361T>A | I454N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454N resides in the GAP domain. ClinVar has no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on benign impact are REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict pathogenicity. High‑accuracy methods further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta predicts a destabilizing, pathogenic change. Overall, the evidence strongly favors a pathogenic classification, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -14.246 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.24 | Destabilizing | 0.1 | 3.56 | Destabilizing | 3.90 | Destabilizing | 2.44 | Destabilizing | 0.497 | Likely Benign | -6.82 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.25 | Benign | 0.00 | Affected | 0.0750 | 0.0412 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1877T>A | I626N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I626N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the unanimous agreement of the majority of tools and the corroborating high‑accuracy predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.109221 | Structured | 0.040732 | Uncertain | 0.970 | 0.223 | 0.000 | -15.240 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.49 | Destabilizing | 0.1 | 3.56 | Destabilizing | 3.53 | Destabilizing | 2.36 | Destabilizing | 0.621 | Likely Pathogenic | -6.41 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.03 | Benign | 0.00 | Affected | 0.0880 | 0.0270 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.929A>G | E310G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310G is listed in ClinVar as Pathogenic (ClinVar ID 2732842.0) and is not reported in gnomAD. Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only premPS predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Consequently, the variant is most likely pathogenic, and this prediction is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | Pathogenic | 1 | -14.132 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.38 | Destabilizing | 0.7 | 3.56 | Destabilizing | 2.97 | Destabilizing | 0.36 | Likely Benign | 0.848 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.12 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.2736 | 0.6932 | -2 | 0 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1163G>C | G388A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G388A is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as Pathogenic. Overall, the predictions are mixed, but the two most reliable tools (AlphaMissense‑Optimized and SGM‑Consensus) favor a benign interpretation, while Foldetta suggests instability. Based on 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 | C2 | 0.736850 | Disordered | 0.420316 | Uncertain | 0.319 | 0.827 | 0.750 | -6.577 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 2.55 | Destabilizing | 1.9 | 3.57 | Destabilizing | 3.06 | Destabilizing | -0.04 | Likely Benign | 0.457 | Likely Benign | -0.57 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 1.33 | Pathogenic | 0.05 | Affected | 0.3969 | 0.4837 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1340T>A | V447D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant V447D lies in the GAP domain. ClinVar has no entry for this change, and it is absent from gnomAD. Prediction tools that agree on benign impact are REVEL and FATHMM, whereas the remaining predictors—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classify the variant as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta also reports a pathogenic effect. Overall, the evidence points to a pathogenic effect for V447D, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | -16.643 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.34 | Destabilizing | 0.1 | 3.59 | Destabilizing | 3.97 | Destabilizing | 2.29 | Destabilizing | 0.491 | Likely Benign | -5.33 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 0.1424 | 0.0541 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||
| c.1478C>A | A493D 2D AISynGAP1 missense variant A493D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Consequently, the variant is most likely pathogenic, and this assessment is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -16.834 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.45 | Destabilizing | 1.5 | 3.59 | Destabilizing | 4.02 | Destabilizing | 1.60 | Destabilizing | 0.925 | Likely Pathogenic | -5.25 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.41 | Pathogenic | 0.01 | Affected | 0.1437 | 0.1541 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1638C>G | C546W 2D 3DClick to see structure in 3D Viewer AIClinVar has no entry for this SynGAP1 missense variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, which scores the substitution as tolerated. The majority of other in silico predictors classify the change as pathogenic: REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) report a likely pathogenic outcome. Predictions that are inconclusive or unavailable are FoldX, Foldetta, and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, while Foldetta’s stability analysis is uncertain. Overall, the consensus of the available evidence points to a pathogenic effect for the variant, and this conclusion does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | -14.685 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | -0.79 | Ambiguous | 1.2 | 3.60 | Destabilizing | 1.41 | Ambiguous | 0.56 | Ambiguous | 0.703 | Likely Pathogenic | -9.09 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.24 | Pathogenic | 0.08 | Tolerated | 0.1855 | 0.2904 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1190G>T | C397F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397F is reported in gnomAD (6-33438095-G-T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, Rosetta, and the protein‑folding stability method Foldetta. FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as benign, while Foldetta indicates a pathogenic effect. Because the majority of tools (nine benign vs. four pathogenic) lean toward a benign outcome and the high‑accuracy consensus is split, the variant is most likely benign. This assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | 6-33438095-G-T | 1 | 6.20e-7 | -6.571 | Likely Benign | 0.194 | Likely Benign | Likely Benign | 1.31 | Ambiguous | 1.7 | 3.61 | Destabilizing | 2.46 | Destabilizing | 0.12 | Likely Benign | 0.493 | Likely Benign | -1.95 | Neutral | 0.952 | Possibly Damaging | 0.497 | Possibly Damaging | 4.65 | Benign | 0.07 | Tolerated | 3.41 | 15 | 0.1426 | 0.5231 | -2 | -4 | 0.3 | 44.04 | ||||||||||||||||||||||||
| c.1236G>C | L412F 2D AIThe SynGAP1 missense variant L412F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas the majority of tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Taken together, the consensus of the majority of evidence points to a pathogenic effect for L412F, 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 | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -8.710 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 7.00 | Destabilizing | 3.5 | 3.61 | Destabilizing | 5.31 | Destabilizing | 0.48 | Likely Benign | 0.286 | Likely Benign | -3.69 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.27 | Benign | 0.04 | Affected | 0.0602 | 0.2891 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1236G>T | L412F 2D AIThe SynGAP1 missense variant L412F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas the majority of tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Taken together, the consensus of the majority of evidence points to a pathogenic effect for L412F, 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 | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -8.710 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 7.00 | Destabilizing | 3.5 | 3.61 | Destabilizing | 5.31 | Destabilizing | 0.48 | Likely Benign | 0.283 | Likely Benign | -3.69 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.27 | Benign | 0.04 | Affected | 0.0602 | 0.2891 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.926G>T | G309V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309V is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.338439 | Uncertain | 0.882 | 0.342 | 0.125 | -13.595 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.55 | Destabilizing | 0.5 | 3.61 | Destabilizing | 4.08 | Destabilizing | 0.76 | Ambiguous | 0.531 | Likely Pathogenic | -8.27 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.67 | Pathogenic | 0.00 | Affected | 0.1256 | 0.3910 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1991T>C | L664S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664S is listed in ClinVar as Benign (ClinVar ID 2429773.0) and is present in gnomAD (ID 6‑33441250‑T‑C). Prediction tools that report a benign effect include only FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the overwhelming majority of pathogenic predictions—including the high‑accuracy tools—the variant is most likely pathogenic, which contradicts its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | Likely Benign | 1 | 6-33441250-T-C | 1 | 6.20e-7 | -16.498 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.75 | Destabilizing | 0.2 | 3.63 | Destabilizing | 3.69 | Destabilizing | 2.77 | Destabilizing | 0.543 | Likely Pathogenic | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.85 | Benign | 0.00 | Affected | 3.38 | 28 | 0.2091 | 0.0896 | -3 | -2 | -4.6 | -26.08 | 215.5 | 50.1 | 0.0 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | The iso-butyl side chain of L664, located on an α-helix (res. Ser641-Glu666), hydrophobically interacts with residues in the inter-helix space between three helices (res. Glu617-Asn635, res. Glu582-Met603, and res. Ser641-Glu666), such as Ile589, Phe663, and Met660. In the variant simulations, the hydroxyl group of Ser664 forms hydrogen bonds with the backbone carbonyl oxygen of another helix residue, such as Met660 or Gln661. This interaction is known to destabilize hydrogen bonding in the α-helix, but this effect was not observed in the simulations. Additionally, Ser664 occasionally forms hydrogen bonds with the carboxylate group of Asp586 on another α-helix (res. Glu582-Met603), which could minimally influence the tertiary structure assembly. Despite these interactions, no major negative effects on the protein structure were observed during the simulations. | |||||||||||||
| c.1258T>A | F420I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy tools, the variant is most likely pathogenic, and this conclusion 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 | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -12.567 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.88 | Destabilizing | 0.0 | 3.64 | Destabilizing | 3.26 | Destabilizing | 1.25 | Destabilizing | 0.330 | Likely Benign | -5.46 | Deleterious | 0.575 | Possibly Damaging | 0.059 | Benign | 3.22 | Benign | 0.02 | Affected | 0.1864 | 0.2113 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.928G>A | E310K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310K is listed in ClinVar with an uncertain significance (ID 981613) and is not reported in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX‑MD (uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Consequently, the variant is most likely pathogenic according to the available predictions, which does not contradict the ClinVar uncertain status but suggests a pathogenic interpretation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | Conflicting | 5 | -14.601 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.97 | Ambiguous | 1.2 | 3.66 | Destabilizing | 2.82 | Destabilizing | 1.02 | Destabilizing | 0.764 | Likely Pathogenic | -3.68 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 1.19 | Pathogenic | 0.01 | Affected | 3.38 | 19 | 0.2496 | 0.8453 | 0 | 1 | -0.4 | -0.94 | 213.4 | 58.0 | 0.1 | 0.0 | 0.2 | 0.1 | X | Potentially Pathogenic | The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the side chain hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand (res. Met289-Arg299). Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the amino group of the Lys310 side chain hydrogen bonds with the GAP domain residues and forms a salt bridge with Glu613. Although no apparent negative effects are seen due to the residue swap, it is possible that the loss of hydrogen bonding with the hydroxyl group of the Thr295 side chain causes problems during folding, potentially compromising the twisting of the β sheet. | ||||||||||||||||
| c.1249T>A | Y417N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -13.912 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.94 | Destabilizing | 0.2 | 3.69 | Destabilizing | 3.82 | Destabilizing | 2.60 | Destabilizing | 0.561 | Likely Pathogenic | -8.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.97 | Benign | 0.00 | Affected | 0.2482 | 0.0728 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1442A>C | H481P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H481P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and FATHMM. Those that predict a pathogenic effect comprise SGM Consensus (Likely Pathogenic), PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and PROVEAN. Tools with inconclusive results are Foldetta (Uncertain) and premPS (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta remains uncertain. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -10.205 | Likely Pathogenic | 0.630 | Likely Pathogenic | Likely Benign | -0.48 | Likely Benign | 0.3 | 3.69 | Destabilizing | 1.61 | Ambiguous | 0.67 | Ambiguous | 0.385 | Likely Benign | -5.84 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.26 | Tolerated | 0.1979 | 0.3553 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.1763T>A | L588H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L588H is listed in ClinVar (ID 422233.0) as Pathogenic and is not reported in gnomAD. All available in silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.082229 | Uncertain | 0.887 | 0.214 | 0.000 | Likely Pathogenic | 1 | -16.947 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.20 | Destabilizing | 0.2 | 3.69 | Destabilizing | 3.95 | Destabilizing | 2.26 | Destabilizing | 0.939 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.42 | Pathogenic | 0.00 | Affected | 3.38 | 34 | 0.0980 | 0.0456 | -2 | -3 | -7.0 | 23.98 | 214.3 | 20.9 | 0.0 | 0.0 | 0.0 | 0.2 | X | X | X | Potentially Pathogenic | The isobutyl group of the Leu588 side chain, located in an α helix (res. Glu582-Met603), packs against hydrophobic residues in the inter-helix hydrophobic space (e.g., Ile584, Trp572, Phe484, Met470, Val473, Ile483).In the variant simulations, the imidazole ring of His588 is aromatic but contains polar delta and epsilon nitrogen atoms that are not suited for the hydrophobic niche. The protonated epsilon nitrogen forms a hydrogen bond with the backbone carbonyl group of Ala469, which can disrupt the continuity of the opposing α helix (res. Phe476-Lys460).While the residue swap could affect the tertiary assembly and the underlying protein folding process, it is difficult to determine if the mutation would be tolerated based solely on the variant simulations. | ||||||||||||||
| c.1541T>G | I514S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -12.512 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 4.03 | Destabilizing | 0.2 | 3.70 | Destabilizing | 3.87 | Destabilizing | 2.11 | Destabilizing | 0.625 | Likely Pathogenic | -5.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.82 | Benign | 0.00 | Affected | 0.2296 | 0.0530 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1754C>A | A585E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A585E is not reported in ClinVar (status: None) and is absent from gnomAD. Prediction tools cluster into two groups: the single benign call comes from SIFT, while all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—label the change as pathogenic or likely pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports pathogenic. Thus, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.055884 | Uncertain | 0.880 | 0.244 | 0.000 | -14.715 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 5.38 | Destabilizing | 0.7 | 3.70 | Destabilizing | 4.54 | Destabilizing | 1.42 | Destabilizing | 0.539 | Likely Pathogenic | -2.59 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.30 | Pathogenic | 0.28 | Tolerated | 0.1160 | 0.1212 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||
| c.1180A>G | K394E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K394E is not listed in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438085‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Those that predict a pathogenic effect are premPS, PROVEAN, SIFT, 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. No prediction or folding‑stability result is available that decisively supports either outcome. Overall, the majority of tools (six benign vs four pathogenic) lean toward a benign interpretation, and this assessment does not contradict the absence of a ClinVar classification. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | 6-33438085-A-G | 1 | 6.20e-7 | -6.903 | Likely Benign | 0.896 | Likely Pathogenic | Ambiguous | 0.07 | Likely Benign | 0.1 | 3.71 | Destabilizing | 1.89 | Ambiguous | 1.20 | Destabilizing | 0.446 | Likely Benign | -2.54 | Deleterious | 0.063 | Benign | 0.038 | Benign | 4.61 | Benign | 0.04 | Affected | 3.44 | 14 | 0.4556 | 0.1916 | 1 | 0 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.1232T>A | I411N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | -14.426 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.00 | Destabilizing | 0.1 | 3.71 | Destabilizing | 3.36 | Destabilizing | 2.16 | Destabilizing | 0.556 | Likely Pathogenic | -6.42 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | 0.0738 | 0.0700 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1472C>T | T491I 2D  AIThe SynGAP1 missense variant T491I is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS; all other evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact, while FoldX is uncertain and therefore not counted in either group. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized reports a pathogenic change, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | -12.525 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.48 | Ambiguous | 1.8 | 3.73 | Destabilizing | 2.61 | Destabilizing | 0.49 | Likely Benign | 0.915 | Likely Pathogenic | -5.89 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.42 | Pathogenic | 0.00 | Affected | 0.0898 | 0.4942 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1540A>T | I514F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—report it as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, classifies the variant as pathogenic. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | Uncertain | 1 | -13.383 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 2.35 | Destabilizing | 0.3 | 3.74 | Destabilizing | 3.05 | Destabilizing | 0.93 | Ambiguous | 0.601 | Likely Pathogenic | -3.98 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.89 | Benign | 0.00 | Affected | 3.37 | 35 | 0.0574 | 0.1629 | 0 | 1 | -1.7 | 34.02 | |||||||||||||||||||||||||
| c.1889T>G | I630S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I630S is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as pathogenic. No contradictory evidence is present. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not conflict with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.036106 | Uncertain | 0.966 | 0.236 | 0.000 | -12.527 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 3.61 | Destabilizing | 0.1 | 3.74 | Destabilizing | 3.68 | Destabilizing | 2.25 | Destabilizing | 0.851 | Likely Pathogenic | -3.86 | Deleterious | 1.000 | Probably Damaging | 0.981 | Probably Damaging | -1.44 | Pathogenic | 0.00 | Affected | 0.2363 | 0.0858 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.2108T>G | L703R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus) all classify the change as pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. The preponderance of pathogenic predictions, together with the high‑accuracy tools’ positive results, suggests that L703R is most likely pathogenic. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -13.244 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 2.85 | Destabilizing | 0.0 | 3.74 | Destabilizing | 3.30 | Destabilizing | 1.79 | Destabilizing | 0.459 | Likely Benign | -4.92 | Deleterious | 0.994 | Probably Damaging | 0.806 | Possibly Damaging | 3.13 | Benign | 0.00 | Affected | 0.1223 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.983A>G | Y328C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (integrating FoldX‑MD and Rosetta outputs) also reports a pathogenic outcome. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.411940 | Structured | 0.392519 | Uncertain | 0.916 | 0.497 | 0.000 | -12.385 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 2.52 | Destabilizing | 0.1 | 3.74 | Destabilizing | 3.13 | Destabilizing | 1.40 | Destabilizing | 0.523 | Likely Pathogenic | -8.01 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.55 | Pathogenic | 0.01 | Affected | 0.3154 | 0.2882 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.1330A>G | K444E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K444E missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and FATHMM; all other evaluated predictors—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic effect. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -15.571 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.99 | Destabilizing | 0.1 | 3.75 | Destabilizing | 3.37 | Destabilizing | 1.10 | Destabilizing | 0.437 | Likely Benign | -3.82 | Deleterious | 0.997 | Probably Damaging | 0.981 | Probably Damaging | 3.40 | Benign | 0.01 | Affected | 0.3486 | 0.0793 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1352T>G | L451R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All available in‑silico predictors classify the substitution as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a pathogenic effect. Based on the unanimous pathogenic predictions and the absence of benign calls, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -16.162 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.32 | Destabilizing | 0.1 | 3.76 | Destabilizing | 3.54 | Destabilizing | 2.25 | Destabilizing | 0.726 | Likely Pathogenic | -5.82 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.1130 | 0.0558 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1826G>T | G609V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from premPS and AlphaMissense‑Optimized, whereas the remaining 10 tools (SGM Consensus, REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM) all predict pathogenicity. High‑accuracy assessments further highlight the discordance: AlphaMissense‑Optimized reports a benign effect, whereas the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both indicate pathogenicity. With the majority of evidence pointing to deleterious impact, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -11.049 | Likely Pathogenic | 0.374 | Ambiguous | Likely Benign | 4.17 | Destabilizing | 0.3 | 3.77 | Destabilizing | 3.97 | Destabilizing | 0.34 | Likely Benign | 0.734 | Likely Pathogenic | -4.47 | Deleterious | 0.974 | Probably Damaging | 0.818 | Possibly Damaging | -1.48 | Pathogenic | 0.02 | Affected | 0.1269 | 0.3317 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1529T>G | I510S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510S is listed in ClinVar as Pathogenic (ClinVar ID 449946.0) and is not reported in gnomAD. Prediction tools that assess the variant’s effect all converge on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate pathogenicity. No tool predicts a benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized is uncertain, SGM‑Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | Likely Pathogenic | 1 | -11.661 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 4.00 | Destabilizing | 0.1 | 3.78 | Destabilizing | 3.89 | Destabilizing | 2.34 | Destabilizing | 0.926 | Likely Pathogenic | -4.63 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.44 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.2395 | 0.0858 | -1 | -2 | -5.3 | -26.08 | 201.4 | 45.9 | -0.4 | 0.2 | 0.0 | 0.3 | X | Potentially Pathogenic | Ile510 is located in the middle of an α-helix (res. Gly502-Tyr518) within the inter-helix space of three helices (res. Gly502-Tyr518, Ala533-Val560, and res. Glu582-Met603). In the WT simulations, the sec-butyl side chain of Ile510 hydrophobically packs with other residues in the inter-helix space (e.g., Leu506, Leu610, Ile514, Ile602, Leu598). In the variant simulations, the hydroxyl group of Ser510 forms a hydrogen bond with the backbone atoms of Leu506 and Gly511 in the same α-helix, which could further weaken the α-helix integrity. This α-helix already shows weakness in the WT simulations due to Gly511. Although the simulations do not show large-scale effects, the residue swap could have a substantial impact due to the fundamental role of hydrophobic packing during protein folding. | ||||||||||||||||
| c.2150T>G | L717R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L717R is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while the remaining 13 tools (SGM‑Consensus, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the majority‑vote SGM Consensus) predict pathogenicity; FoldX is uncertain. High‑accuracy methods reinforce a pathogenic verdict: AlphaMissense‑Optimized scores it as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta also predicts pathogenic. No prediction is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.429342 | Uncertain | 0.969 | 0.397 | 0.000 | -11.352 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 1.66 | Ambiguous | 0.1 | 3.78 | Destabilizing | 2.72 | Destabilizing | 1.57 | Destabilizing | 0.353 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.28 | Benign | 0.00 | Affected | 0.1169 | 0.0558 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.776G>C | R259P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods further support this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.338208 | Uncertain | 0.885 | 0.255 | 0.250 | -14.876 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.34 | Destabilizing | 1.6 | 3.78 | Destabilizing | 5.06 | Destabilizing | 1.16 | Destabilizing | 0.902 | Likely Pathogenic | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.84 | Benign | 0.00 | Affected | 0.2051 | 0.5249 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1805T>G | I602S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I602S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No conflicting benign evidence is available. Therefore, based on the consensus of all available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -15.558 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 3.50 | Destabilizing | 0.1 | 3.79 | Destabilizing | 3.65 | Destabilizing | 2.04 | Destabilizing | 0.935 | Likely Pathogenic | -5.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -2.01 | Pathogenic | 0.00 | Affected | 0.2213 | 0.1087 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1742G>C | R581P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R581P is not reported in ClinVar and is present in gnomAD (variant ID 6‑33440794‑G‑C). Functional prediction tools that agree on a benign effect include premPS and SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, FoldX, Rosetta, Foldetta, 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, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is pathogenic. No predictions are inconclusive or missing. Overall, the evidence strongly favors a pathogenic classification for R581P, and this 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 | 0.104810 | Structured | 0.029544 | Uncertain | 0.829 | 0.236 | 0.000 | 6-33440794-G-C | 1 | 6.20e-7 | -13.309 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.13 | Destabilizing | 0.1 | 3.80 | Destabilizing | 3.97 | Destabilizing | 0.44 | Likely Benign | 0.562 | Likely Pathogenic | -5.68 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.01 | Pathogenic | 0.07 | Tolerated | 3.37 | 34 | 0.2192 | 0.3639 | -2 | 0 | 2.9 | -59.07 | ||||||||||||||||||||||||
| c.1094T>A | V365E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365E is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts pathogenic. With all available evidence pointing to a damaging effect and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | -16.263 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.99 | Destabilizing | 0.3 | 3.81 | Destabilizing | 3.90 | Destabilizing | 2.20 | Destabilizing | 0.613 | Likely Pathogenic | -5.02 | Deleterious | 0.989 | Probably Damaging | 0.688 | Possibly Damaging | 1.66 | Pathogenic | 0.00 | Affected | 0.0849 | 0.2083 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.1250A>G | Y417C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also classifies the variant as pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -12.021 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 4.03 | Destabilizing | 0.1 | 3.81 | Destabilizing | 3.92 | Destabilizing | 2.52 | Destabilizing | 0.597 | Likely Pathogenic | -8.59 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.95 | Benign | 0.00 | Affected | 0.2960 | 0.2005 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.1282T>A | Y428N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y428N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are limited to FATHMM, which classifies the change as benign. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | -12.164 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 2.34 | Destabilizing | 0.0 | 3.81 | Destabilizing | 3.08 | Destabilizing | 1.85 | Destabilizing | 0.533 | Likely Pathogenic | -8.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.48 | Benign | 0.03 | Affected | 0.2607 | 0.0971 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1205T>G | L402R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402R is listed in ClinVar as Pathogenic (ClinVar ID 559657.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the overwhelming agreement among pathogenic predictions and the concordance with ClinVar, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.243554 | Structured | 0.431978 | Uncertain | 0.961 | 0.383 | 0.000 | Likely Pathogenic | 1 | -13.800 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 4.10 | Destabilizing | 0.2 | 3.82 | Destabilizing | 3.96 | Destabilizing | 2.24 | Destabilizing | 0.522 | Likely Pathogenic | -4.69 | Deleterious | 0.967 | Probably Damaging | 0.459 | Possibly Damaging | 3.69 | Benign | 0.00 | Affected | 3.38 | 28 | 0.1467 | 0.1173 | -3 | -2 | -8.3 | 43.03 | 259.5 | -55.4 | 0.0 | 0.0 | 1.4 | 0.0 | X | X | X | Potentially Pathogenic | The iso-butyl side chain of Leu402, located in an anti-parallel β sheet strand (res. Ala399-Ile411), packs with residues inside the hydrophobic core of the C2 domain (e.g., Ile268, Ala404, Leu266, Val400). In the variant simulations, the positively charged guanidinium group of the Arg402 side chain is not suitable for the hydrophobic niche. Consequently, the side chain moves outward from the hydrophobic C2 domain core and stacks with the phenol ring of Tyr363 or forms H-bonds with the carboxamide group of the Gln361 side chain in the β sheet strand (res. Thr359-Tyr364). This movement induces extensive negative effects on the C2 domain structure. | ||||||||||||||
| c.1886T>A | V629D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V629D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic or likely pathogenic calls, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized indicates pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts pathogenic. No predictions are missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.034796 | Uncertain | 0.970 | 0.236 | 0.000 | -17.143 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.85 | Destabilizing | 0.1 | 3.82 | Destabilizing | 3.84 | Destabilizing | 2.17 | Destabilizing | 0.713 | Likely Pathogenic | -6.37 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 0.1284 | 0.0541 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||
| c.875C>A | A292E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292E is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for A292E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -14.282 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.07 | Destabilizing | 1.2 | 3.82 | Destabilizing | 4.95 | Destabilizing | 1.54 | Destabilizing | 0.475 | Likely Benign | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.69 | Pathogenic | 0.02 | Affected | 0.1444 | 0.2205 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||
| c.1232T>G | I411S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | -13.763 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.59 | Destabilizing | 0.2 | 3.83 | Destabilizing | 3.71 | Destabilizing | 1.91 | Destabilizing | 0.603 | Likely Pathogenic | -5.50 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.30 | Benign | 0.00 | Affected | 0.2262 | 0.1487 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1171G>C | G391R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G391R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include premPS, PROVEAN, and SIFT, whereas those that predict pathogenicity comprise REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further show AlphaMissense‑Optimized labeling the variant as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.637480 | Disordered | 0.409509 | Uncertain | 0.279 | 0.741 | 0.750 | -9.115 | Likely Pathogenic | 0.709 | Likely Pathogenic | Likely Benign | 2.80 | Destabilizing | 1.3 | 3.86 | Destabilizing | 3.33 | Destabilizing | 0.32 | Likely Benign | 0.628 | Likely Pathogenic | -0.95 | Neutral | 0.999 | Probably Damaging | 0.960 | Probably Damaging | 1.32 | Pathogenic | 0.17 | Tolerated | 0.1313 | 0.4124 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.871T>G | Y291D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291D is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.383842 | Uncertain | 0.912 | 0.251 | 0.000 | -17.570 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.13 | Destabilizing | 0.6 | 3.86 | Destabilizing | 4.00 | Destabilizing | 1.91 | Destabilizing | 0.650 | Likely Pathogenic | -8.19 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.75 | Pathogenic | 0.01 | Affected | 0.4300 | 0.0331 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1436G>C | R479P 2D 3DClick to see structure in 3D Viewer AIClinVar lists the SynGAP1 R479P variant as Uncertain, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. Those that predict a pathogenic effect are FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive are AlphaMissense‑Optimized and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as pathogenic. Overall, the majority of tools and the high‑accuracy methods support a pathogenic classification, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | Uncertain | 1 | -11.795 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 2.86 | Destabilizing | 0.2 | 3.88 | Destabilizing | 3.37 | Destabilizing | 0.81 | Ambiguous | 0.277 | Likely Benign | -3.52 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.41 | Benign | 0.18 | Tolerated | 0.1993 | 0.3747 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||
| c.982T>A | Y328N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.411940 | Structured | 0.392519 | Uncertain | 0.916 | 0.497 | 0.000 | -13.778 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.72 | Destabilizing | 0.1 | 3.88 | Destabilizing | 3.30 | Destabilizing | 2.06 | Destabilizing | 0.548 | Likely Pathogenic | -8.07 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.53 | Pathogenic | 0.01 | Affected | 0.2374 | 0.0703 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1739G>T | G580V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G580V is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. The only inconclusive result is premPS, which is listed as uncertain. No tool predicts a benign effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.025952 | Uncertain | 0.853 | 0.236 | 0.000 | -13.705 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 4.10 | Destabilizing | 0.1 | 3.89 | Destabilizing | 4.00 | Destabilizing | 0.79 | Ambiguous | 0.750 | Likely Pathogenic | -8.66 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.18 | Pathogenic | 0.04 | Affected | 0.1270 | 0.2909 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.617T>G | I206S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I206S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and polyPhen‑2 HumVar. All other evaluated algorithms (SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is pathogenic. Based on the preponderance of evidence from these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -13.711 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.73 | Destabilizing | 0.3 | 3.89 | Destabilizing | 3.81 | Destabilizing | 1.74 | Destabilizing | 0.251 | Likely Benign | -4.86 | Deleterious | 0.838 | Possibly Damaging | 0.368 | Benign | 3.63 | Benign | 0.00 | Affected | 0.2189 | 0.0728 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1084T>A | W362R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W362R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—return pathogenic or likely pathogenic calls. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.430310 | Uncertain | 0.957 | 0.552 | 0.125 | -14.004 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.64 | Destabilizing | 0.3 | 3.90 | Destabilizing | 3.27 | Destabilizing | 1.10 | Destabilizing | 0.706 | Likely Pathogenic | -12.87 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 3.39 | 24 | 0.4811 | 0.0571 | 2 | -3 | -3.6 | -30.03 | 287.5 | -34.1 | -0.2 | 0.1 | -0.6 | 0.2 | X | X | X | Potentially Pathogenic | The indole ring of Trp362, located on the surface of an anti-parallel β sheet (res. Thr359-Pro364) in the C2 domain, stacks with nearby residues (e.g., Arg401, Arg272). In the variant simulations, the guanidinium group of the introduced residue Arg362 forms a salt bridge with the carboxylate group of Glu273 and, like Trp362, stacks with other arginine residues (e.g., Arg401, Arg272). This residue is at both the C2-membrane interface and the C2-RasGTPase interface, so the residue swap could potentially affect both interactions. However, these phenomena cannot be addressed using solvent-only simulations. Notably, Arg272, which stacks with both the non-mutated Trp362 and the mutated Arg362, forms a salt bridge directly with Asp105 of Ras in the WT simulations. Therefore, the residue swap could affect the C2 domain stability, the SynGAP-membrane association, and the SynGAP-Ras association. | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||
| c.1084T>C | W362R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W362R (ClinVar ID 41461.0) is listed as Pathogenic and is not reported in gnomAD. All available in silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.430310 | Uncertain | 0.957 | 0.552 | 0.125 | Pathogenic | 2 | -14.004 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.64 | Destabilizing | 0.3 | 3.90 | Destabilizing | 3.27 | Destabilizing | 1.10 | Destabilizing | 0.706 | Likely Pathogenic | -12.87 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 3.39 | 24 | 0.4811 | 0.0571 | 2 | -3 | -3.6 | -30.03 | 287.5 | -34.1 | -0.2 | 0.1 | -0.6 | 0.2 | X | X | X | Potentially Pathogenic | The indole ring of Trp362, located on the surface of an anti-parallel β sheet (res. Thr359-Pro364) in the C2 domain, stacks with nearby residues (e.g., Arg401, Arg272). In the variant simulations, the guanidinium group of the introduced residue Arg362 forms a salt bridge with the carboxylate group of Glu273 and, like Trp362, stacks with other arginine residues (e.g., Arg401, Arg272). This residue is at both the C2-membrane interface and the C2-RasGTPase interface, so the residue swap could potentially affect both interactions. However, these phenomena cannot be addressed using solvent-only simulations. Notably, Arg272, which stacks with both the non-mutated Trp362 and the mutated Arg362, forms a salt bridge directly with Asp105 of Ras in the WT simulations. Therefore, the residue swap could affect the C2 domain stability, the SynGAP-membrane association, and the SynGAP-Ras association. | 10.1016/j.ajhg.2020.11.011 | |||||||||||||
| c.1727G>A | C576Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C576Y is not reported in ClinVar and has no gnomAD allele. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized all classify the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also indicates pathogenicity. No tool yields an inconclusive result. Based on the consensus of available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.017684 | Uncertain | 0.913 | 0.245 | 0.000 | -13.891 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 8.77 | Destabilizing | 0.5 | 3.90 | Destabilizing | 6.34 | Destabilizing | 0.63 | Ambiguous | 0.612 | Likely Pathogenic | -9.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.38 | Benign | 0.00 | Affected | 0.1398 | 0.3009 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1088A>C | Y363S 2D AIThe SynGAP1 missense variant Y363S 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, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic”; AlphaMissense‑Optimized is classified as “Uncertain”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic effect. Taken together, the overwhelming majority of evidence points to a pathogenic effect for Y363S, 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 | 0.321458 | Structured | 0.435392 | Uncertain | 0.954 | 0.586 | 0.125 | -11.578 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 3.09 | Destabilizing | 0.6 | 3.92 | Destabilizing | 3.51 | Destabilizing | 1.45 | Destabilizing | 0.420 | Likely Benign | -8.04 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 1.56 | Pathogenic | 0.01 | Affected | 0.5750 | 0.4208 | Weaken | -3 | -2 | 0.5 | -76.10 | ||||||||||||||||||||||||||||
| c.1937T>G | L646R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic calls are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, SGM Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the preponderance of evidence points to a pathogenic effect for L646R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -12.393 | Likely Pathogenic | 0.920 | Likely Pathogenic | Ambiguous | 4.44 | Destabilizing | 0.2 | 3.94 | Destabilizing | 4.19 | Destabilizing | 2.75 | Destabilizing | 0.455 | Likely Benign | -3.56 | Deleterious | 0.014 | Benign | 0.002 | Benign | 3.17 | Benign | 0.03 | Affected | 0.2304 | 0.1405 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.860A>T | D287V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D287V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS; all other evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, while FoldX is uncertain and thus not counted as evidence. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.102787 | Structured | 0.389029 | Uncertain | 0.912 | 0.268 | 0.000 | -14.418 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.71 | Ambiguous | 0.4 | 3.94 | Destabilizing | 2.83 | Destabilizing | 0.25 | Likely Benign | 0.516 | Likely Pathogenic | -8.27 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.57 | Pathogenic | 0.01 | Affected | 0.0884 | 0.7788 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1088A>G | Y363C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y363C is not reported in ClinVar (ClinVar ID: None) but is present in gnomAD (ID 6‑33437993‑A‑G). Prediction tools cluster into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—indicate pathogenicity. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. With the majority of evidence pointing to deleterious effects and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.435392 | Uncertain | 0.954 | 0.586 | 0.125 | 6-33437993-A-G | 1 | 7.13e-7 | -9.059 | Likely Pathogenic | 0.721 | Likely Pathogenic | Likely Benign | 2.21 | Destabilizing | 0.1 | 3.96 | Destabilizing | 3.09 | Destabilizing | 2.05 | Destabilizing | 0.414 | Likely Benign | -8.07 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.54 | Pathogenic | 0.00 | Affected | 3.39 | 24 | 0.3759 | 0.3463 | -2 | 0 | 3.8 | -60.04 | ||||||||||||||||||||||||
| c.1135T>A | S379T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are Rosetta, polyPhen‑2 HumDiv, and the Foldetta stability method. FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as pathogenic. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.433206 | Uncertain | 0.327 | 0.931 | 0.625 | -5.646 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 1.42 | Ambiguous | 0.6 | 3.96 | Destabilizing | 2.69 | Destabilizing | 0.06 | Likely Benign | 0.230 | Likely Benign | -0.50 | Neutral | 0.462 | Possibly Damaging | 0.084 | Benign | 3.87 | Benign | 0.16 | Tolerated | 0.2293 | 0.6248 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2162T>G | I721S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: the single benign prediction comes from REVEL, while all other evaluated algorithms (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | Uncertain | 1 | -14.032 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.91 | Destabilizing | 0.1 | 3.96 | Destabilizing | 3.94 | Destabilizing | 2.28 | Destabilizing | 0.466 | Likely Benign | -5.26 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.21 | Pathogenic | 0.00 | Affected | 3.50 | 9 | 0.2606 | 0.1110 | -1 | -2 | -5.3 | -26.08 | 203.3 | 49.3 | -0.1 | 0.0 | -1.1 | 0.0 | X | Uncertain | The sec-butyl side chain of Ile721, located on an α-helix (res. Leu714-Arg726), engages in hydrophobic packing with other residues in the hydrophobic inter-helix space, such as Phe420, Tyr417, His693, and Leu717. In the variant simulations, the hydroxyl side chain of Ser721 forms hydrogen bonds with nearby residues, such as Leu717 and His693. Although no major structural changes are observed during the variant simulations, the hydrophilic residue Ser721 could disrupt the hydrophobic packing during folding. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | ||||||||||||||||
| c.1489T>A | Y497N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. Based on these concordant predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -11.884 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 3.64 | Destabilizing | 0.1 | 3.97 | Destabilizing | 3.81 | Destabilizing | 2.49 | Destabilizing | 0.870 | Likely Pathogenic | -8.85 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.66 | Pathogenic | 0.01 | Affected | 0.2114 | 0.0612 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1715G>T | W572L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W572L is 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, which scores the variant as benign. All other evaluated predictors—REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a pathogenic effect. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.150080 | Structured | 0.039626 | Uncertain | 0.935 | 0.256 | 0.000 | -15.765 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 2.62 | Destabilizing | 0.1 | 3.97 | Destabilizing | 3.30 | Destabilizing | 0.90 | Ambiguous | 0.591 | Likely Pathogenic | -11.52 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.91 | Pathogenic | 0.31 | Tolerated | 0.2246 | 0.2837 | -2 | -2 | 4.7 | -73.05 | |||||||||||||||||||||||||||||
| c.2000T>G | I667S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I667S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.083597 | Uncertain | 0.927 | 0.379 | 0.000 | -14.328 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.69 | Destabilizing | 0.1 | 3.97 | Destabilizing | 3.83 | Destabilizing | 2.48 | Destabilizing | 0.690 | Likely Pathogenic | -5.90 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.96 | Benign | 0.00 | Affected | 0.2462 | 0.0858 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1637G>T | C546F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant C546F is not reported in ClinVar and is absent from gnomAD. In silico predictors that classify the variant as benign include premPS and SIFT, whereas the majority of tools predict pathogenicity: REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus score (Likely Pathogenic). High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, SGM Consensus also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for C546F, and this assessment does not conflict with the current ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | -13.479 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | -1.21 | Ambiguous | 0.9 | 3.98 | Destabilizing | 1.39 | Ambiguous | 0.34 | Likely Benign | 0.800 | Likely Pathogenic | -8.99 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.20 | Pathogenic | 0.12 | Tolerated | 0.1622 | 0.3533 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.2132T>G | L711R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L711R lies in the GAP domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM; all other evaluated algorithms (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions or stability results are missing or inconclusive. Based on the overwhelming majority of computational evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.377436 | Uncertain | 0.950 | 0.364 | 0.000 | -14.009 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.71 | Destabilizing | 0.0 | 3.98 | Destabilizing | 3.85 | Destabilizing | 2.13 | Destabilizing | 0.432 | Likely Benign | -5.71 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.35 | Benign | 0.00 | Affected | 0.1345 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1682T>G | F561C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F561C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only SIFT, whereas all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024826 | Structured | 0.018013 | Uncertain | 0.903 | 0.196 | 0.000 | -13.035 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.92 | Destabilizing | 0.0 | 3.99 | Destabilizing | 3.96 | Destabilizing | 1.22 | Destabilizing | 0.769 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.25 | Pathogenic | 0.15 | Tolerated | 0.2720 | 0.0615 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.626T>G | V209G 2D AIThe SynGAP1 missense variant V209G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a pathogenic classification; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. Taken together, the overwhelming majority of computational evidence indicates that V209G is likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -13.763 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 3.05 | Destabilizing | 0.5 | 3.99 | Destabilizing | 3.52 | Destabilizing | 1.27 | Destabilizing | 0.390 | Likely Benign | -5.49 | Deleterious | 0.829 | Possibly Damaging | 0.995 | Probably Damaging | 3.65 | Benign | 0.04 | Affected | 0.1600 | 0.2035 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.799T>G | W267G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy methods corroborate this: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic, with no contradiction to its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -15.020 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 4.40 | Destabilizing | 0.2 | 3.99 | Destabilizing | 4.20 | Destabilizing | 1.20 | Destabilizing | 0.678 | Likely Pathogenic | -11.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.96 | Pathogenic | 0.03 | Affected | 0.4049 | 0.1481 | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||||||
| c.815G>C | R272P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R272P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the single uncertain call (premPS) does not alter the overall consensus. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.071867 | Structured | 0.425620 | Uncertain | 0.925 | 0.215 | 0.125 | -11.812 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 5.64 | Destabilizing | 0.2 | 3.99 | Destabilizing | 4.82 | Destabilizing | 0.80 | Ambiguous | 0.561 | Likely Pathogenic | -3.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.74 | Pathogenic | 0.01 | Affected | 0.2057 | 0.4102 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1195G>C | A399P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A399P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, FATHMM, and polyPhen‑2 HumVar; pathogenic predictions come from FoldX, Rosetta, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a pathogenic effect. Overall, the majority of evidence points toward a deleterious impact. The variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | -8.809 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | 2.29 | Destabilizing | 0.1 | 4.00 | Destabilizing | 3.15 | Destabilizing | 0.74 | Ambiguous | 0.498 | Likely Benign | -1.82 | Neutral | 0.596 | Possibly Damaging | 0.188 | Benign | 5.56 | Benign | 0.10 | Tolerated | 0.1847 | 0.5472 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||
| c.1823T>C | F608S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608S is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. All available predictions are consistent and conclusive. Based on the unanimous computational evidence, 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 | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -15.181 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 3.16 | Destabilizing | 0.2 | 4.00 | Destabilizing | 3.58 | Destabilizing | 1.66 | Destabilizing | 0.917 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.59 | Pathogenic | 0.02 | Affected | 0.4366 | 0.0400 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.980T>C | L327P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L327P (ClinVar ID 660421) is classified as Pathogenic in ClinVar and is not reported in gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, leaving no tools in the benign category. High‑accuracy assessments further support this: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is Pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.409189 | Uncertain | 0.939 | 0.490 | 0.000 | Pathogenic/Likely path. | 4 | -16.602 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.38 | Destabilizing | 0.1 | 4.00 | Destabilizing | 4.69 | Destabilizing | 2.62 | Destabilizing | 0.658 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.52 | Pathogenic | 0.01 | Affected | 3.38 | 23 | 0.3921 | 0.1703 | -3 | -3 | -5.4 | -16.04 | 221.7 | 69.4 | 0.1 | 0.0 | 0.6 | 0.1 | X | Potentially Pathogenic | The backbone amide group of Leu327, located in the middle of an anti-parallel β sheet strand (res. Ala322-Asp330), forms a hydrogen bond with the carbonyl group of Gly344 on a neighboring β strand (res. Lys336-Pro349) in the WT simulations. In contrast, in the variant simulations, the introduction of Pro327 destabilizes the hydrogen bonding between the two anti-parallel β strands because proline lacks the backbone amide group altogether. Additionally, in the WT simulations, the iso-butyl side chain of Leu327 packs against multiple hydrophobic residues (e.g., Leu274, V400, Val343), whereas the less bulky cyclic five-membered pyrrolidine ring of Pro327 cannot fill the same space as effectively. Thus, although no large-scale unfolding is observed during the variant simulations, the residue swap is likely to cause severe problems for the correct C2 domain folding, which could also affect the SynGAP-membrane association. | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||
| c.2099T>A | L700Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L700Q is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. All other evaluated tools—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized indicates a benign change, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. No predictions are missing or inconclusive. Overall, the preponderance of evidence from the majority of tools points to a pathogenic effect, 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 | 0.113710 | Structured | 0.416255 | Uncertain | 0.927 | 0.331 | 0.000 | -10.522 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 2.41 | Destabilizing | 0.1 | 4.02 | Destabilizing | 3.22 | Destabilizing | 1.35 | Destabilizing | 0.321 | Likely Benign | -3.79 | Deleterious | 0.994 | Probably Damaging | 0.896 | Possibly Damaging | 3.34 | Benign | 0.01 | Affected | 0.1074 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.797T>C | L266P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No conflicting benign evidence is present. Therefore, the variant is most likely pathogenic, and this conclusion is consistent with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -15.752 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 7.08 | Destabilizing | 0.1 | 4.02 | Destabilizing | 5.55 | Destabilizing | 2.31 | Destabilizing | 0.654 | Likely Pathogenic | -6.06 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.3158 | 0.1021 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1100T>C | L367P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L367P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict pathogenicity are FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, SIFT, and FATHMM; premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Overall, the majority of predictions lean toward a benign effect, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.370445 | Structured | 0.441805 | Uncertain | 0.790 | 0.657 | 0.250 | -2.418 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 2.13 | Destabilizing | 0.4 | 4.05 | Destabilizing | 3.09 | Destabilizing | 0.72 | Ambiguous | 0.212 | Likely Benign | -0.50 | Neutral | 0.627 | Possibly Damaging | 0.196 | Benign | 1.72 | Pathogenic | 0.02 | Affected | 0.3946 | 0.1874 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.647A>C | Q216P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216P is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, which scores the variant as benign. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic impact. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; SGM‑Consensus indicates likely pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. premPS is inconclusive and is treated as unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -13.128 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 4.35 | Destabilizing | 0.8 | 4.05 | Destabilizing | 4.20 | Destabilizing | 0.53 | Ambiguous | 0.830 | Likely Pathogenic | -4.69 | Deleterious | 0.989 | Probably Damaging | 0.737 | Possibly Damaging | 5.84 | Benign | 0.01 | Affected | 0.2603 | 0.5736 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.1086G>C | W362C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W362C is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect, so the benign group is empty. High‑accuracy methods reinforce this assessment: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic based on the consensus of all predictions, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.430310 | Uncertain | 0.957 | 0.552 | 0.125 | -11.200 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.68 | Destabilizing | 0.1 | 4.06 | Destabilizing | 3.87 | Destabilizing | 1.00 | Destabilizing | 0.618 | Likely Pathogenic | -11.95 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.24 | Pathogenic | 0.00 | Affected | 0.4158 | 0.1622 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||
| c.1086G>T | W362C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W362C is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact on protein stability. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.430310 | Uncertain | 0.957 | 0.552 | 0.125 | -11.200 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.68 | Destabilizing | 0.1 | 4.06 | Destabilizing | 3.87 | Destabilizing | 1.00 | Destabilizing | 0.618 | Likely Pathogenic | -11.95 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.24 | Pathogenic | 0.00 | Affected | 0.4158 | 0.1622 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||
| c.1148G>T | G383V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383V is not 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, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect are FoldX, Rosetta, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions lean toward a benign impact, 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. | Likely Benign | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | -5.769 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 5.13 | Destabilizing | 2.1 | 4.06 | Destabilizing | 4.60 | Destabilizing | -0.26 | Likely Benign | 0.406 | Likely Benign | -0.72 | Neutral | 0.668 | Possibly Damaging | 0.207 | Benign | 4.12 | Benign | 0.01 | Affected | 0.1597 | 0.3493 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1427T>C | F476S 2D AIThe SynGAP1 missense variant F476S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields an equal split of pathogenic and benign signals. Overall, the balance of evidence favors a pathogenic effect for F476S, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -12.675 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 3.02 | Destabilizing | 0.9 | 4.07 | Destabilizing | 3.55 | Destabilizing | 1.23 | Destabilizing | 0.278 | Likely Benign | -2.33 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.56 | Benign | 0.44 | Tolerated | 0.3387 | 0.0558 | -3 | -2 | -3.6 | -60.10 | ||||||||||||||||||||||||||||||
| c.2051A>G | D684G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess the variant’s effect largely agree on a deleterious outcome. Benign predictions come from premPS and FATHMM, whereas the remaining 12 tools—including REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify it as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. No prediction is inconclusive or missing. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -14.238 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.34 | Destabilizing | 1.0 | 4.07 | Destabilizing | 3.71 | Destabilizing | -0.30 | Likely Benign | 0.561 | Likely Pathogenic | -6.98 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.37 | Benign | 0.01 | Affected | 0.3686 | 0.5403 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1217A>C | Y406S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y406S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FoldX, Rosetta, premPS, and Foldetta all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -12.014 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 3.51 | Destabilizing | 0.3 | 4.08 | Destabilizing | 3.80 | Destabilizing | 1.40 | Destabilizing | 0.190 | Likely Benign | -6.72 | Deleterious | 0.991 | Probably Damaging | 0.886 | Possibly Damaging | 3.80 | Benign | 0.06 | Tolerated | 0.4719 | 0.2817 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.1267T>A | Y423N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y423N is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include SIFT and FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Based on the overwhelming majority of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -10.937 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 3.97 | Destabilizing | 0.1 | 4.08 | Destabilizing | 4.03 | Destabilizing | 2.07 | Destabilizing | 0.501 | Likely Pathogenic | -7.47 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.06 | Tolerated | 0.1405 | 0.0412 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1304T>C | L435S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -12.662 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 4.18 | Destabilizing | 0.0 | 4.09 | Destabilizing | 4.14 | Destabilizing | 1.83 | Destabilizing | 0.596 | Likely Pathogenic | -5.63 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.18 | Benign | 0.01 | Affected | 0.2705 | 0.0505 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||
| c.1448T>G | I483R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -17.066 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 5.14 | Destabilizing | 0.4 | 4.09 | Destabilizing | 4.62 | Destabilizing | 1.97 | Destabilizing | 0.595 | Likely Pathogenic | -6.50 | Deleterious | 0.997 | Probably Damaging | 0.991 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | 0.1120 | 0.0870 | -2 | -3 | -9.0 | 43.03 | |||||||||||||||||||||||||||||
| c.1726T>C | C576R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant C576R is listed in ClinVar with an uncertain significance (ClinVar ID 2780076.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it pathogenic, the SGM‑Consensus (derived from the majority of high‑confidence predictors) is pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Taken together, the overwhelming majority of computational evidence indicates that C576R is likely pathogenic, a conclusion that is consistent with, but not in conflict with, the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.017684 | Uncertain | 0.913 | 0.245 | 0.000 | Conflicting | 2 | -14.886 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 7.20 | Destabilizing | 1.0 | 4.09 | Destabilizing | 5.65 | Destabilizing | 1.64 | Destabilizing | 0.579 | Likely Pathogenic | -10.88 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.38 | Benign | 0.00 | Affected | 3.37 | 35 | 0.1887 | 0.1279 | -3 | -4 | -7.0 | 53.05 | |||||||||||||||||||||||||
| c.1142G>T | G381V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381V is listed in ClinVar with an uncertain significance (ClinVar ID 1940172.0) and is present in the gnomAD database (6‑33438047‑G‑T). Functional prediction tools that report a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, FoldX, Rosetta, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a majority‑benign vote and is reported as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.724957 | Disordered | 0.431692 | Uncertain | 0.301 | 0.951 | 0.750 | Uncertain | 1 | 6-33438047-G-T | 2 | 1.25e-6 | -5.967 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 7.16 | Destabilizing | 1.0 | 4.10 | Destabilizing | 5.63 | Destabilizing | -0.32 | Likely Benign | 0.618 | Likely Pathogenic | -0.95 | Neutral | 0.386 | Benign | 0.157 | Benign | 1.32 | Pathogenic | 0.10 | Tolerated | 4.32 | 9 | 0.1621 | 0.3902 | -1 | -3 | 4.6 | 42.08 | 214.6 | -68.8 | 0.3 | 0.7 | -0.5 | 0.3 | Uncertain | Gly381 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Val381 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effects on Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||
| c.947A>T | N316I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and premPS, whereas the majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. No prediction is missing or inconclusive beyond the uncertain AlphaMissense‑Optimized result. Based on the preponderance of pathogenic predictions and the high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.385187 | Uncertain | 0.817 | 0.246 | 0.125 | -11.164 | Likely Pathogenic | 0.899 | Likely Pathogenic | Ambiguous | 2.74 | Destabilizing | 0.2 | 4.10 | Destabilizing | 3.42 | Destabilizing | 0.18 | Likely Benign | 0.318 | Likely Benign | -6.37 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.00 | Pathogenic | 0.03 | Affected | 0.0734 | 0.7422 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.658T>G | F220V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220V is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -11.599 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.83 | Destabilizing | 0.1 | 4.11 | Destabilizing | 3.97 | Destabilizing | 1.56 | Destabilizing | 0.911 | Likely Pathogenic | -5.81 | Deleterious | 0.075 | Benign | 0.015 | Benign | 4.04 | Benign | 0.01 | Affected | 0.2351 | 0.3315 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.974T>G | L325R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. No predictions or stability results are missing or inconclusive. **Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status (no ClinVar entry).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.352862 | Structured | 0.424577 | Uncertain | 0.955 | 0.436 | 0.000 | -16.612 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.34 | Destabilizing | 0.3 | 4.11 | Destabilizing | 4.23 | Destabilizing | 1.94 | Destabilizing | 0.551 | Likely Pathogenic | -4.39 | Deleterious | 0.999 | Probably Damaging | 0.969 | Probably Damaging | 1.33 | Pathogenic | 0.00 | Affected | 0.1405 | 0.1047 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1766T>G | I589S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I589S is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also labels it pathogenic. Based on the uniform predictions, the variant is most likely pathogenic, and this 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 | 0.018415 | Structured | 0.084536 | Uncertain | 0.927 | 0.214 | 0.000 | -15.223 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.62 | Destabilizing | 0.1 | 4.12 | Destabilizing | 3.87 | Destabilizing | 2.21 | Destabilizing | 0.954 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.99 | Pathogenic | 0.00 | Affected | 0.2786 | 0.1130 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.2020A>C | T674P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T674P missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The high‑accuracy AlphaMissense‑Optimized predicts benign, while Foldetta predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. No other high‑accuracy tool provides a definitive call. Consequently, the evidence is evenly split between benign and pathogenic, leaving the variant’s clinical significance uncertain. This uncertainty does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.129801 | Structured | 0.109297 | Uncertain | 0.521 | 0.349 | 0.000 | -8.661 | Likely Pathogenic | 0.109 | Likely Benign | Likely Benign | 0.91 | Ambiguous | 0.6 | 4.12 | Destabilizing | 2.52 | Destabilizing | 0.12 | Likely Benign | 0.143 | Likely Benign | -2.69 | Deleterious | 0.995 | Probably Damaging | 0.891 | Possibly Damaging | 3.50 | Benign | 0.16 | Tolerated | 0.2039 | 0.6103 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||
| c.1661T>G | V554G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V554G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, while the remaining eleven tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as pathogenic. No predictions are missing or inconclusive. Overall, the variant is most likely pathogenic based on the collective evidence, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | -13.879 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | 3.31 | Destabilizing | 0.1 | 4.13 | Destabilizing | 3.72 | Destabilizing | 2.40 | Destabilizing | 0.594 | Likely Pathogenic | -6.96 | Deleterious | 0.997 | Probably Damaging | 1.000 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 0.1619 | 0.1548 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1406C>A | A469D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469D is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: the single benign prediction from SIFT, and a consensus of pathogenic predictions from the remaining 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus). High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. Taken together, the overwhelming majority of evidence points to a pathogenic effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | Uncertain | 1 | -14.643 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.09 | Destabilizing | 0.2 | 4.16 | Destabilizing | 4.63 | Destabilizing | 1.68 | Destabilizing | 0.738 | Likely Pathogenic | -3.48 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.34 | Pathogenic | 0.21 | Tolerated | 3.37 | 34 | 0.1372 | 0.1583 | 0 | -2 | -5.3 | 44.01 | 237.0 | -58.2 | -0.2 | 0.1 | 0.8 | 0.1 | X | X | Potentially Pathogenic | The methyl group of Ala469, located in an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Trp572, Leu588, Met470) in an inter-helix space formed by two other α helices (res. Glu582–Ser604, res. Arg563–Gly580). In the variant simulations, Asp469 introduces a negatively charged and bulky side chain into the hydrophobic niche. Consequently, the side chain of Asp469 rotates outward, allowing the carboxylate group to form a salt bridge with the guanidinium group of Arg575 on the protein surface. This interaction affects the continuity of the parent α helix (Ala461–Phe476). Due to the importance of hydrophobic packing, the structural effects could be more pronounced during actual protein folding. | |||||||||||||||
| c.1840T>G | Y614D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y614D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM predicts it to be benign, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify it as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.314870 | Structured | 0.182134 | Uncertain | 0.852 | 0.254 | 0.000 | -15.073 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.14 | Destabilizing | 0.6 | 4.16 | Destabilizing | 3.15 | Destabilizing | 1.69 | Destabilizing | 0.597 | Likely Pathogenic | -9.83 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.02 | Affected | 0.4013 | 0.0573 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1790T>G | F597C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F597C is reported in gnomAD (variant ID 6-33440842‑T‑G) but has no ClinVar entry. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). 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 | 6-33440842-T-G | 1 | 6.19e-7 | -12.099 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 3.77 | Destabilizing | 0.2 | 4.17 | Destabilizing | 3.97 | Destabilizing | 1.97 | Destabilizing | 0.953 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -2.19 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.2618 | 0.0783 | -2 | -4 | -0.3 | -44.04 | ||||||||||||||||||||||||
| c.838T>A | Y280N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only SIFT, whereas all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the overwhelming consensus of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for Y280N. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.161087 | Structured | 0.321243 | Uncertain | 0.917 | 0.248 | 0.125 | -13.090 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 4.26 | Destabilizing | 0.2 | 4.18 | Destabilizing | 4.22 | Destabilizing | 1.82 | Destabilizing | 0.589 | Likely Pathogenic | -8.27 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.95 | Pathogenic | 0.06 | Tolerated | 0.1902 | 0.0212 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1282T>G | Y428D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y428D is not reported in ClinVar and is absent from gnomAD. Across a broad panel of in silico predictors, 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) uniformly predict a deleterious effect, whereas only FATHMM classifies it as benign. 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 this: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote) is likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic effect. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | -13.473 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.24 | Destabilizing | 0.0 | 4.19 | Destabilizing | 3.72 | Destabilizing | 1.64 | Destabilizing | 0.554 | Likely Pathogenic | -9.55 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.50 | Benign | 0.01 | Affected | 0.4458 | 0.1003 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1631G>C | R544P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R544P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Across the available in‑silico predictors, none indicate a benign effect; all 13 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. Consequently, the variant is most likely pathogenic based on current predictions, which contradicts the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038858 | Structured | 0.016004 | Uncertain | 0.967 | 0.333 | 0.000 | Uncertain | 2 | -16.905 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.70 | Destabilizing | 0.1 | 4.19 | Destabilizing | 4.45 | Destabilizing | 1.14 | Destabilizing | 0.762 | Likely Pathogenic | -4.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.48 | Pathogenic | 0.05 | Affected | 3.37 | 35 | 0.2024 | 0.3038 | 0 | -2 | 2.9 | -59.07 | 192.0 | 123.8 | 0.1 | 0.0 | -0.3 | 0.0 | X | X | Potentially Pathogenic | Arg544 is located in the middle of an α-helix (res. Ala533-Val560). In the WT simulations, the guanidinium side chain of Arg544 forms a salt bridge with the carboxylate groups of Glu548 on the same α-helix, and with Glu651 and Glu656 on an opposing α-helix (res. Glu666-Asp644). In the variant simulations, the pyrrolidine side chain of Pro544 cannot form any of the salt bridges that Arg544 does in the WT, potentially weakening the tertiary structure assembly. Additionally, Pro544 lacks the amide group, and thus, unlike Arg544 in the WT, is unable to form a hydrogen bond with the carbonyl of Gln540. This disruption breaks the continuity of the secondary structure element, causing the α-helix to bend slightly in the variant simulations. These negative structural effects could be more pronounced during protein folding and are likely to be undermined in the MD simulations. | |||||||||||||||
| c.2099T>G | L700R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L700R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic calls are made by Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, SGM Consensus remains Likely Pathogenic, and Foldetta predicts a destabilizing, pathogenic effect. Overall, the preponderance of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.416255 | Uncertain | 0.927 | 0.331 | 0.000 | -12.389 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 1.82 | Ambiguous | 0.1 | 4.19 | Destabilizing | 3.01 | Destabilizing | 1.89 | Destabilizing | 0.485 | Likely Benign | -4.29 | Deleterious | 0.728 | Possibly Damaging | 0.249 | Benign | 3.35 | Benign | 0.01 | Affected | 0.1210 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1235T>C | L412S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L412S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic or likely pathogenic scores, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized indicates pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) also predicts pathogenic. No prediction is inconclusive or missing. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -13.884 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.03 | Destabilizing | 0.2 | 4.20 | Destabilizing | 4.12 | Destabilizing | 2.01 | Destabilizing | 0.557 | Likely Pathogenic | -5.53 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.22 | Benign | 0.00 | Affected | 0.2821 | 0.0505 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||
| c.1538T>G | F513C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513C is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also labels it pathogenic. Based on the uniform predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -11.389 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.92 | Destabilizing | 0.3 | 4.20 | Destabilizing | 4.06 | Destabilizing | 1.64 | Destabilizing | 0.919 | Likely Pathogenic | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.40 | Pathogenic | 0.03 | Affected | 0.2384 | 0.0783 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.709G>C | A237P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, Rosetta, and Foldetta. High‑accuracy assessments further support pathogenicity: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, Foldetta is pathogenic, and AlphaMissense‑Optimized is uncertain (treated as unavailable). Overall, the preponderance of evidence indicates that A237P is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar status is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -9.119 | Likely Pathogenic | 0.827 | Likely Pathogenic | Ambiguous | 0.10 | Likely Benign | 0.5 | 4.20 | Destabilizing | 2.15 | Destabilizing | 1.04 | Destabilizing | 0.752 | Likely Pathogenic | -3.68 | Deleterious | 0.995 | Probably Damaging | 0.832 | Possibly Damaging | 5.77 | Benign | 0.03 | Affected | 0.1593 | 0.3724 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1874T>G | L625R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L625R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | -14.507 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 2.31 | Destabilizing | 0.7 | 4.21 | Destabilizing | 3.26 | Destabilizing | 1.88 | Destabilizing | 0.733 | Likely Pathogenic | -5.93 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.99 | Benign | 0.00 | Affected | 0.1091 | 0.0615 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.611C>T | S204F 2D  AIThe SynGAP1 missense variant S204F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, and FATHMM, whereas a majority of tools (FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding‑stability method combining FoldX‑MD and Rosetta outputs, predicts a pathogenic effect. Overall, the balance of evidence—seven pathogenic versus four benign predictions, with high‑accuracy tools supporting pathogenicity—suggests that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -8.693 | Likely Pathogenic | 0.842 | Likely Pathogenic | Ambiguous | 7.35 | Destabilizing | 6.1 | 4.21 | Destabilizing | 5.78 | Destabilizing | -0.09 | Likely Benign | 0.161 | Likely Benign | -0.88 | Neutral | 0.978 | Probably Damaging | 0.694 | Possibly Damaging | 4.16 | Benign | 0.03 | Affected | 0.0468 | 0.5764 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||
| c.1580A>G | D527G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D527G is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools cluster into two groups: the single benign prediction comes from premPS, while all other evaluated algorithms—SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—indicate pathogenicity. FoldX is uncertain and therefore not counted as evidence for either side. High‑accuracy methods reinforce the pathogenic assessment: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No contradictory evidence exists in ClinVar. **Thus, the variant is most likely pathogenic based on the collective predictions, with no ClinVar status to contradict this assessment.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -15.177 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.71 | Ambiguous | 1.0 | 4.22 | Destabilizing | 2.97 | Destabilizing | 0.33 | Likely Benign | 0.933 | Likely Pathogenic | -6.86 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -2.39 | Pathogenic | 0.01 | Affected | 0.2847 | 0.4366 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.692T>C | F231S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -14.655 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.89 | Destabilizing | 0.4 | 4.22 | Destabilizing | 3.56 | Destabilizing | 2.22 | Destabilizing | 0.909 | Likely Pathogenic | -6.92 | Deleterious | 0.608 | Possibly Damaging | 0.205 | Benign | 5.48 | Benign | 0.00 | Affected | 0.4297 | 0.0544 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1031G>C | G344A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G344A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default, while only SIFT predicts a benign outcome. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. Overall, the consensus of the majority of predictors indicates a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | -10.439 | Likely Pathogenic | 0.931 | Likely Pathogenic | Ambiguous | 5.11 | Destabilizing | 0.4 | 4.23 | Destabilizing | 4.67 | Destabilizing | 0.58 | Ambiguous | 0.873 | Likely Pathogenic | -5.38 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -0.32 | Pathogenic | 0.10 | Tolerated | 0.3964 | 0.5685 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1469C>A | A490D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A490D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that assess pathogenicity are unanimous: AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, SIFT, polyPhen‑2 (HumDiv and HumVar), REVEL, premPS, FoldX, Rosetta, and Foldetta all classify the variant as pathogenic. No tool predicts a benign effect, so the benign group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this assessment is consistent with the absence of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.120615 | Structured | 0.322979 | Uncertain | 0.938 | 0.210 | 0.125 | -16.643 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.33 | Destabilizing | 0.1 | 4.23 | Destabilizing | 3.78 | Destabilizing | 1.33 | Destabilizing | 0.946 | Likely Pathogenic | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.48 | Pathogenic | 0.00 | Affected | 0.1532 | 0.1741 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1705T>A | F569I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F569I is not listed in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classifies the substitution as pathogenic. No predictor reports a benign outcome, so the benign group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also indicates pathogenicity. 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 | 0.024393 | Structured | 0.054289 | Uncertain | 0.941 | 0.242 | 0.000 | -15.362 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.75 | Destabilizing | 0.2 | 4.23 | Destabilizing | 3.99 | Destabilizing | 1.51 | Destabilizing | 0.903 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 0.1950 | 0.1973 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1901C>A | A634D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A634D is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.052058 | Uncertain | 0.932 | 0.242 | 0.000 | -16.727 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.26 | Destabilizing | 0.5 | 4.24 | Destabilizing | 4.75 | Destabilizing | 1.79 | Destabilizing | 0.731 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.1790 | 0.1816 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1049T>G | V350G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350G lies in the C2 domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, polyPhen‑2 HumDiv, and AlphaMissense‑Optimized. The remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—predict it to be pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All predictions are available and consistent. Based on the preponderance of pathogenic calls, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -12.267 | Likely Pathogenic | 0.597 | Likely Pathogenic | Likely Benign | 2.57 | Destabilizing | 0.0 | 4.25 | Destabilizing | 3.41 | Destabilizing | 1.93 | Destabilizing | 0.330 | Likely Benign | -5.46 | Deleterious | 0.435 | Benign | 0.920 | Probably Damaging | 1.61 | Pathogenic | 0.02 | Affected | 0.2316 | 0.2522 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.836G>C | R279P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. No tool predicts a benign effect. FoldX reports an uncertain outcome, but Rosetta, Foldetta, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all predict pathogenicity. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus, based on a majority vote of the aforementioned predictors, is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | -14.926 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 1.42 | Ambiguous | 0.9 | 4.27 | Destabilizing | 2.85 | Destabilizing | 1.21 | Destabilizing | 0.626 | Likely Pathogenic | -5.01 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.90 | Pathogenic | 0.02 | Affected | 0.2179 | 0.3281 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.922T>A | W308R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.333942 | Uncertain | 0.907 | 0.314 | 0.125 | -12.264 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.40 | Destabilizing | 0.5 | 4.27 | Destabilizing | 4.84 | Destabilizing | 1.88 | Destabilizing | 0.868 | Likely Pathogenic | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.4751 | 0.0361 | 2 | -3 | -3.6 | -30.03 | 290.4 | -26.7 | -0.1 | 0.1 | 0.0 | 0.2 | X | X | X | Potentially Pathogenic | The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The guanidinium group of Arg308 is comparably sized to the tryptophan it replaced; however, it is also positively charged.In the variant simulations, the charged side chain remains buried deep in the hydrophobic part of the C2 domain, where it forms new hydrogen bonds with the backbone carbonyl atoms of surrounding residues (e.g., Val306, Ile268). However, the residue swap is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | ||||||||||||||||
| c.922T>C | W308R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308R is listed in ClinVar (ID 391294.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.333942 | Uncertain | 0.907 | 0.314 | 0.125 | Pathogenic | 1 | -12.264 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.40 | Destabilizing | 0.5 | 4.27 | Destabilizing | 4.84 | Destabilizing | 1.88 | Destabilizing | 0.868 | Likely Pathogenic | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.4751 | 0.0361 | 2 | -3 | -3.6 | -30.03 | 290.4 | -26.7 | -0.1 | 0.1 | 0.0 | 0.2 | X | X | X | Potentially Pathogenic | The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The guanidinium group of Arg308 is comparably sized to the tryptophan it replaced; however, it is also positively charged.In the variant simulations, the charged side chain remains buried deep in the hydrophobic part of the C2 domain, where it forms new hydrogen bonds with the backbone carbonyl atoms of surrounding residues (e.g., Val306, Ile268). However, the residue swap is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | ||||||||||||||
| c.1169G>A | G390E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G390E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, FoldX, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Default. A high‑accuracy assessment shows AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions support a pathogenic effect, and this aligns with the ClinVar designation of uncertain significance rather than contradicting it. 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. | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | Uncertain | 1 | -7.913 | In-Between | 0.646 | Likely Pathogenic | Likely Benign | 2.61 | Destabilizing | 0.9 | 4.28 | Destabilizing | 3.45 | Destabilizing | 0.47 | Likely Benign | 0.575 | Likely Pathogenic | -0.87 | Neutral | 0.276 | Benign | 0.045 | Benign | 1.32 | Pathogenic | 0.05 | Affected | 4.32 | 8 | 0.1595 | 0.4309 | 0 | -2 | -3.1 | 72.06 | 241.5 | -108.4 | 0.6 | 0.5 | -0.1 | 0.1 | Uncertain | Gly390 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. This loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play significant roles in protein functions that require flexibility, and so they are rich in glycine residues, prolines, and to a lesser extent, small hydrophilic residues to ensure maximum flexibility. Thus, the variant’s Glu390 may not be as well tolerated in the Ω loop. Additionally, the carboxylate group of Glu390 occasionally forms H-bonds with other loop residues in the variant simulations. The interaction between the acidic carboxylate side chain and the acidic membrane lipids may further influence the SynGAP-membrane complex. However, 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.1216T>G | Y406D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y406D is not 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. In contrast, the majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic,” while premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the preponderance of evidence, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -14.832 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.82 | Destabilizing | 0.3 | 4.28 | Destabilizing | 4.05 | Destabilizing | 0.98 | Ambiguous | 0.347 | Likely Benign | -7.64 | Deleterious | 0.999 | Probably Damaging | 0.950 | Probably Damaging | 3.77 | Benign | 0.01 | Affected | 0.4439 | 0.0903 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1489T>G | Y497D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a destabilizing, pathogenic effect. All available predictions are concordant and indicate a likely pathogenic impact. Thus, based on the collective computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -12.128 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 4.70 | Destabilizing | 0.2 | 4.29 | Destabilizing | 4.50 | Destabilizing | 2.36 | Destabilizing | 0.918 | Likely Pathogenic | -9.81 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.67 | Pathogenic | 0.01 | Affected | 0.3621 | 0.0612 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.851T>G | L284R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L284R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.094817 | Structured | 0.371601 | Uncertain | 0.950 | 0.255 | 0.000 | -17.698 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.05 | Destabilizing | 0.5 | 4.29 | Destabilizing | 4.67 | Destabilizing | 2.14 | Destabilizing | 0.797 | Likely Pathogenic | -5.38 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.65 | Pathogenic | 0.00 | Affected | 0.1175 | 0.0600 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.917T>A | V306D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306D is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All available in‑silico predictors that were evaluated return a pathogenic or likely‑pathogenic assessment: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.363090 | Structured | 0.315026 | Uncertain | 0.896 | 0.287 | 0.125 | Uncertain | 1 | -18.289 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 4.40 | Destabilizing | 0.3 | 4.29 | Destabilizing | 4.35 | Destabilizing | 2.44 | Destabilizing | 0.530 | Likely Pathogenic | -5.44 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.74 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.1317 | 0.0768 | -2 | -3 | -7.7 | 15.96 | 212.3 | -18.3 | -0.2 | 0.4 | 0.0 | 0.2 | X | X | X | Potentially Pathogenic | The isopropyl group of Val396, located at the beginning of an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Leu274, Trp308, Ala271) in the WT simulations. However, in the variant simulations, the negatively charged carboxylate group of the Asp306 side chain is not suitable for this hydrophobic niche. Consequently, the side chain moves out to interact with Ser300 in the β strand (res. Met289-Arg299) and the guanidinium group of Arg299 in the β hairpin loop.In the third simulation, the residue swap disrupts the C2 domain secondary structure and tertiary assembly to a large degree when the amino group of the Lys297 side chain rotates to form a salt bridge with Asp306. This drastic effect could potentially reflect the challenge presented by the residue swap during the C2 domain folding. Because the residue swap affects the C2 domain structure, the SynGAP-membrane association could also be impacted. However, this is beyond the scope of the solvent-only simulations to unravel. | ||||||||||||||
| c.950T>C | L317P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L317P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tools predict a benign effect, so the benign group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.106997 | Structured | 0.394031 | Uncertain | 0.874 | 0.240 | 0.125 | -14.778 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.61 | Destabilizing | 1.4 | 4.29 | Destabilizing | 3.95 | Destabilizing | 1.26 | Destabilizing | 0.654 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.82 | Pathogenic | 0.00 | Affected | 0.3405 | 0.1153 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1201C>G | R401G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.314870 | Structured | 0.424277 | Uncertain | 0.961 | 0.419 | 0.000 | -13.353 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.06 | Destabilizing | 0.2 | 4.31 | Destabilizing | 3.69 | Destabilizing | 1.01 | Destabilizing | 0.741 | Likely Pathogenic | -6.45 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 5.45 | Benign | 0.00 | Affected | 0.3549 | 0.2866 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1391T>G | F464C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -13.011 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.18 | Destabilizing | 0.0 | 4.31 | Destabilizing | 4.25 | Destabilizing | 2.20 | Destabilizing | 0.740 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.2298 | 0.1219 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1471A>C | T491P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T491P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | -13.603 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 3.19 | Destabilizing | 0.6 | 4.32 | Destabilizing | 3.76 | Destabilizing | 0.96 | Ambiguous | 0.882 | Likely Pathogenic | -5.89 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.49 | Pathogenic | 0.00 | Affected | 0.2024 | 0.3759 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1513T>A | Y505N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505N is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools largely agree on a deleterious effect: all available predictors except FATHMM classify the variant as pathogenic or likely pathogenic. The benign group contains only FATHMM, whereas the pathogenic group includes SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -14.139 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 3.38 | Destabilizing | 0.0 | 4.33 | Destabilizing | 3.86 | Destabilizing | 2.47 | Destabilizing | 0.695 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 0.2124 | 0.0612 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1550T>G | L517R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517R is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the only tool with an uncertain outcome is FoldX. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts Likely Pathogenic, and Foldetta predicts Pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -14.761 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.75 | Ambiguous | 0.2 | 4.33 | Destabilizing | 3.04 | Destabilizing | 1.83 | Destabilizing | 0.936 | Likely Pathogenic | -5.79 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | 0.1202 | 0.0688 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1343C>A | A448D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448D is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or folding result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -17.290 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 8.13 | Destabilizing | 0.2 | 4.35 | Destabilizing | 6.24 | Destabilizing | 1.40 | Destabilizing | 0.662 | Likely Pathogenic | -5.93 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | 0.1541 | 0.1741 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1390T>A | F464I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are limited to FATHMM, while all other evaluated algorithms—including SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -11.210 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 4.77 | Destabilizing | 0.2 | 4.35 | Destabilizing | 4.56 | Destabilizing | 1.23 | Destabilizing | 0.539 | Likely Pathogenic | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | 0.1439 | 0.2002 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1781T>G | F594C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F594C is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. All available evidence points to a damaging effect. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009187 | Structured | 0.120166 | Uncertain | 0.946 | 0.147 | 0.000 | -14.591 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.97 | Destabilizing | 0.0 | 4.35 | Destabilizing | 4.16 | Destabilizing | 1.36 | Destabilizing | 0.943 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -2.05 | Pathogenic | 0.03 | Affected | 0.2595 | 0.0615 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1955T>G | F652C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F652C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. No prediction is inconclusive or missing. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -12.023 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.27 | Destabilizing | 0.1 | 4.35 | Destabilizing | 3.81 | Destabilizing | 2.54 | Destabilizing | 0.695 | Likely Pathogenic | -7.74 | Deleterious | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.99 | Benign | 0.00 | Affected | 0.2293 | 0.0783 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1301T>G | V434G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434G has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are SIFT and FATHMM, while the remaining tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default) all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as pathogenic. Taken together, the overwhelming majority of evidence indicates a deleterious effect. Therefore, 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. | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -12.519 | Likely Pathogenic | 0.809 | Likely Pathogenic | Ambiguous | 3.08 | Destabilizing | 0.0 | 4.37 | Destabilizing | 3.73 | Destabilizing | 1.91 | Destabilizing | 0.564 | Likely Pathogenic | -5.16 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.39 | Benign | 0.07 | Tolerated | 0.1758 | 0.2408 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1514A>G | Y505C 2D AIThe SynGAP1 missense variant Y505C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -11.784 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 3.41 | Destabilizing | 0.5 | 4.37 | Destabilizing | 3.89 | Destabilizing | 2.32 | Destabilizing | 0.578 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 0.3203 | 0.1814 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.924G>C | W308C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308C is listed in ClinVar as Pathogenic (ClinVar ID 981381.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Pathogenic”; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.333942 | Uncertain | 0.907 | 0.314 | 0.125 | Pathogenic/Likely path. | 2 | -12.791 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.56 | Destabilizing | 0.3 | 4.38 | Destabilizing | 4.97 | Destabilizing | 1.26 | Destabilizing | 0.738 | Likely Pathogenic | -11.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.4390 | 0.1621 | -8 | -2 | 3.4 | -83.07 | 230.8 | 60.5 | -0.3 | 0.1 | -0.4 | 0.4 | X | Potentially Pathogenic | The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The introduced Cys308 is smaller than the tryptophan it replaced. The thiol group of the Cys308 side chain is well-suited for the inner hydrophobic part of the C2 domain. Although the negative effects are essentially missing from the simulations, the side chain size difference between the residues is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | ||||||||||||||||
| c.924G>T | W308C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308C is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a deleterious effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.333942 | Uncertain | 0.907 | 0.314 | 0.125 | -12.791 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.56 | Destabilizing | 0.3 | 4.38 | Destabilizing | 4.97 | Destabilizing | 1.26 | Destabilizing | 0.738 | Likely Pathogenic | -11.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.4390 | 0.1621 | -8 | -2 | 3.4 | -83.07 | 230.8 | 60.5 | -0.3 | 0.1 | -0.4 | 0.4 | X | Potentially Pathogenic | The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The introduced Cys308 is smaller than the tryptophan it replaced. The thiol group of the Cys308 side chain is well-suited for the inner hydrophobic part of the C2 domain. Although the negative effects are essentially missing from the simulations, the side chain size difference between the residues is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | ||||||||||||||||||
| c.1028T>G | V343G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V343G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—classify the variant as pathogenic. AlphaMissense‑Optimized is uncertain, providing no definitive direction. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Thus, the preponderance of evidence indicates that V343G 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. | C2 | 0.291804 | Structured | 0.383911 | Uncertain | 0.882 | 0.497 | 0.250 | -11.332 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 2.49 | Destabilizing | 0.1 | 4.40 | Destabilizing | 3.45 | Destabilizing | 1.68 | Destabilizing | 0.421 | Likely Benign | -5.84 | Deleterious | 0.898 | Possibly Damaging | 0.996 | Probably Damaging | 1.60 | Pathogenic | 0.00 | Affected | 0.1982 | 0.3341 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1885G>T | V629F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V629F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain and is not counted as evidence. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta is pathogenic. No prediction is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions and the absence of any ClinVar annotation, the variant is most likely pathogenic, with no contradiction from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.034796 | Uncertain | 0.970 | 0.236 | 0.000 | -13.484 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 3.41 | Destabilizing | 0.5 | 4.40 | Destabilizing | 3.91 | Destabilizing | 0.64 | Ambiguous | 0.642 | Likely Pathogenic | -4.68 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.07 | Benign | 0.00 | Affected | 0.0560 | 0.2915 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||
| c.2068T>C | S690P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, a conclusion that does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | Uncertain | 1 | -14.568 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.84 | Destabilizing | 0.3 | 4.40 | Destabilizing | 4.62 | Destabilizing | 1.42 | Destabilizing | 0.431 | Likely Benign | -4.77 | Deleterious | 0.998 | Probably Damaging | 0.790 | Possibly Damaging | 3.44 | Benign | 0.01 | Affected | 3.42 | 17 | 0.1787 | 0.4050 | 1 | -1 | -0.8 | 10.04 | 207.5 | 15.1 | 0.1 | 0.0 | -0.1 | 0.2 | X | X | Potentially Pathogenic | The hydroxyl side chain of Ser690, located in an α-helix (res. Leu696-Leu685), forms a hydrogen bond with the backbone carbonyl group of Ser410 in an anti-parallel β-sheet of the C2 domain (res. Ile411-Ala399). In the variant simulations, the pyrrolidine side chain of Pro690 cannot form hydrogen bonds with the C2 domain residue, resulting in the loss of this inter-domain connection. Additionally, prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Gly686, introducing a slight bend in the α-helix and compromising its integrity. | |||||||||||||||
| c.1451T>C | F484S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -15.666 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.68 | Destabilizing | 0.1 | 4.42 | Destabilizing | 4.55 | Destabilizing | 2.26 | Destabilizing | 0.705 | Likely Pathogenic | -7.76 | Deleterious | 1.000 | Probably Damaging | 0.986 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 0.3993 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1538T>C | F513S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only SIFT, whereas all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -12.172 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.21 | Destabilizing | 0.4 | 4.43 | Destabilizing | 4.32 | Destabilizing | 2.25 | Destabilizing | 0.917 | Likely Pathogenic | -7.75 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.27 | Pathogenic | 0.10 | Tolerated | 0.3864 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1130T>A | M377K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are Rosetta and Foldetta. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome, while premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.675549 | Disordered | 0.431183 | Uncertain | 0.324 | 0.884 | 0.625 | -3.718 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.20 | Likely Benign | 0.2 | 4.44 | Destabilizing | 2.32 | Destabilizing | 0.62 | Ambiguous | 0.440 | Likely Benign | -0.26 | Neutral | 0.002 | Benign | 0.003 | Benign | 5.46 | Benign | 0.07 | Tolerated | 0.2423 | 0.1671 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.1147G>T | G383W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G383W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438052‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and Foldetta as pathogenic. Because the majority of conventional predictors favor pathogenicity while the high‑accuracy subset is split, the overall evidence leans toward a pathogenic interpretation. This conclusion does not conflict with the ClinVar uncertain status, which reflects the current lack of definitive clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | Uncertain | 1 | 6-33438052-G-T | 1 | 6.22e-7 | -10.161 | Likely Pathogenic | 0.439 | Ambiguous | Likely Benign | 5.81 | Destabilizing | 3.6 | 4.44 | Destabilizing | 5.13 | Destabilizing | 0.08 | Likely Benign | 0.469 | Likely Benign | -1.01 | Neutral | 0.959 | Probably Damaging | 0.704 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 4.32 | 7 | 0.0972 | 0.3785 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||
| c.1394T>G | L465R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No inconclusive or missing results are present. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | -17.976 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.52 | Destabilizing | 0.7 | 4.44 | Destabilizing | 4.48 | Destabilizing | 2.41 | Destabilizing | 0.761 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 0.1597 | 0.0963 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1361T>G | I454S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -13.025 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.50 | Destabilizing | 0.1 | 4.45 | Destabilizing | 4.48 | Destabilizing | 2.20 | Destabilizing | 0.574 | Likely Pathogenic | -5.83 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.2116 | 0.0800 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1703T>G | V568G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V568G is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID 6‑33440755‑T‑G). Prediction tools that agree on a pathogenic effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tools predict 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 outputs) as Pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024826 | Structured | 0.053503 | Uncertain | 0.937 | 0.257 | 0.000 | 6-33440755-T-G | -15.135 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 3.39 | Destabilizing | 0.1 | 4.45 | Destabilizing | 3.92 | Destabilizing | 2.34 | Destabilizing | 0.933 | Likely Pathogenic | -6.81 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.46 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.1822 | 0.1877 | -3 | -1 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.1706T>G | F569C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F569C is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also labels it pathogenic. Based on the uniform predictions, the variant is most likely pathogenic, and this 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 | 0.024393 | Structured | 0.054289 | Uncertain | 0.941 | 0.242 | 0.000 | -13.237 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 4.08 | Destabilizing | 0.0 | 4.45 | Destabilizing | 4.27 | Destabilizing | 1.20 | Destabilizing | 0.867 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.96 | Pathogenic | 0.04 | Affected | 0.2722 | 0.0462 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.839A>G | Y280C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic or likely pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a pathogenic effect on protein stability. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.161087 | Structured | 0.321243 | Uncertain | 0.917 | 0.248 | 0.125 | -10.645 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 3.85 | Destabilizing | 0.2 | 4.45 | Destabilizing | 4.15 | Destabilizing | 1.68 | Destabilizing | 0.629 | Likely Pathogenic | -8.24 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.96 | Pathogenic | 0.01 | Affected | 0.2877 | 0.1296 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.1191C>G | C397W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus, whereas pathogenic calls are made by REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, but Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts pathogenic. Overall, the majority of tools lean toward a benign effect, and this is consistent with the lack of ClinVar evidence. Therefore, the variant is most likely benign, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -6.857 | Likely Benign | 0.614 | Likely Pathogenic | Likely Benign | 2.40 | Destabilizing | 2.3 | 4.46 | Destabilizing | 3.43 | Destabilizing | 0.19 | Likely Benign | 0.545 | Likely Pathogenic | -1.87 | Neutral | 0.987 | Probably Damaging | 0.814 | Possibly Damaging | 4.64 | Benign | 0.02 | Affected | 0.1637 | 0.5092 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1979T>A | M660K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M660K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a pathogenic effect. Based on the overwhelming consensus of pathogenic predictions and the corroborating high‑accuracy tools, 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 | 0.047319 | Structured | 0.134270 | Uncertain | 0.944 | 0.289 | 0.000 | -14.123 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.13 | Destabilizing | 0.1 | 4.46 | Destabilizing | 3.80 | Destabilizing | 2.36 | Destabilizing | 0.604 | Likely Pathogenic | -5.99 | Deleterious | 0.862 | Possibly Damaging | 0.216 | Benign | 3.34 | Benign | 0.00 | Affected | 0.1389 | 0.0856 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.872A>C | Y291S 2D AIThe SynGAP1 missense variant Y291S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in silico predictors classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.383842 | Uncertain | 0.912 | 0.251 | 0.000 | -11.928 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 3.47 | Destabilizing | 0.8 | 4.47 | Destabilizing | 3.97 | Destabilizing | 2.01 | Destabilizing | 0.588 | Likely Pathogenic | -7.31 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.83 | Pathogenic | 0.02 | Affected | 0.4850 | 0.2079 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.968T>G | L323R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L323R is listed in ClinVar (ID 978601.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Consequently, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.268042 | Structured | 0.428564 | Uncertain | 0.956 | 0.369 | 0.000 | Likely Pathogenic | 1 | -14.568 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.75 | Destabilizing | 0.4 | 4.47 | Destabilizing | 4.11 | Destabilizing | 2.15 | Destabilizing | 0.692 | Likely Pathogenic | -4.70 | Deleterious | 0.999 | Probably Damaging | 0.969 | Probably Damaging | 0.59 | Pathogenic | 0.01 | Affected | 3.39 | 22 | 0.1066 | 0.0600 | -3 | -2 | -8.3 | 43.03 | 261.8 | -61.6 | -0.4 | 0.2 | 0.8 | 0.2 | X | X | X | Potentially Pathogenic | The iso-butyl side chain of Leu323, located at the beginning of an anti-parallel β sheet strand (res. Ala322-Asp330), packs against multiple hydrophobic leucine residues (e.g., Leu264, Leu266, Leu284, Leu286). In contrast, in the variant simulations, the positively charged guanidinium group of the Arg323 side chain is unsuitable for the hydrophobic niche. Consequently, the side chain either rotates away from the center of the C2 domain or, if it remains within the C2 domain core, it reorients nearby residues to form hydrogen bonds. Regardless, the residue swap extensively disrupts the C2 domain structure. | ||||||||||||||
| c.1268A>G | Y423C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y423C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. The remaining tools—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain (treated as unavailable), SGM‑Consensus as Likely Pathogenic, and Foldetta as Pathogenic. With the majority of evidence pointing to deleterious effects, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -9.003 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 4.01 | Destabilizing | 0.1 | 4.49 | Destabilizing | 4.25 | Destabilizing | 1.84 | Destabilizing | 0.286 | Likely Benign | -7.51 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.38 | Benign | 0.03 | Affected | 0.2381 | 0.1096 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.2140C>A | L714M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L714M is not reported in ClinVar (no entry) and is absent from gnomAD. Benign predictions are provided by REVEL, FoldX, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (likely benign). Pathogenic predictions come from Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy tools give mixed results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign; Foldetta (combining FoldX‑MD and Rosetta) predicts pathogenic. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.314870 | Structured | 0.402311 | Uncertain | 0.961 | 0.369 | 0.000 | -0.989 | Likely Benign | 0.827 | Likely Pathogenic | Ambiguous | 0.45 | Likely Benign | 0.0 | 4.49 | Destabilizing | 2.47 | Destabilizing | 1.00 | Destabilizing | 0.249 | Likely Benign | -1.86 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 0.0687 | 0.2626 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.821T>C | L274P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool in the dataset predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.066181 | Structured | 0.377483 | Uncertain | 0.866 | 0.195 | 0.250 | -14.667 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.62 | Destabilizing | 1.5 | 4.49 | Destabilizing | 5.06 | Destabilizing | 1.66 | Destabilizing | 0.804 | Likely Pathogenic | -6.30 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.00 | Pathogenic | 0.00 | Affected | 0.3535 | 0.0625 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1987T>A | F663I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -15.006 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.63 | Destabilizing | 0.1 | 4.51 | Destabilizing | 3.57 | Destabilizing | 1.60 | Destabilizing | 0.641 | Likely Pathogenic | -5.99 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 0.1740 | 0.1955 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1886T>G | V629G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V629G 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 only FATHMM, whereas the remaining eleven tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) uniformly predict a pathogenic outcome; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. Taken together, the overwhelming majority of evidence indicates that V629G is likely pathogenic, 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. | GAP | 0.040537 | Structured | 0.034796 | Uncertain | 0.970 | 0.236 | 0.000 | -13.150 | Likely Pathogenic | 0.871 | Likely Pathogenic | Ambiguous | 3.81 | Destabilizing | 0.0 | 4.52 | Destabilizing | 4.17 | Destabilizing | 1.94 | Destabilizing | 0.678 | Likely Pathogenic | -6.47 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.07 | Benign | 0.00 | Affected | 0.1903 | 0.2240 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1231A>T | I411F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411F 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, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | -13.377 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 5.71 | Destabilizing | 0.1 | 4.53 | Destabilizing | 5.12 | Destabilizing | 0.73 | Ambiguous | 0.503 | Likely Pathogenic | -3.69 | Deleterious | 0.998 | Probably Damaging | 0.973 | Probably Damaging | 3.30 | Benign | 0.00 | Affected | 0.0538 | 0.2853 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.841T>G | Y281D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SIFT classifies it as benign, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict it to be pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. No tool yields an inconclusive result. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.337647 | Uncertain | 0.927 | 0.254 | 0.000 | -15.506 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 4.27 | Destabilizing | 0.0 | 4.53 | Destabilizing | 4.40 | Destabilizing | 1.48 | Destabilizing | 0.813 | Likely Pathogenic | -6.73 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.98 | Pathogenic | 0.06 | Tolerated | 0.4173 | 0.1175 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1682T>C | F561S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F561S is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No predictions are inconclusive. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024826 | Structured | 0.018013 | Uncertain | 0.903 | 0.196 | 0.000 | -13.515 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.75 | Destabilizing | 0.0 | 4.54 | Destabilizing | 4.65 | Destabilizing | 2.08 | Destabilizing | 0.803 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.33 | Pathogenic | 0.00 | Affected | 0.4142 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1877T>G | I626S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I626S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.109221 | Structured | 0.040732 | Uncertain | 0.970 | 0.223 | 0.000 | -14.449 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 3.80 | Destabilizing | 0.0 | 4.54 | Destabilizing | 4.17 | Destabilizing | 2.16 | Destabilizing | 0.706 | Likely Pathogenic | -5.41 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.04 | Benign | 0.00 | Affected | 0.2308 | 0.0858 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1988T>G | F663C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -13.544 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.83 | Destabilizing | 0.1 | 4.54 | Destabilizing | 4.19 | Destabilizing | 1.91 | Destabilizing | 0.772 | Likely Pathogenic | -7.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.96 | Benign | 0.00 | Affected | 0.2343 | 0.0783 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.2042G>A | G681D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G681D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL and FATHMM, whereas the remaining 11 tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score all predict pathogenicity. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized returns a pathogenic classification; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. premPS is inconclusive and is treated as unavailable. Taken together, the overwhelming majority of evidence points to a pathogenic impact for G681D. 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 | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | -12.451 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 2.62 | Destabilizing | 1.5 | 4.54 | Destabilizing | 3.58 | Destabilizing | 0.96 | Ambiguous | 0.471 | Likely Benign | -6.98 | Deleterious | 0.999 | Probably Damaging | 0.840 | Possibly Damaging | 3.45 | Benign | 0.00 | Affected | 0.1697 | 0.1695 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.803T>G | I268S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -13.032 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.93 | Destabilizing | 0.1 | 4.54 | Destabilizing | 4.74 | Destabilizing | 2.10 | Destabilizing | 0.841 | Likely Pathogenic | -5.34 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.2037 | 0.0530 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1085G>C | W362S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W362S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic, while premPS remains uncertain. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) also indicates pathogenic. No tool predicts a benign outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.430310 | Uncertain | 0.957 | 0.552 | 0.125 | -13.228 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 4.08 | Destabilizing | 0.0 | 4.55 | Destabilizing | 4.32 | Destabilizing | 0.95 | Ambiguous | 0.625 | Likely Pathogenic | -12.87 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.31 | Pathogenic | 0.00 | Affected | 0.5106 | 0.1215 | Weaken | -2 | -3 | 0.1 | -99.14 | ||||||||||||||||||||||||||||
| c.983A>C | Y328S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328S is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact on protein stability. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.411940 | Structured | 0.392519 | Uncertain | 0.916 | 0.497 | 0.000 | -12.358 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 3.13 | Destabilizing | 0.1 | 4.55 | Destabilizing | 3.84 | Destabilizing | 1.80 | Destabilizing | 0.586 | Likely Pathogenic | -8.01 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.54 | Pathogenic | 0.01 | Affected | 0.4924 | 0.2449 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.1906T>A | F636I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F636I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | -14.031 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 2.96 | Destabilizing | 0.2 | 4.57 | Destabilizing | 3.77 | Destabilizing | 1.10 | Destabilizing | 0.501 | Likely Pathogenic | -5.78 | Deleterious | 0.994 | Probably Damaging | 0.977 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | 0.1660 | 0.2153 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1829T>G | L610R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L610R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports a pathogenic outcome; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Consequently, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.209504 | Uncertain | 0.888 | 0.253 | 0.000 | -13.855 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 5.14 | Destabilizing | 0.5 | 4.60 | Destabilizing | 4.87 | Destabilizing | 1.89 | Destabilizing | 0.949 | Likely Pathogenic | -5.94 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | -1.58 | Pathogenic | 0.00 | Affected | 0.1334 | 0.0615 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.875C>T | A292V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -11.170 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 2.04 | Destabilizing | 0.5 | 4.60 | Destabilizing | 3.32 | Destabilizing | 0.85 | Ambiguous | 0.430 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.75 | Pathogenic | 0.03 | Affected | 0.1272 | 0.6253 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.610T>C | S204P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S204P variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and polyPhen‑2 HumVar, whereas a separate group predicts a pathogenic effect: FoldX, Rosetta, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The remaining tools (premPS) are inconclusive and are not counted in either group. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain (treated as unavailable), the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie and therefore unavailable, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Overall, the majority of consensus predictions lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -8.855 | Likely Pathogenic | 0.820 | Likely Pathogenic | Ambiguous | 3.71 | Destabilizing | 0.4 | 4.61 | Destabilizing | 4.16 | Destabilizing | 0.61 | Ambiguous | 0.137 | Likely Benign | -1.28 | Neutral | 0.808 | Possibly Damaging | 0.382 | Benign | 4.13 | Benign | 0.12 | Tolerated | 0.1430 | 0.4815 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.1037T>G | V346G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All available in‑silico predictors classify it as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports pathogenic. With all evidence converging on a deleterious impact and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | -12.779 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 4.24 | Destabilizing | 0.2 | 4.62 | Destabilizing | 4.43 | Destabilizing | 2.15 | Destabilizing | 0.667 | Likely Pathogenic | -6.03 | Deleterious | 0.991 | Probably Damaging | 0.999 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | 0.2378 | 0.2522 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1340T>G | V447G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V447G 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, while the remaining tools—FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that V447G is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | -13.648 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 3.81 | Destabilizing | 0.1 | 4.62 | Destabilizing | 4.22 | Destabilizing | 2.28 | Destabilizing | 0.499 | Likely Benign | -5.43 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | 0.1863 | 0.2240 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1703T>A | V568E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V568E is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign effect, so the benign‑prediction group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this 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 | 0.024826 | Structured | 0.053503 | Uncertain | 0.937 | 0.257 | 0.000 | -13.835 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.48 | Destabilizing | 0.1 | 4.62 | Destabilizing | 3.55 | Destabilizing | 2.03 | Destabilizing | 0.940 | Likely Pathogenic | -5.88 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.46 | Pathogenic | 0.00 | Affected | 0.0891 | 0.1495 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.659T>C | F220S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: all available scores (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default) indicate pathogenicity, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also labels it pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -15.258 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.06 | Destabilizing | 0.1 | 4.67 | Destabilizing | 4.37 | Destabilizing | 1.44 | Destabilizing | 0.954 | Likely Pathogenic | -6.67 | Deleterious | 0.928 | Possibly Damaging | 0.477 | Possibly Damaging | 4.03 | Benign | 0.01 | Affected | 0.3813 | 0.1143 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1490A>C | Y497S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497S is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized) classifies the change as pathogenic, leaving no benign predictions. High‑accuracy methods reinforce this assessment: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, indicates a destabilizing, pathogenic effect. No prediction or stability result is missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar annotation, the variant is most likely pathogenic, with no contradictory ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -13.171 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 3.65 | Destabilizing | 0.1 | 4.68 | Destabilizing | 4.17 | Destabilizing | 2.22 | Destabilizing | 0.814 | Likely Pathogenic | -8.82 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.64 | Pathogenic | 0.03 | Affected | 0.3770 | 0.1419 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.2134G>C | G712R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G712R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors—PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, SIFT, ESM1b, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, Rosetta, and the SGM Consensus—classify it as pathogenic. Two tools, FoldX and premPS, return uncertain results. High‑accuracy methods all support pathogenicity: AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta each predict a deleterious effect. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.384858 | Uncertain | 0.947 | 0.365 | 0.000 | -11.776 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 1.75 | Ambiguous | 0.0 | 4.68 | Destabilizing | 3.22 | Destabilizing | 0.82 | Ambiguous | 0.458 | Likely Benign | -6.58 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.35 | Benign | 0.01 | Affected | 0.1229 | 0.4482 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1466T>C | L489P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All evaluated in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Overall, the variant is most likely pathogenic based on the consensus of predictive tools, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | Conflicting | 2 | -13.520 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.50 | Destabilizing | 0.1 | 4.69 | Destabilizing | 3.60 | Destabilizing | 1.73 | Destabilizing | 0.939 | Likely Pathogenic | -6.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.56 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.3673 | 0.1474 | -3 | -3 | -5.4 | -16.04 | 209.9 | 61.9 | 0.1 | 0.0 | 0.6 | 0.1 | X | Potentially Pathogenic | The iso-butyl side chain of Leu489, located in the α-helix (res. Leu489-Glu519) within an inter-helix space of four helices (res. Ala461-Phe476, res. Val441-Ser457, and res. Met414-Glu436), packs with hydrophobic residues (e.g., Cys432, Ala448, Lys444, Ala493, Val447, Met468). In the variant simulations, Pro489 is located near the beginning of the α-helix, so the residue swap with Leu489 does not affect the continuity of the secondary structure element. However, the side chain of proline is not as optimal as that of leucine for maintaining hydrophobic packing with nearby residues (e.g., Ala448, Lys444). Additionally, the consistently maintained hydrogen bond interaction between the backbone amide group of Leu489 and the carbonyl of Glu436 is lost due to the residue swap, potentially affecting the tertiary structure integrity. | ||||||||||||||||
| c.1988T>C | F663S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -14.800 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.15 | Destabilizing | 0.0 | 4.69 | Destabilizing | 4.42 | Destabilizing | 2.50 | Destabilizing | 0.800 | Likely Pathogenic | -7.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | 0.3965 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1513T>G | Y505D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505D is listed in ClinVar as Pathogenic (ClinVar ID 3172759.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect are limited to FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized scores the variant as Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as Pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | Likely Pathogenic | 1 | -14.078 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 4.98 | Destabilizing | 0.1 | 4.72 | Destabilizing | 4.85 | Destabilizing | 2.49 | Destabilizing | 0.718 | Likely Pathogenic | -9.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 3.37 | 35 | 0.3940 | 0.0612 | -3 | -4 | -2.2 | -48.09 | |||||||||||||||||||||||||
| c.2084T>C | L695P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L695P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.373419 | Uncertain | 0.942 | 0.258 | 0.000 | -17.496 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.63 | Destabilizing | 0.2 | 4.73 | Destabilizing | 4.68 | Destabilizing | 2.11 | Destabilizing | 0.612 | Likely Pathogenic | -6.85 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.16 | Benign | 0.00 | Affected | 0.3044 | 0.0992 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1637G>A | C546Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C546Y is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include FoldX, premPS, and SIFT, whereas the remaining tools—SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports a pathogenic effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic impact. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | -10.771 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | -0.08 | Likely Benign | 1.8 | 4.75 | Destabilizing | 2.34 | Destabilizing | 0.09 | Likely Benign | 0.794 | Likely Pathogenic | -8.74 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.07 | Pathogenic | 0.29 | Tolerated | 0.1433 | 0.3015 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.980T>G | L327R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L327R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a destabilizing, pathogenic effect. All available predictions are concordant and indicate a likely pathogenic impact. Thus, based on the current computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.409189 | Uncertain | 0.939 | 0.490 | 0.000 | -13.403 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.46 | Destabilizing | 0.3 | 4.75 | Destabilizing | 4.61 | Destabilizing | 1.95 | Destabilizing | 0.619 | Likely Pathogenic | -5.28 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.52 | Pathogenic | 0.00 | Affected | 0.1281 | 0.1085 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1292T>G | L431R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L431R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | -14.777 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.45 | Destabilizing | 0.0 | 4.76 | Destabilizing | 4.11 | Destabilizing | 1.93 | Destabilizing | 0.654 | Likely Pathogenic | -5.47 | Deleterious | 0.997 | Probably Damaging | 0.833 | Possibly Damaging | 2.93 | Benign | 0.00 | Affected | 0.1191 | 0.0730 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1490A>G | Y497C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497C is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all return a deleterious signal: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenic. No tool reports a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM Consensus as “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) as “Pathogenic.” Overall, the variant is most likely pathogenic based on the consensus of predictive algorithms, which contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | Uncertain | 1 | -11.872 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 3.88 | Destabilizing | 0.1 | 4.76 | Destabilizing | 4.32 | Destabilizing | 1.40 | Destabilizing | 0.806 | Likely Pathogenic | -8.82 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.65 | Pathogenic | 0.03 | Affected | 3.37 | 35 | 0.2905 | 0.1488 | 0 | -2 | 3.8 | -60.04 | 209.9 | 59.1 | -0.1 | 0.0 | -0.3 | 0.1 | X | X | Potentially Pathogenic | Tyr497 is located in the α-helix (res. Leu489-Glu519) within the inter-helix space of four α-helices (res. Leu489-Ile501, res. Val441-Ser457, res. Arg563-Glu578, res. Ala461-Val473). In the WT simulations, the phenol ring of Tyr497 hydrophobically packs with other residues in the inter-helix space (e.g., Leu465, Leu565, Val568). The hydroxyl group of Tyr497 also alternately forms hydrogen bonds with the carboxylate side chain of Gln456 and the backbone carbonyl of Glu564. Thus, Tyr497 plays a role in the folding and maintenance of the tertiary structure assembly between these four helices.In the variant simulations, the comparatively smaller residue, Cys497, cannot maintain any of the interactions seen with Tyr497 in the WT. Although no severe deleterious consequences are observed in the simulations, the structural effects could be more pronounced during actual protein folding. Indeed, the tertiary structure is seen to slightly break apart in the variant simulations. | |||||||||||||||
| c.1268A>C | Y423S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y423S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the preponderance of evidence points to a pathogenic effect for Y423S. 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 | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -10.847 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 4.28 | Destabilizing | 0.1 | 4.78 | Destabilizing | 4.53 | Destabilizing | 1.95 | Destabilizing | 0.345 | Likely Benign | -7.39 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.09 | Tolerated | 0.3152 | 0.1259 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.1787G>C | R596P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R596P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while no tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized indicates pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No contradictory evidence is present. Based on the uniform predictions, 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 | 0.017797 | Structured | 0.135423 | Uncertain | 0.918 | 0.134 | 0.000 | -13.786 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 6.80 | Destabilizing | 0.1 | 4.78 | Destabilizing | 5.79 | Destabilizing | 1.15 | Destabilizing | 0.780 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.2335 | 0.3356 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1037T>A | V346E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All evaluated in silico predictors classify the change as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a pathogenic outcome; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic impact. **Conclusion:** The variant is most likely pathogenic based on the unanimous computational evidence, and this assessment is not contradicted by the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | -14.004 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.30 | Destabilizing | 0.4 | 4.79 | Destabilizing | 4.05 | Destabilizing | 2.13 | Destabilizing | 0.720 | Likely Pathogenic | -5.52 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 1.47 | Pathogenic | 0.00 | Affected | 0.1088 | 0.1568 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.1162G>C | G388R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G388R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, and AlphaMissense‑Optimized, whereas the remaining eleven tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) uniformly predict a pathogenic impact. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized indicates benign, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.736850 | Disordered | 0.420316 | Uncertain | 0.319 | 0.827 | 0.750 | -9.142 | Likely Pathogenic | 0.694 | Likely Pathogenic | Likely Benign | 6.54 | Destabilizing | 8.5 | 4.79 | Destabilizing | 5.67 | Destabilizing | 0.31 | Likely Benign | 0.606 | Likely Pathogenic | -0.74 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.02 | Affected | 0.1296 | 0.4417 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1267T>G | Y423D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y423D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -13.279 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 4.67 | Destabilizing | 0.1 | 4.79 | Destabilizing | 4.73 | Destabilizing | 1.78 | Destabilizing | 0.553 | Likely Pathogenic | -8.28 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.38 | Benign | 0.04 | Affected | 0.3262 | 0.0412 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1577T>G | V526G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V526G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on pathogenicity include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; no tool predicts it benign. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. All available evidence points to a deleterious effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.139895 | Structured | 0.023118 | Uncertain | 0.943 | 0.403 | 0.000 | -15.811 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 3.21 | Destabilizing | 0.3 | 4.79 | Destabilizing | 4.00 | Destabilizing | 2.19 | Destabilizing | 0.935 | Likely Pathogenic | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.49 | Pathogenic | 0.00 | Affected | 0.1636 | 0.1837 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.2134G>A | G712S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G712S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. Uncertain results come from premPS, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive and therefore unavailable. Overall, the majority of evidence points to a pathogenic effect for G712S. This conclusion does not contradict ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.278302 | Structured | 0.384858 | Uncertain | 0.947 | 0.365 | 0.000 | -7.942 | In-Between | 0.422 | Ambiguous | Likely Benign | 2.30 | Destabilizing | 0.1 | 4.79 | Destabilizing | 3.55 | Destabilizing | 0.62 | Ambiguous | 0.282 | Likely Benign | -4.84 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.02 | Affected | 0.2862 | 0.4501 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||
| c.839A>C | Y280S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; all evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the substitution as pathogenic. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely pathogenic verdict, and Foldetta (integrating FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is consistent with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.161087 | Structured | 0.321243 | Uncertain | 0.917 | 0.248 | 0.125 | -13.491 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 4.63 | Destabilizing | 0.3 | 4.80 | Destabilizing | 4.72 | Destabilizing | 2.03 | Destabilizing | 0.635 | Likely Pathogenic | -8.27 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.00 | Pathogenic | 0.05 | Affected | 0.3993 | 0.1227 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.1130T>G | M377R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377R is present in gnomAD (6‑33438035‑T‑G) and has no ClinVar entry. Prediction tools that report a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are Rosetta and Foldetta. The high‑accuracy consensus (SGM‑Consensus) is “Likely Benign,” derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—all of which are benign. AlphaMissense‑Optimized also predicts benign, whereas Foldetta predicts pathogenic. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict the ClinVar status (which is currently absent). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.675549 | Disordered | 0.431183 | Uncertain | 0.324 | 0.884 | 0.625 | 6-33438035-T-G | -3.150 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.49 | Likely Benign | 0.4 | 4.81 | Destabilizing | 2.65 | Destabilizing | 0.69 | Ambiguous | 0.471 | Likely Benign | -0.64 | Neutral | 0.004 | Benign | 0.009 | Benign | 5.46 | Benign | 0.18 | Tolerated | 4.32 | 12 | 0.2369 | 0.1918 | -1 | 0 | -6.4 | 24.99 | ||||||||||||||||||||||||||
| c.1172G>T | G391V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G391V is listed in ClinVar as Benign (ClinVar ID 1014488.0) and is present in gnomAD (variant ID 6‑33438077‑G‑T). Prediction tools that classify the variant as benign include premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. Tools that predict pathogenicity are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. With two high‑accuracy tools supporting benign and one supporting pathogenic, the overall prediction leans toward a benign effect. This conclusion aligns with the ClinVar benign classification, so there is no contradiction with the existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.637480 | Disordered | 0.409509 | Uncertain | 0.279 | 0.741 | 0.750 | Likely Benign | 1 | 6-33438077-G-T | 3 | 1.86e-6 | -6.642 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 4.23 | Destabilizing | 1.3 | 4.81 | Destabilizing | 4.52 | Destabilizing | -0.11 | Likely Benign | 0.595 | Likely Pathogenic | -0.98 | Neutral | 0.994 | Probably Damaging | 0.887 | Possibly Damaging | 1.32 | Pathogenic | 0.10 | Tolerated | 3.69 | 8 | 0.1621 | 0.3821 | -1 | -3 | 4.6 | 42.08 | 228.6 | -69.0 | 0.0 | 0.8 | -0.5 | 0.3 | Uncertain | Gly387 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. This loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play significant roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Val391 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. Since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||
| c.1855A>C | T619P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T619P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX and SIFT, while pathogenic predictions are made by REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments further clarify the variant’s impact: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Overall, the majority of evidence points to a pathogenic effect for T619P, 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 | 0.219301 | Structured | 0.119723 | Uncertain | 0.929 | 0.237 | 0.000 | -12.879 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 0.43 | Likely Benign | 0.2 | 4.81 | Destabilizing | 2.62 | Destabilizing | 0.82 | Ambiguous | 0.860 | Likely Pathogenic | -5.51 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.39 | Pathogenic | 0.09 | Tolerated | 0.1940 | 0.3806 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1094T>G | V365G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign effect. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. All available evidence points to a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | -13.020 | Likely Pathogenic | 0.944 | Likely Pathogenic | Ambiguous | 4.18 | Destabilizing | 0.2 | 4.83 | Destabilizing | 4.51 | Destabilizing | 2.18 | Destabilizing | 0.576 | Likely Pathogenic | -5.88 | Deleterious | 0.688 | Possibly Damaging | 0.989 | Probably Damaging | 1.66 | Pathogenic | 0.00 | Affected | 0.1835 | 0.2717 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1271T>G | V424G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V424G 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. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic consensus (3 pathogenic vs. 1 benign); and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. No predictions are missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -13.697 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 3.90 | Destabilizing | 0.1 | 4.84 | Destabilizing | 4.37 | Destabilizing | 2.44 | Destabilizing | 0.622 | Likely Pathogenic | -6.26 | Deleterious | 0.994 | Probably Damaging | 1.000 | Probably Damaging | 3.34 | Benign | 0.00 | Affected | 0.1396 | 0.2029 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1168G>A | G390R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G390R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the majority of tools and the high‑accuracy methods indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | -9.242 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | 2.43 | Destabilizing | 0.9 | 4.85 | Destabilizing | 3.64 | Destabilizing | 0.16 | Likely Benign | 0.605 | Likely Pathogenic | -0.92 | Neutral | 0.480 | Possibly Damaging | 0.163 | Benign | 1.32 | Pathogenic | 0.08 | Tolerated | 0.1190 | 0.4524 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1168G>C | G390R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G390R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the majority of tools and the high‑accuracy methods indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | -9.242 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | 2.43 | Destabilizing | 0.9 | 4.85 | Destabilizing | 3.64 | Destabilizing | 0.16 | Likely Benign | 0.605 | Likely Pathogenic | -0.92 | Neutral | 0.480 | Possibly Damaging | 0.163 | Benign | 1.32 | Pathogenic | 0.08 | Tolerated | 0.1190 | 0.4524 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1898T>G | L633R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L633R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Based on the overwhelming consensus of pathogenic predictions and the absence of any benign signal, 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 | 0.045352 | Structured | 0.045407 | Uncertain | 0.952 | 0.252 | 0.000 | -14.360 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 4.41 | Destabilizing | 0.2 | 4.85 | Destabilizing | 4.63 | Destabilizing | 2.15 | Destabilizing | 0.667 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.70 | Benign | 0.00 | Affected | 0.1674 | 0.0518 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1514A>C | Y505S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only FATHMM, whereas all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No predictions are missing or inconclusive. Overall, the consensus of the available computational evidence indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently contains no entry for Y505S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -14.053 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 3.49 | Destabilizing | 0.1 | 4.86 | Destabilizing | 4.18 | Destabilizing | 2.33 | Destabilizing | 0.559 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.61 | Benign | 0.00 | Affected | 0.4056 | 0.1945 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.1169G>T | G390V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G390V has no ClinVar entry and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, FoldX, Rosetta, Foldetta, SIFT, and FATHMM, while ESM1b remains uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default (benign), ESM1b (uncertain), FATHMM (pathogenic), and PROVEAN (benign), also yields a benign verdict; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, indicates pathogenic. With two high‑accuracy tools supporting benign and one supporting pathogenic, the overall evidence leans toward a benign effect. This conclusion does not contradict ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | -7.137 | In-Between | 0.146 | Likely Benign | Likely Benign | 3.74 | Destabilizing | 0.6 | 4.88 | Destabilizing | 4.31 | Destabilizing | -0.16 | Likely Benign | 0.509 | Likely Pathogenic | -0.88 | Neutral | 0.002 | Benign | 0.002 | Benign | 1.32 | Pathogenic | 0.01 | Affected | 0.1537 | 0.4004 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||
| c.1711T>C | S571P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S571P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains inconclusive. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Consequently, the aggregate evidence strongly supports a pathogenic effect for S571P, and this conclusion does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.045569 | Uncertain | 0.928 | 0.270 | 0.000 | Uncertain | 1 | -14.701 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.18 | Destabilizing | 0.2 | 4.89 | Destabilizing | 4.04 | Destabilizing | 0.87 | Ambiguous | 0.814 | Likely Pathogenic | -4.68 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.30 | Pathogenic | 0.02 | Affected | 0.2195 | 0.3760 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||
| c.1391T>C | F464S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -13.361 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.84 | Destabilizing | 0.0 | 4.90 | Destabilizing | 4.87 | Destabilizing | 2.52 | Destabilizing | 0.748 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.27 | Benign | 0.00 | Affected | 0.3700 | 0.0358 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1466T>G | L489R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | -15.365 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.32 | Destabilizing | 0.3 | 4.90 | Destabilizing | 4.61 | Destabilizing | 1.74 | Destabilizing | 0.949 | Likely Pathogenic | -5.86 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.61 | Pathogenic | 0.00 | Affected | 0.1306 | 0.1145 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1790T>C | F597S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F597S is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. All available predictions are consistent and conclusive. Based on the unanimous computational evidence, 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 | GAP | 0.010926 | Structured | 0.142961 | Uncertain | 0.944 | 0.151 | 0.000 | -14.943 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.53 | Destabilizing | 0.3 | 4.90 | Destabilizing | 4.22 | Destabilizing | 2.18 | Destabilizing | 0.953 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -2.19 | Pathogenic | 0.00 | Affected | 0.4035 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1955T>C | F652S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F652S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -13.679 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.16 | Destabilizing | 0.2 | 4.92 | Destabilizing | 4.04 | Destabilizing | 2.16 | Destabilizing | 0.665 | Likely Pathogenic | -7.78 | Deleterious | 1.000 | Probably Damaging | 0.948 | Probably Damaging | 3.05 | Benign | 0.00 | Affected | 0.3777 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1162G>T | G388C 2D 3DClick to see structure in 3D Viewer AISynGAP1 G388C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from AlphaMissense‑Default, AlphaMissense‑Optimized, premPS, and PROVEAN, while pathogenic predictions arise from REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts benign, Foldetta predicts pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Because the majority of evidence points to pathogenicity and there is no ClinVar entry to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.736850 | Disordered | 0.420316 | Uncertain | 0.319 | 0.827 | 0.750 | -8.088 | Likely Pathogenic | 0.121 | Likely Benign | Likely Benign | 4.01 | Destabilizing | 3.7 | 4.95 | Destabilizing | 4.48 | Destabilizing | 0.03 | Likely Benign | 0.603 | Likely Pathogenic | -0.98 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 0.1497 | 0.4112 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||
| c.1364T>G | L455R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455R resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -16.347 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 6.36 | Destabilizing | 0.2 | 4.96 | Destabilizing | 5.66 | Destabilizing | 2.08 | Destabilizing | 0.648 | Likely Pathogenic | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0.1126 | 0.0600 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1724G>C | R575P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R575P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only SIFT, whereas all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Based on the overwhelming consensus of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for R575P. 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 | -16.008 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.50 | Destabilizing | 0.1 | 4.97 | Destabilizing | 4.24 | Destabilizing | 1.13 | Destabilizing | 0.774 | Likely Pathogenic | -3.69 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.33 | Pathogenic | 0.10 | Tolerated | 0.2080 | 0.2670 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.935T>G | F312C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312C is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Based on the unanimous pathogenic predictions and the absence of benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -11.991 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.98 | Destabilizing | 0.3 | 4.97 | Destabilizing | 3.98 | Destabilizing | 1.46 | Destabilizing | 0.870 | Likely Pathogenic | -7.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.16 | Pathogenic | 0.00 | Affected | 0.2293 | 0.2010 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.982T>G | Y328D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328D is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classifies the substitution as pathogenic; no tool predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.411940 | Structured | 0.392519 | Uncertain | 0.916 | 0.497 | 0.000 | -13.701 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.32 | Destabilizing | 0.2 | 4.97 | Destabilizing | 4.65 | Destabilizing | 1.87 | Destabilizing | 0.680 | Likely Pathogenic | -8.93 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.52 | Pathogenic | 0.01 | Affected | 0.4233 | 0.0703 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1829T>A | L610H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L610H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.209504 | Uncertain | 0.888 | 0.253 | 0.000 | -14.573 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 4.83 | Destabilizing | 0.5 | 4.98 | Destabilizing | 4.91 | Destabilizing | 2.03 | Destabilizing | 0.927 | Likely Pathogenic | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.59 | Pathogenic | 0.00 | Affected | 0.1067 | 0.0741 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.2135G>C | G712A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G712A missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. Two tools report uncertainty: premPS and AlphaMissense‑Default. High‑accuracy assessments further refine the picture. AlphaMissense‑Optimized classifies the variant as benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign verdict (2 benign vs. 1 pathogenic vote). Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic effect. Because the majority of conventional predictors (7/11) indicate pathogenicity, the overall consensus leans toward a pathogenic impact, despite the mixed high‑accuracy results. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.278302 | Structured | 0.384858 | Uncertain | 0.947 | 0.365 | 0.000 | -6.444 | Likely Benign | 0.553 | Ambiguous | Likely Benign | 2.89 | Destabilizing | 0.1 | 4.98 | Destabilizing | 3.94 | Destabilizing | 0.70 | Ambiguous | 0.281 | Likely Benign | -4.99 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.44 | Benign | 0.02 | Affected | 0.3993 | 0.4105 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||
| c.986G>C | R329P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R329P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of algorithms predict a pathogenic outcome: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic,” and premPS is uncertain. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. Overall, the evidence overwhelmingly points to a pathogenic effect for R329P, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.376086 | Uncertain | 0.887 | 0.479 | 0.250 | -14.528 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 3.06 | Destabilizing | 0.2 | 4.99 | Destabilizing | 4.03 | Destabilizing | 0.73 | Ambiguous | 0.350 | Likely Benign | -4.28 | Deleterious | 0.902 | Possibly Damaging | 0.544 | Possibly Damaging | 4.00 | Benign | 0.01 | Affected | 0.2215 | 0.4099 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1376G>T | G459V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G459V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; premPS is inconclusive and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the consensus of these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for G459V. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -13.606 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.79 | Destabilizing | 0.1 | 5.01 | Destabilizing | 4.40 | Destabilizing | 0.71 | Ambiguous | 0.605 | Likely Pathogenic | -8.46 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.99 | Benign | 0.00 | Affected | 0.0997 | 0.4240 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1171G>T | G391C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G391C 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 AlphaMissense‑Default, AlphaMissense‑Optimized, premPS, and PROVEAN, whereas the remaining tools—REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—predict it to be pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence points to a pathogenic effect. This prediction 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 | 0.637480 | Disordered | 0.409509 | Uncertain | 0.279 | 0.741 | 0.750 | -8.596 | Likely Pathogenic | 0.123 | Likely Benign | Likely Benign | 2.65 | Destabilizing | 0.7 | 5.03 | Destabilizing | 3.84 | Destabilizing | 0.11 | Likely Benign | 0.640 | Likely Pathogenic | -1.29 | Neutral | 1.000 | Probably Damaging | 0.970 | Probably Damaging | 1.32 | Pathogenic | 0.03 | Affected | 0.1483 | 0.4225 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||
| c.659T>G | F220C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220C is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -12.948 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.67 | Destabilizing | 0.0 | 5.03 | Destabilizing | 4.35 | Destabilizing | 2.22 | Destabilizing | 0.941 | Likely Pathogenic | -6.72 | Deleterious | 0.994 | Probably Damaging | 0.753 | Possibly Damaging | 4.03 | Benign | 0.00 | Affected | 0.2264 | 0.2012 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.2153T>G | L718R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L718R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.438417 | Uncertain | 0.966 | 0.385 | 0.000 | -16.119 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.90 | Destabilizing | 0.2 | 5.05 | Destabilizing | 5.48 | Destabilizing | 2.57 | Destabilizing | 0.484 | Likely Benign | -5.69 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 0.1254 | 0.0600 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1150G>C | G384R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G384R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, PROVEAN, and AlphaMissense‑Optimized, whereas pathogenic calls are made by FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, but SGM‑Consensus and Foldetta both predict pathogenic, with Foldetta integrating FoldX‑MD and Rosetta stability outputs. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.728858 | Disordered | 0.427831 | Uncertain | 0.323 | 0.934 | 0.750 | -9.186 | Likely Pathogenic | 0.719 | Likely Pathogenic | Likely Benign | 2.16 | Destabilizing | 0.4 | 5.06 | Destabilizing | 3.61 | Destabilizing | 0.25 | Likely Benign | 0.475 | Likely Benign | -0.96 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.02 | Affected | 0.1250 | 0.4156 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.922T>G | W308G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308G is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. No tool predicts a benign effect, so the benign group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.333942 | Uncertain | 0.907 | 0.314 | 0.125 | -16.271 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 6.88 | Destabilizing | 0.2 | 5.07 | Destabilizing | 5.98 | Destabilizing | 1.97 | Destabilizing | 0.860 | Likely Pathogenic | -11.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 0.4884 | 0.1644 | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||||||
| c.1157G>T | G386V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G386V is reported in gnomAD (6-33438062‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools, including the high‑accuracy methods, lean toward a benign classification, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.733139 | Disordered | 0.424156 | Uncertain | 0.334 | 0.898 | 0.750 | 6-33438062-G-T | -6.405 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 4.88 | Destabilizing | 3.0 | 5.09 | Destabilizing | 4.99 | Destabilizing | -0.17 | Likely Benign | 0.458 | Likely Benign | -0.64 | Neutral | 0.985 | Probably Damaging | 0.720 | Possibly Damaging | 3.91 | Benign | 0.01 | Affected | 4.32 | 3 | 0.1685 | 0.4189 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||
| c.1381G>C | A461P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and FATHMM, whereas the majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS remains uncertain. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is pathogenic. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -13.869 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | -0.35 | Likely Benign | 0.1 | 5.09 | Destabilizing | 2.37 | Destabilizing | 0.84 | Ambiguous | 0.451 | Likely Benign | -4.52 | Deleterious | 0.999 | Probably Damaging | 0.849 | Possibly Damaging | 3.32 | Benign | 0.03 | Affected | 0.1748 | 0.3949 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1259T>G | F420C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420C is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. When grouped by consensus, the benign prediction is singular (FATHMM), whereas the pathogenic predictions comprise the remaining eleven tools. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). 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 | -11.931 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.31 | Destabilizing | 0.1 | 5.11 | Destabilizing | 4.71 | Destabilizing | 2.49 | Destabilizing | 0.500 | Likely Pathogenic | -7.40 | Deleterious | 0.998 | Probably Damaging | 0.869 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.2458 | 0.0662 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1577T>A | V526E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V526E is not listed in ClinVar and has no reported allele in gnomAD. In silico prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Because all available evidence points to a damaging effect and there is no conflicting ClinVar annotation or population frequency data, the variant is most likely pathogenic. This conclusion aligns with the absence of ClinVar status and gnomAD entries, indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.023118 | Uncertain | 0.943 | 0.403 | 0.000 | -16.080 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 5.19 | Destabilizing | 0.3 | 5.12 | Destabilizing | 5.16 | Destabilizing | 2.32 | Destabilizing | 0.962 | Likely Pathogenic | -5.94 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.46 | Pathogenic | 0.00 | Affected | 0.0766 | 0.1326 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.1286G>C | R429P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R429P is not 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 comprise Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b; AlphaMissense‑Default and FoldX 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 (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools and the high‑accuracy methods favor a pathogenic interpretation. Thus, the variant is most likely pathogenic, 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. | GAP | 0.074921 | Structured | 0.390504 | Uncertain | 0.959 | 0.290 | 0.000 | -9.771 | Likely Pathogenic | 0.556 | Ambiguous | Likely Benign | 1.53 | Ambiguous | 0.2 | 5.13 | Destabilizing | 3.33 | Destabilizing | 1.01 | Destabilizing | 0.265 | Likely Benign | -2.89 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.25 | Tolerated | 0.1881 | 0.3790 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||
| c.1906T>G | F636V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F636V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | -14.603 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 3.06 | Destabilizing | 0.1 | 5.13 | Destabilizing | 4.10 | Destabilizing | 1.07 | Destabilizing | 0.533 | Likely Pathogenic | -6.74 | Deleterious | 0.991 | Probably Damaging | 0.985 | Probably Damaging | 3.44 | Benign | 0.04 | Affected | 0.1841 | 0.2030 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.680G>C | G227A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, and AlphaMissense‑Default. Predictions that remain uncertain are premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic majority, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.106997 | Structured | 0.329995 | Uncertain | 0.800 | 0.329 | 0.250 | -7.344 | In-Between | 0.920 | Likely Pathogenic | Ambiguous | 2.45 | Destabilizing | 0.4 | 5.14 | Destabilizing | 3.80 | Destabilizing | 0.78 | Ambiguous | 0.682 | Likely Pathogenic | -5.08 | Deleterious | 0.097 | Benign | 0.023 | Benign | 5.71 | Benign | 0.04 | Affected | 0.3987 | 0.5221 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||
| c.1448T>A | I483K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -18.260 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.53 | Destabilizing | 0.1 | 5.15 | Destabilizing | 4.34 | Destabilizing | 2.01 | Destabilizing | 0.585 | Likely Pathogenic | -6.50 | Deleterious | 0.962 | Probably Damaging | 0.991 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | 0.0868 | 0.0670 | -2 | -3 | -8.4 | 15.01 | |||||||||||||||||||||||||||||
| c.880A>C | T294P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T294P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX (Uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool reports a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.316932 | Uncertain | 0.919 | 0.267 | 0.125 | -17.477 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.97 | Ambiguous | 0.3 | 5.18 | Destabilizing | 3.58 | Destabilizing | 1.15 | Destabilizing | 0.741 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -0.19 | Pathogenic | 0.01 | Affected | 0.1906 | 0.4479 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1214G>C | R405P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R405P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates it is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies it as pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” status. 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 | Uncertain | 1 | -14.206 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.11 | Destabilizing | 0.3 | 5.19 | Destabilizing | 4.15 | Destabilizing | 1.26 | Destabilizing | 0.572 | Likely Pathogenic | -6.32 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.62 | Benign | 0.01 | Affected | 3.38 | 28 | 0.2140 | 0.5138 | -2 | 0 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.1571G>T | C524F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524F is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic, while only premPS predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized reports pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.024729 | Uncertain | 0.916 | 0.385 | 0.125 | -12.145 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.18 | Destabilizing | 1.4 | 5.20 | Destabilizing | 3.69 | Destabilizing | -0.04 | Likely Benign | 0.831 | Likely Pathogenic | -10.94 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.22 | Pathogenic | 0.05 | Affected | 0.1678 | 0.4259 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.1781T>C | F594S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F594S is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. With unanimous pathogenic predictions and no ClinVar evidence to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009187 | Structured | 0.120166 | Uncertain | 0.946 | 0.147 | 0.000 | -15.930 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.70 | Destabilizing | 0.3 | 5.20 | Destabilizing | 4.95 | Destabilizing | 2.60 | Destabilizing | 0.952 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -2.04 | Pathogenic | 0.00 | Affected | 0.3804 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.611C>A | S204Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S204Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus (SGM Consensus) is inconclusive because it receives an equal split between pathogenic and benign calls. AlphaMissense‑Optimized, a high‑accuracy model, predicts benign, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts pathogenic. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -10.518 | Likely Pathogenic | 0.782 | Likely Pathogenic | Likely Benign | 8.99 | Destabilizing | 3.8 | 5.20 | Destabilizing | 7.10 | Destabilizing | -0.03 | Likely Benign | 0.170 | Likely Benign | -0.96 | Neutral | 0.978 | Probably Damaging | 0.694 | Possibly Damaging | 4.14 | Benign | 0.03 | Affected | 0.0452 | 0.5625 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||
| c.1349C>A | A450E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A450E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include SIFT and FATHMM, whereas the majority of tools predict it to be pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No predictions are inconclusive. Overall, the evidence strongly favors a pathogenic impact for A450E, which does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | Uncertain | 1 | -16.578 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 3.86 | Destabilizing | 0.2 | 5.23 | Destabilizing | 4.55 | Destabilizing | 1.59 | Destabilizing | 0.653 | Likely Pathogenic | -4.67 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.38 | Benign | 0.07 | Tolerated | 3.37 | 32 | 0.0823 | 0.1695 | 0 | -1 | -5.3 | 58.04 | 240.1 | -82.6 | 0.0 | 0.0 | 0.7 | 0.0 | X | X | Potentially Pathogenic | The methyl group of Ala450, located in an α helix (res. Asn440-Thr458), packs against hydrophobic residues in the inter-helix space (e.g., Leu692). In the variant simulations, the carboxylate group of the Glu450 side chain rotates outward, away from the hydrophobic niche, where it does not form any lasting salt bridges or H-bonds. Although the residue swap does not negatively affect the protein structure based on the simulations, it is possible that the introduction of the negatively charged residue adversely affects the folding process or tertiary assembly. | |||||||||||||||
| c.2141T>A | L714Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L714Q is not reported in ClinVar (ClinVar: not reported) and is absent from gnomAD (gnomAD: not found). Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated tools—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.314870 | Structured | 0.402311 | Uncertain | 0.961 | 0.369 | 0.000 | -12.145 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.91 | Destabilizing | 0.0 | 5.23 | Destabilizing | 4.07 | Destabilizing | 2.13 | Destabilizing | 0.378 | Likely Benign | -5.56 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.11 | Benign | 0.00 | Affected | 0.1096 | 0.0558 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.665T>G | V222G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V222G resides in the PH domain. ClinVar has no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining eleven tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Thus, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict the ClinVar status, which currently contains no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -14.857 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 4.54 | Destabilizing | 0.4 | 5.25 | Destabilizing | 4.90 | Destabilizing | 2.05 | Destabilizing | 0.962 | Likely Pathogenic | -6.05 | Deleterious | 0.987 | Probably Damaging | 0.998 | Probably Damaging | 5.21 | Benign | 0.00 | Affected | 0.1678 | 0.1996 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1084T>G | W362G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W362G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD, so no population frequency data are available. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the single uncertain call (premPS) does not alter the overall consensus. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Thus, based on the collective predictions, the variant is most likely pathogenic, and this conclusion is consistent with the absence of any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.430310 | Uncertain | 0.957 | 0.552 | 0.125 | -14.242 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 4.22 | Destabilizing | 0.1 | 5.28 | Destabilizing | 4.75 | Destabilizing | 0.95 | Ambiguous | 0.707 | Likely Pathogenic | -11.95 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 1.25 | Pathogenic | 0.00 | Affected | 0.4751 | 0.1281 | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||||||
| c.1187G>T | G396V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G396V is catalogued in gnomAD (6‑33438092‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are FoldX, Rosetta, Foldetta, and PROVEAN. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a pathogenic effect. Overall, the majority of predictions lean toward a benign impact, and this consensus does not contradict any ClinVar status (none reported). Thus, based on the available computational evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | 6-33438092-G-T | 6 | 3.72e-6 | -5.663 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 3.49 | Destabilizing | 1.7 | 5.28 | Destabilizing | 4.39 | Destabilizing | 0.34 | Likely Benign | 0.332 | Likely Benign | -2.56 | Deleterious | 0.062 | Benign | 0.014 | Benign | 3.90 | Benign | 0.24 | Tolerated | 3.41 | 15 | 0.1287 | 0.4337 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||
| c.676T>C | S226P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S226P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) all predict a pathogenic or likely pathogenic outcome. Uncertain results are reported by FoldX, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Overall, the preponderance of evidence indicates that S226P is most likely pathogenic, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.129801 | Structured | 0.334959 | Uncertain | 0.800 | 0.324 | 0.250 | -11.030 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 1.51 | Ambiguous | 1.1 | 5.29 | Destabilizing | 3.40 | Destabilizing | 0.57 | Ambiguous | 0.776 | Likely Pathogenic | -3.22 | Deleterious | 0.971 | Probably Damaging | 0.543 | Possibly Damaging | 5.74 | Benign | 0.04 | Affected | 0.2837 | 0.7038 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.679G>A | G227R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of other in silico predictors classify the variant as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized (premPS is inconclusive). High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a pathogenic effect. Overall, the preponderance of evidence points to a pathogenic classification for G227R, with no conflict from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.106997 | Structured | 0.329995 | Uncertain | 0.800 | 0.329 | 0.250 | -9.776 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.31 | Destabilizing | 0.3 | 5.29 | Destabilizing | 3.80 | Destabilizing | 0.90 | Ambiguous | 0.765 | Likely Pathogenic | -6.49 | Deleterious | 0.020 | Benign | 0.018 | Benign | 6.02 | Benign | 0.01 | Affected | 3.43 | 12 | 0.0997 | 0.4195 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||
| c.679G>C | G227R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227R is not reported in ClinVar (no ClinVar ID) but is present in gnomAD (ID 6‑33435530‑G‑C). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect comprise REVEL, FoldX, Rosetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. The premPS score is uncertain and does not influence the consensus. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Based on the overwhelming agreement among high‑confidence predictors, the variant is most likely pathogenic; this conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.106997 | Structured | 0.329995 | Uncertain | 0.800 | 0.329 | 0.250 | 6-33435530-G-C | 1 | 6.20e-7 | -9.776 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.31 | Destabilizing | 0.3 | 5.29 | Destabilizing | 3.80 | Destabilizing | 0.90 | Ambiguous | 0.765 | Likely Pathogenic | -6.49 | Deleterious | 0.020 | Benign | 0.018 | Benign | 6.02 | Benign | 0.01 | Affected | 3.43 | 12 | 0.0997 | 0.4195 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||
| c.1168G>T | G390W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G390W is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include AlphaMissense‑Optimized, premPS, and PROVEAN, whereas the remaining tools—REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts benign, but the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict, and Foldetta also indicates pathogenic. With the majority of evidence pointing to a deleterious effect, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | -9.405 | Likely Pathogenic | 0.487 | Ambiguous | Likely Benign | 3.69 | Destabilizing | 1.9 | 5.31 | Destabilizing | 4.50 | Destabilizing | 0.14 | Likely Benign | 0.639 | Likely Pathogenic | -1.11 | Neutral | 0.987 | Probably Damaging | 0.744 | Possibly Damaging | 1.31 | Pathogenic | 0.00 | Affected | 0.0917 | 0.4368 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||
| c.923G>C | W308S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308S is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.333942 | Uncertain | 0.907 | 0.314 | 0.125 | -15.425 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.42 | Destabilizing | 0.2 | 5.31 | Destabilizing | 5.87 | Destabilizing | 1.93 | Destabilizing | 0.861 | Likely Pathogenic | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 0.5089 | 0.1406 | Weaken | -2 | -3 | 0.1 | -99.14 | ||||||||||||||||||||||||||||
| c.1250A>C | Y417S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are limited to FATHMM, while all other evaluated algorithms—including SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -14.339 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 4.36 | Destabilizing | 0.1 | 5.32 | Destabilizing | 4.84 | Destabilizing | 2.17 | Destabilizing | 0.593 | Likely Pathogenic | -8.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | 0.4408 | 0.1961 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.1481T>A | I494K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I494K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -15.950 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 4.23 | Destabilizing | 0.2 | 5.33 | Destabilizing | 4.78 | Destabilizing | 1.89 | Destabilizing | 0.925 | Likely Pathogenic | -6.40 | Deleterious | 0.987 | Probably Damaging | 0.937 | Probably Damaging | -1.41 | Pathogenic | 0.00 | Affected | 0.1015 | 0.0870 | -2 | -3 | -8.4 | 15.01 | |||||||||||||||||||||||||||||
| c.1372A>C | T458P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T458P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are SIFT and FATHMM, while the remaining tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, ESM1b, and the SGM‑Consensus) all predict a pathogenic impact; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a pathogenic effect. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -13.547 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 3.05 | Destabilizing | 0.2 | 5.36 | Destabilizing | 4.21 | Destabilizing | 0.78 | Ambiguous | 0.557 | Likely Pathogenic | -5.33 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.35 | Benign | 0.06 | Tolerated | 0.2098 | 0.5395 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.2087T>G | L696R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L696R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: all available predictors except FATHMM (which flags it as benign) report pathogenicity. The benign group contains only FATHMM; the pathogenic group includes SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | -19.609 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.67 | Destabilizing | 0.0 | 5.36 | Destabilizing | 4.52 | Destabilizing | 2.44 | Destabilizing | 0.624 | Likely Pathogenic | -5.68 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.01 | Benign | 0.00 | Affected | 0.1200 | 0.0688 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.680G>A | G227E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227E is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33435531-G-A). Functional prediction tools largely agree on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report pathogenicity, while only polyPhen‑2 (HumVar) and FATHMM predict a benign outcome; premPS remains inconclusive. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Taken together, the overwhelming majority of evidence points to a pathogenic effect. This conclusion is consistent with the ClinVar “Uncertain” classification, which does not contradict the predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.106997 | Structured | 0.329995 | Uncertain | 0.800 | 0.329 | 0.250 | Conflicting | 2 | 6-33435531-G-A | 3 | 1.86e-6 | -9.186 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.56 | Destabilizing | 0.4 | 5.36 | Destabilizing | 3.96 | Destabilizing | 0.94 | Ambiguous | 0.792 | Likely Pathogenic | -6.49 | Deleterious | 0.906 | Possibly Damaging | 0.360 | Benign | 5.72 | Benign | 0.01 | Affected | 3.43 | 12 | 0.1414 | 0.4049 | 0 | -2 | -3.1 | 72.06 | 237.7 | -112.1 | 0.1 | 0.3 | 0.0 | 0.3 | X | X | Uncertain | The introduced residue Glu227 is located in a β hairpin loop connecting two anti-parallel β sheet strands (res. Cys219-Thr224 and Thr228-Ala232). In the variant simulations, the carboxylate group of Glu227 frequently forms a salt bridge with the amino group of the neighboring residue Lys229. Despite this interaction, the integrity of the secondary structure element is not compromised. However, the β hairpins are potential nucleation sites during the initial stages of protein folding. Additionally, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||
| c.1249T>G | Y417D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417D is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any existing 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 | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -14.955 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.13 | Destabilizing | 0.1 | 5.37 | Destabilizing | 5.25 | Destabilizing | 2.43 | Destabilizing | 0.688 | Likely Pathogenic | -9.55 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.96 | Benign | 0.00 | Affected | 0.4388 | 0.0400 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.2135G>A | G712D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G712D is catalogued in gnomAD (ID 6‑33441600‑G‑A) but has no ClinVar entry. In silico predictors show mixed results: benign calls come from REVEL, SIFT, and FATHMM, while pathogenic calls are made by FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain predictions are reported by premPS and AlphaMissense‑Optimized. The high‑accuracy consensus tools give a pathogenic verdict: AlphaMissense‑Optimized is inconclusive, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Overall, the majority of reliable predictors and the consensus methods lean toward a pathogenic effect, and this assessment does not conflict with ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.384858 | Uncertain | 0.947 | 0.365 | 0.000 | 6-33441600-G-A | 1 | 6.20e-7 | -8.211 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 2.87 | Destabilizing | 0.1 | 5.37 | Destabilizing | 4.12 | Destabilizing | 0.90 | Ambiguous | 0.320 | Likely Benign | -5.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.67 | Benign | 0.12 | Tolerated | 3.50 | 9 | 0.2146 | 0.2533 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||
| c.1706T>C | F569S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F569S is listed in ClinVar (ID 1878965.0) as Pathogenic and is not reported in gnomAD. Across the available in‑silico predictors, every tool examined (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classifies the variant as pathogenic; no tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024393 | Structured | 0.054289 | Uncertain | 0.941 | 0.242 | 0.000 | Likely Pathogenic | 2 | -13.384 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.70 | Destabilizing | 0.1 | 5.38 | Destabilizing | 5.54 | Destabilizing | 2.45 | Destabilizing | 0.916 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.32 | Pathogenic | 0.00 | Affected | 3.37 | 34 | 0.4275 | 0.0200 | -3 | -2 | -3.6 | -60.10 | 213.7 | 67.9 | -0.1 | 0.0 | -1.0 | 0.1 | X | Potentially Pathogenic | Phe569 is located on an α-helix (res. Arg563-Glu578). In the WT simulations, the phenyl side chain of Phe569 packs with hydrophobic residues such as Trp572, Leu565, Ile589, Ile667, and Phe561, originating from three different α-helices (res. Ala533-Val560, res. Arg563-Glu578, and res. Ser641-Glu666). In the variant simulations, the acceptor/donor hydroxyl group of Ser569 forms hydrogen bonds with the carbonyl groups of Glu567 and Lys566 on the same α-helix, which could affect the α-helix integrity, although this is not observed in the simulations. While the simulations do not show large-scale effects, the residue swap could have a substantial impact on the protein structure due to the fundamental role of hydrophobic packing during protein folding. | ||||||||||||||||
| c.1199T>G | V400G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V400G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumDiv and FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | -11.508 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 4.84 | Destabilizing | 0.1 | 5.40 | Destabilizing | 5.12 | Destabilizing | 2.40 | Destabilizing | 0.819 | Likely Pathogenic | -5.70 | Deleterious | 0.335 | Benign | 0.920 | Probably Damaging | 5.27 | Benign | 0.00 | Affected | 0.2296 | 0.2522 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1424G>C | R475P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: benign‑predicting algorithms are not present, while pathogenic‑predicting tools—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—all classify the substitution as pathogenic. High‑accuracy assessments corroborate this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. Consequently, the variant is most likely pathogenic based on the available computational evidence, and this assessment does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | -16.637 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.93 | Destabilizing | 0.4 | 5.40 | Destabilizing | 4.17 | Destabilizing | 1.02 | Destabilizing | 0.835 | Likely Pathogenic | -6.53 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.43 | Pathogenic | 0.00 | Affected | 0.1943 | 0.3295 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1705T>G | F569V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F569V is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024393 | Structured | 0.054289 | Uncertain | 0.941 | 0.242 | 0.000 | -14.248 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 4.74 | Destabilizing | 0.2 | 5.40 | Destabilizing | 5.07 | Destabilizing | 1.73 | Destabilizing | 0.874 | Likely Pathogenic | -6.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.29 | Pathogenic | 0.00 | Affected | 0.2054 | 0.1422 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.644G>T | G215V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215V is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining twelve tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the variant as pathogenic. premPS is uncertain and does not influence the consensus. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.382818 | Uncertain | 0.791 | 0.291 | 0.000 | -12.960 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.69 | Destabilizing | 0.2 | 5.41 | Destabilizing | 4.55 | Destabilizing | 0.53 | Ambiguous | 0.884 | Likely Pathogenic | -7.66 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.56 | Benign | 0.00 | Affected | 0.1087 | 0.4777 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.964G>C | A322P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A322P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, and SIFT, while pathogenic calls are made by SGM‑Consensus, Rosetta, Foldetta, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: FoldX and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Thus, the variant is most likely pathogenic, with no ClinVar evidence to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -10.558 | Likely Pathogenic | 0.878 | Likely Pathogenic | Ambiguous | 1.26 | Ambiguous | 1.3 | 5.43 | Destabilizing | 3.35 | Destabilizing | 0.40 | Likely Benign | 0.343 | Likely Benign | -1.72 | Neutral | 0.784 | Possibly Damaging | 0.390 | Benign | 1.90 | Pathogenic | 0.18 | Tolerated | 0.2064 | 0.5400 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.863A>T | D288V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are provided by REVEL and premPS, whereas the remaining tools—FoldX (uncertain), Rosetta, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—all indicate a pathogenic effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -15.812 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 1.74 | Ambiguous | 0.5 | 5.44 | Destabilizing | 3.59 | Destabilizing | 0.13 | Likely Benign | 0.481 | Likely Benign | -7.14 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.63 | Pathogenic | 0.05 | Affected | 0.0838 | 0.5545 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1728C>G | C576W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C576W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, while the majority of other in silico predictors (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of benign consensus, the variant is most likely pathogenic, with no contradiction to ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.017684 | Uncertain | 0.913 | 0.245 | 0.000 | -14.796 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 13.87 | Destabilizing | 1.5 | 5.46 | Destabilizing | 9.67 | Destabilizing | 0.60 | Ambiguous | 0.473 | Likely Benign | -10.01 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.38 | Benign | 0.00 | Affected | 0.1894 | 0.3017 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.2041G>C | G681R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G681R is listed in gnomAD (6-33441300-G-C) but has no ClinVar entry. In silico predictors largely converge on a deleterious effect: benign calls are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—report pathogenicity. premPS is inconclusive. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates pathogenic folding instability. No prediction tool suggests a benign outcome, and the variant’s presence in gnomAD does not alter the consensus. Thus, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | 6-33441300-G-C | 1 | 6.20e-7 | -12.170 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.25 | Destabilizing | 1.7 | 5.46 | Destabilizing | 3.86 | Destabilizing | 0.99 | Ambiguous | 0.556 | Likely Pathogenic | -7.98 | Deleterious | 0.999 | Probably Damaging | 0.928 | Probably Damaging | 3.42 | Benign | 0.00 | Affected | 3.43 | 14 | 0.1022 | 0.3879 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||
| c.1150G>T | G384C 2D AIThe SynGAP1 missense variant G384C is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic; and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split and is treated as unavailable. Overall, the majority of predictions (seven pathogenic vs. five benign) and the pathogenic Foldetta result indicate that the variant is most likely pathogenic, with no contradiction to ClinVar status because the variant is not yet classified there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.427831 | Uncertain | 0.323 | 0.934 | 0.750 | -8.363 | Likely Pathogenic | 0.135 | Likely Benign | Likely Benign | 2.41 | Destabilizing | 2.0 | 5.50 | Destabilizing | 3.96 | Destabilizing | 0.17 | Likely Benign | 0.456 | Likely Benign | -1.07 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 0.1530 | 0.4240 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||
| c.1505G>T | G502V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: all evaluated algorithms except premPS (which predicts benign) classify the substitution as pathogenic or likely pathogenic. The consensus of high‑accuracy predictors is consistent: AlphaMissense‑Optimized reports a pathogenic effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a destabilizing, pathogenic outcome. In contrast, premPS is the sole tool suggesting a benign impact. Overall, the overwhelming majority of evidence points to a pathogenic effect for G502V, and this conclusion does not conflict with the absence of a ClinVar classification. Thus, the variant is most likely pathogenic, and this assessment is not contradicted by ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -15.278 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 3.56 | Destabilizing | 1.0 | 5.50 | Destabilizing | 4.53 | Destabilizing | 0.43 | Likely Benign | 0.917 | Likely Pathogenic | -8.65 | Deleterious | 0.999 | Probably Damaging | 0.944 | Probably Damaging | -1.67 | Pathogenic | 0.00 | Affected | 0.1406 | 0.3387 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1163G>T | G388V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G388V is catalogued in gnomAD (6-33438068-G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Pathogenic predictions arise from REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized remains benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates benign, whereas Foldetta—combining FoldX‑MD and Rosetta stability outputs—labels the variant as pathogenic. Overall, the majority of tools and the Foldetta result point to a pathogenic effect. This conclusion does not conflict with ClinVar, which currently contains no classification for G388V. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.736850 | Disordered | 0.420316 | Uncertain | 0.319 | 0.827 | 0.750 | 6-33438068-G-T | -6.887 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 6.58 | Destabilizing | 6.6 | 5.51 | Destabilizing | 6.05 | Destabilizing | -0.11 | Likely Benign | 0.620 | Likely Pathogenic | -0.93 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 4.32 | 3 | 0.1600 | 0.3897 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||
| c.2075T>G | L692R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | -16.656 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.34 | Destabilizing | 0.0 | 5.51 | Destabilizing | 4.93 | Destabilizing | 1.96 | Destabilizing | 0.611 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.895 | Possibly Damaging | 3.07 | Benign | 0.00 | Affected | 0.1204 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2014A>C | T672P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T672P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain results come from premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. No predictions are missing or inconclusive. Overall, the majority of evidence points to a pathogenic impact for T672P. This conclusion is not contradicted by ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.116183 | Structured | 0.102069 | Uncertain | 0.586 | 0.362 | 0.000 | -11.022 | Likely Pathogenic | 0.346 | Ambiguous | Likely Benign | 2.22 | Destabilizing | 0.2 | 5.54 | Destabilizing | 3.88 | Destabilizing | 0.55 | Ambiguous | 0.087 | Likely Benign | -4.20 | Deleterious | 0.968 | Probably Damaging | 0.824 | Possibly Damaging | 3.40 | Benign | 0.01 | Affected | 0.1988 | 0.5532 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||
| c.758A>T | N253I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253I is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (ID 6‑33435609‑A‑T). Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are limited to premPS and FATHMM. High‑accuracy assessments reinforce the pathogenic view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | 6-33435609-A-T | 1 | 6.20e-7 | -15.241 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 2.95 | Destabilizing | 0.1 | 5.56 | Destabilizing | 4.26 | Destabilizing | 0.25 | Likely Benign | 0.836 | Likely Pathogenic | -7.83 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.57 | Benign | 0.01 | Affected | 3.39 | 15 | 0.0803 | 0.7553 | -3 | -2 | 8.0 | -0.94 | ||||||||||||||||||||||||
| c.1716G>C | W572C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W572C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.150080 | Structured | 0.039626 | Uncertain | 0.935 | 0.256 | 0.000 | -15.589 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.49 | Destabilizing | 0.2 | 5.59 | Destabilizing | 5.54 | Destabilizing | 1.72 | Destabilizing | 0.861 | Likely Pathogenic | -11.82 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.25 | Pathogenic | 0.00 | Affected | 0.3648 | 0.1304 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||
| c.1716G>T | W572C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W572C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No inconclusive or missing predictions are present. Based on the consensus of all available computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.150080 | Structured | 0.039626 | Uncertain | 0.935 | 0.256 | 0.000 | -15.589 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.49 | Destabilizing | 0.2 | 5.59 | Destabilizing | 5.54 | Destabilizing | 1.72 | Destabilizing | 0.861 | Likely Pathogenic | -11.82 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.25 | Pathogenic | 0.00 | Affected | 0.3648 | 0.1304 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||
| c.2080G>C | A694P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A694P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, while the majority of other in silico predictors (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as Likely Pathogenic, with three of four votes pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Taken together, the preponderance of evidence points to a pathogenic effect for A694P. This conclusion is consistent with the absence of ClinVar annotation and gnomAD data, and there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.127496 | Structured | 0.352199 | Uncertain | 0.938 | 0.269 | 0.000 | -10.569 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 3.39 | Destabilizing | 0.2 | 5.59 | Destabilizing | 4.49 | Destabilizing | 0.82 | Ambiguous | 0.209 | Likely Benign | -2.77 | Deleterious | 0.988 | Probably Damaging | 0.578 | Possibly Damaging | 3.44 | Benign | 0.03 | Affected | 0.2265 | 0.3829 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1109G>T | G370V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster into two groups: benign (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Benign) and pathogenic (FoldX, Rosetta, Foldetta, and FATHMM). High‑accuracy assessments further refine this picture: AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic outcome. Overall, the majority of evidence points toward a benign impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -5.328 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 4.98 | Destabilizing | 3.8 | 5.61 | Destabilizing | 5.30 | Destabilizing | -0.43 | Likely Benign | 0.427 | Likely Benign | 0.03 | Neutral | 0.000 | Benign | 0.000 | Benign | 1.32 | Pathogenic | 0.29 | Tolerated | 0.1306 | 0.4198 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.2066T>G | L689R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. No predictions are missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -17.776 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.91 | Destabilizing | 0.6 | 5.61 | Destabilizing | 5.76 | Destabilizing | 2.14 | Destabilizing | 0.609 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.932 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 0.1208 | 0.0530 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1450T>A | F484I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are inconclusive or missing. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -16.197 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.62 | Destabilizing | 0.2 | 5.62 | Destabilizing | 5.62 | Destabilizing | 1.33 | Destabilizing | 0.399 | Likely Benign | -5.70 | Deleterious | 0.894 | Possibly Damaging | 0.332 | Benign | 2.74 | Benign | 0.00 | Affected | 0.1516 | 0.1885 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.935T>C | F312S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All available in‑silico predictors classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, with no contradiction to ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -14.075 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.74 | Destabilizing | 0.3 | 5.64 | Destabilizing | 4.69 | Destabilizing | 2.70 | Destabilizing | 0.880 | Likely Pathogenic | -7.35 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.17 | Pathogenic | 0.00 | Affected | 0.3563 | 0.1578 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.2126T>C | L709P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709P is not reported in ClinVar and is absent from gnomAD. Benign predictions come from REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from FoldX, Rosetta, Foldetta, polyPhen2_HumDiv, polyPhen2_HumVar, and AlphaMissense‑Default. High‑accuracy tools give mixed results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, FATHMM, PROVEAN) also predicts benign; Foldetta predicts pathogenic. Because the majority of standard predictors and the SGM Consensus favor benign, the variant is most likely benign, and this is consistent with the lack of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.243554 | Structured | 0.365830 | Uncertain | 0.934 | 0.379 | 0.000 | -7.517 | In-Between | 0.767 | Likely Pathogenic | Likely Benign | 2.81 | Destabilizing | 0.0 | 5.65 | Destabilizing | 4.23 | Destabilizing | 0.31 | Likely Benign | 0.167 | Likely Benign | -1.93 | Neutral | 1.000 | Probably Damaging | 0.975 | Probably Damaging | 3.47 | Benign | 0.37 | Tolerated | 0.3004 | 0.0825 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||
| c.2147G>C | R716P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R716P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, and FATHMM; pathogenic predictions come from AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, Rosetta, Foldetta, and the SGM‑Consensus score. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.419135 | Uncertain | 0.962 | 0.379 | 0.000 | -10.744 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.18 | Likely Benign | 0.1 | 5.67 | Destabilizing | 2.93 | Destabilizing | 0.49 | Likely Benign | 0.320 | Likely Benign | -5.75 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.33 | Benign | 0.01 | Affected | 0.2140 | 0.3576 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1462A>C | T488P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T488P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining twelve tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity; premPS is uncertain and therefore not counted. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Based on the overwhelming consensus of these predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -13.432 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 4.40 | Destabilizing | 0.7 | 5.68 | Destabilizing | 5.04 | Destabilizing | 0.68 | Ambiguous | 0.505 | Likely Pathogenic | -5.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0.1518 | 0.3557 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1505G>A | G502D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502D is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the uniform predictions, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | Uncertain | 1 | -14.796 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.79 | Destabilizing | 0.9 | 5.69 | Destabilizing | 4.74 | Destabilizing | 1.38 | Destabilizing | 0.915 | Likely Pathogenic | -6.80 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | -1.66 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.1715 | 0.1172 | 1 | -1 | -3.1 | 58.04 | 224.2 | -80.0 | -0.8 | 0.7 | 0.6 | 0.3 | X | X | X | Potentially Pathogenic | Gly502 is located in a hinge in the middle of an α-helix (res. Leu489-Glu519). In the WT, Gly502 acts as an α-helix breaker due to its lack of a side chain, facilitating a bend in the middle of the α-helix. In the variant simulations, the carboxylate group of Asp502 forms hydrogen bonds with neighboring residues (e.g., Ser677, Lys504), disrupting the hinge. Additionally, Asp502 struggles to fit into the α-helix hinge and cannot generate a similar bend as Gly502, which would drastically affect the secondary structure during folding. Thus, the deleterious effect seen in the simulations is likely an underestimate of the impact of the residue swap on the protein structure during protein folding. | ||||||||||||||
| c.1043T>G | V348G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods reinforce this assessment: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a pathogenic effect. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among pathogenic predictions and the lack of a benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -12.793 | Likely Pathogenic | 0.964 | Likely Pathogenic | Likely Pathogenic | 3.97 | Destabilizing | 0.2 | 5.70 | Destabilizing | 4.84 | Destabilizing | 2.23 | Destabilizing | 0.419 | Likely Benign | -6.18 | Deleterious | 0.637 | Possibly Damaging | 0.989 | Probably Damaging | 1.56 | Pathogenic | 0.00 | Affected | 0.2229 | 0.2082 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.2134G>T | G712C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G712C is catalogued in gnomAD (6‑33441599‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.384858 | Uncertain | 0.947 | 0.365 | 0.000 | 6-33441599-G-T | 1 | 6.20e-7 | -11.376 | Likely Pathogenic | 0.829 | Likely Pathogenic | Ambiguous | 2.54 | Destabilizing | 0.0 | 5.72 | Destabilizing | 4.13 | Destabilizing | 0.56 | Ambiguous | 0.516 | Likely Pathogenic | -7.75 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.31 | Benign | 0.00 | Affected | 3.50 | 9 | 0.1513 | 0.3947 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||
| c.1004G>C | R335P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R335P has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and SIFT, whereas pathogenic predictions are reported by FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments give a more focused view: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a pathogenic effect. Taken together, the majority of evidence points to a pathogenic impact for R335P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.305330 | Structured | 0.331028 | Uncertain | 0.483 | 0.428 | 0.500 | -13.952 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 3.23 | Destabilizing | 0.8 | 5.73 | Destabilizing | 4.48 | Destabilizing | 0.43 | Likely Benign | 0.250 | Likely Benign | -4.22 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.69 | Pathogenic | 0.09 | Tolerated | 0.1866 | 0.4497 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1259T>C | F420S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420S (ClinVar ID 981441.0) is reported as Pathogenic in ClinVar and is not present in gnomAD. Prediction tools largely agree on a deleterious effect: all listed predictors except FATHMM return a pathogenic or likely pathogenic call. The single benign prediction comes from FATHMM. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts Pathogenic. No predictions or folding‑stability results are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, consistent with its ClinVar status. 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 | Likely Pathogenic | 1 | -13.231 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.34 | Destabilizing | 0.1 | 5.73 | Destabilizing | 5.54 | Destabilizing | 2.14 | Destabilizing | 0.544 | Likely Pathogenic | -7.43 | Deleterious | 0.998 | Probably Damaging | 0.938 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 3.37 | 29 | 0.4167 | 0.0200 | -3 | -2 | -3.6 | -60.10 | 213.3 | 57.8 | 0.0 | 0.0 | -0.4 | 0.1 | X | Potentially Pathogenic | In the WT, the phenyl ring of the Phe420 side chain, located on an α helix (res. Met414-Glu436), packs against hydrophobic residues in the interhelix area of the GAP domain (e.g., Leu689, Leu714, Leu717, Leu718). Although no large-scale adverse effects are seen in the variant simulations, the polar hydroxyl group of Ser420 is not suitable for the hydrophobic inter-helix space. Thus, the residue swap could affect protein folding. In theory, the introduced hydroxyl group could also lower the α helix integrity by H-bonding with the backbone atoms of neighboring residues in the same α helix. However, no such effect is seen in the variant simulations. | ||||||||||||||||
| c.2119G>C | A707P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A707P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, SIFT, and FATHMM, whereas pathogenic predictions come from Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as Pathogenic. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.371229 | Uncertain | 0.927 | 0.365 | 0.000 | -8.082 | Likely Pathogenic | 0.885 | Likely Pathogenic | Ambiguous | 0.28 | Likely Benign | 0.1 | 5.75 | Destabilizing | 3.02 | Destabilizing | 0.76 | Ambiguous | 0.228 | Likely Benign | -2.92 | Deleterious | 0.996 | Probably Damaging | 0.983 | Probably Damaging | 3.41 | Benign | 0.09 | Tolerated | 0.1375 | 0.3095 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1516C>T | L506F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506F is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact; premPS and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, which is consistent with its ClinVar “Uncertain” classification and does not contradict the available data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | Uncertain | 1 | -11.262 | Likely Pathogenic | 0.883 | Likely Pathogenic | Ambiguous | 4.92 | Destabilizing | 0.8 | 5.76 | Destabilizing | 5.34 | Destabilizing | 0.91 | Ambiguous | 0.464 | Likely Benign | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.62 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.0566 | 0.1471 | 0 | 2 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.1802C>A | A601E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601E is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | Conflicting | 2 | -16.752 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 6.68 | Destabilizing | 0.8 | 5.76 | Destabilizing | 6.22 | Destabilizing | 1.24 | Destabilizing | 0.588 | Likely Pathogenic | -4.98 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.54 | Benign | 0.00 | Affected | 3.37 | 35 | 0.1346 | 0.1444 | 0 | -1 | -5.3 | 58.04 | 240.0 | -82.3 | 0.0 | 0.0 | 0.7 | 0.1 | X | X | X | Potentially Pathogenic | 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, the carboxylate group of Glu601 faces the inter-helix space and is forced to shift slightly away from the hydrophobic niche. Additionally, in two of the simulations, Glu601 forms a salt bridge with Arg499, causing the otherwise stable salt bridge between Arg499 and Glu496 at the outer surface of an α helix (res. Leu489-Glu519) to break due to the residue swap.These effects suggest that the protein folding process could be seriously affected. Moreover, due to its location at the GAP-Ras interface, it could also impact the complex formation with the GTPase. | ||||||||||||||
| c.851T>C | L284P 2D AIThe SynGAP1 missense variant L284P is listed in ClinVar as Pathogenic (ClinVar ID 3344808.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.094817 | Structured | 0.371601 | Uncertain | 0.950 | 0.255 | 0.000 | Likely Pathogenic | 1 | -15.588 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.83 | Destabilizing | 0.2 | 5.81 | Destabilizing | 5.82 | Destabilizing | 1.89 | Destabilizing | 0.794 | Likely Pathogenic | -6.17 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.64 | Pathogenic | 0.00 | Affected | 0.3540 | 0.1021 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||
| c.1205T>C | L402P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L402P is not reported in ClinVar and is absent from gnomAD. Consensus among in‑silico predictors is overwhelmingly pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect, whereas only FATHMM predicts a benign outcome. High‑accuracy tools reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Taken together, the evidence strongly supports a pathogenic classification, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.243554 | Structured | 0.431978 | Uncertain | 0.961 | 0.383 | 0.000 | -12.030 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 7.40 | Destabilizing | 0.1 | 5.82 | Destabilizing | 6.61 | Destabilizing | 2.22 | Destabilizing | 0.616 | Likely Pathogenic | -4.80 | Deleterious | 1.000 | Probably Damaging | 0.980 | Probably Damaging | 3.68 | Benign | 0.01 | Affected | 0.3628 | 0.1874 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1640G>T | C547F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547F is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect fall into two groups: the single benign prediction comes from premPS, while all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify it as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a destabilizing, pathogenic effect. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions and the absence of any ClinVar annotation, the variant is most likely pathogenic, with no contradiction from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | -15.404 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 5.63 | Destabilizing | 1.2 | 5.82 | Destabilizing | 5.73 | Destabilizing | 0.49 | Likely Benign | 0.828 | Likely Pathogenic | -10.57 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.29 | Pathogenic | 0.05 | Affected | 0.1603 | 0.3260 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.1639T>C | C547R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547R is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while no tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | Uncertain | 1 | -16.967 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 7.76 | Destabilizing | 0.8 | 5.83 | Destabilizing | 6.80 | Destabilizing | 1.69 | Destabilizing | 0.900 | Likely Pathogenic | -11.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.33 | Pathogenic | 0.02 | Affected | 3.37 | 35 | 0.1802 | 0.1408 | -4 | -3 | -7.0 | 53.05 | 267.4 | -90.3 | 0.0 | 0.0 | -0.1 | 0.1 | X | X | X | X | Potentially Pathogenic | Cys547 is located in an α-helix (res. Ala533-Val560). The thiol side chain of Cys is situated in a hydrophobic inter-helix space, where it packs hydrophobically with other residues such as Ile626, Leu551, and Phe652. Additionally, the thiol side chain of Cys547 weakly hydrogen bonds with the carbonyl group of Leu543 in the same α-helix. In the variant simulations, the bulkier, positively charged guanidinium group of Arg547 must rotate out of the hydrophobic space. Consequently, it forms ionic interactions with the carboxylate groups of Glu548 in the same helix and Glu656 in the neighboring α-helix (res. Glu666-Asp644). This causes the two helices to slightly separate, significantly affecting the secondary structure integrity of the latter helix. These negative structural effects could be more pronounced during protein folding and are likely to be undermined in the MD simulations. | |||||||||||||
| c.1880C>A | A627D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A627D is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. All available evidence points to a damaging impact. Consequently, 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 | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -16.603 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.09 | Destabilizing | 1.3 | 5.83 | Destabilizing | 5.96 | Destabilizing | 1.58 | Destabilizing | 0.726 | Likely Pathogenic | -5.93 | Deleterious | 0.999 | Probably Damaging | 0.961 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.1502 | 0.1816 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1958T>G | L653R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L653R 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 limited to FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.335213 | Uncertain | 0.963 | 0.332 | 0.000 | -16.078 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 6.92 | Destabilizing | 1.1 | 5.84 | Destabilizing | 6.38 | Destabilizing | 2.55 | Destabilizing | 0.649 | Likely Pathogenic | -5.75 | Deleterious | 0.997 | Probably Damaging | 0.806 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.1501 | 0.0805 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1517T>G | L506R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Thus, all available evidence indicates that the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | -14.119 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 4.92 | Destabilizing | 0.6 | 5.85 | Destabilizing | 5.39 | Destabilizing | 1.77 | Destabilizing | 0.738 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.54 | Pathogenic | 0.00 | Affected | 0.1207 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1784T>C | L595P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L595P is listed in ClinVar with an “Uncertain” status (ClinVar ID 3172762.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.015344 | Structured | 0.128444 | Uncertain | 0.920 | 0.150 | 0.000 | Uncertain | 1 | -11.856 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.09 | Destabilizing | 0.8 | 5.88 | Destabilizing | 3.99 | Destabilizing | 1.78 | Destabilizing | 0.747 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.72 | Benign | 0.00 | Affected | 3.37 | 35 | 0.3336 | 0.1713 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.838T>G | Y280D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280D is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.161087 | Structured | 0.321243 | Uncertain | 0.917 | 0.248 | 0.125 | -16.885 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.91 | Destabilizing | 0.2 | 5.89 | Destabilizing | 5.90 | Destabilizing | 2.00 | Destabilizing | 0.580 | Likely Pathogenic | -9.19 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.94 | Pathogenic | 0.02 | Affected | 0.3593 | 0.0212 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.917T>G | V306G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign effect. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. All available evidence points to a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.363090 | Structured | 0.315026 | Uncertain | 0.896 | 0.287 | 0.125 | -12.313 | Likely Pathogenic | 0.795 | Likely Pathogenic | Ambiguous | 4.39 | Destabilizing | 0.2 | 5.89 | Destabilizing | 5.14 | Destabilizing | 2.46 | Destabilizing | 0.529 | Likely Pathogenic | -5.48 | Deleterious | 0.998 | Probably Damaging | 1.000 | Probably Damaging | 1.78 | Pathogenic | 0.00 | Affected | 0.1874 | 0.2035 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1753G>C | A585P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A585P is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools cluster into two groups: the single benign prediction comes from SIFT, while all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic outcome. Based on the convergence of these predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.055884 | Uncertain | 0.880 | 0.244 | 0.000 | -10.999 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 5.44 | Destabilizing | 0.1 | 5.92 | Destabilizing | 5.68 | Destabilizing | 0.77 | Ambiguous | 0.549 | Likely Pathogenic | -3.09 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.33 | Pathogenic | 0.16 | Tolerated | 0.1884 | 0.2943 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.652T>A | F218I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218I is reported in gnomAD (variant ID 6‑33435294‑T‑A) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while benign predictions are limited to polyPhen‑2 (HumVar), SIFT, and FATHMM. High‑accuracy assessments reinforce the pathogenic view: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | 6-33435294-T-A | 1 | 6.20e-7 | -12.211 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 4.69 | Destabilizing | 0.2 | 5.93 | Destabilizing | 5.31 | Destabilizing | 1.18 | Destabilizing | 0.612 | Likely Pathogenic | -3.81 | Deleterious | 0.510 | Possibly Damaging | 0.066 | Benign | 5.85 | Benign | 0.08 | Tolerated | 3.41 | 13 | 0.2106 | 0.2459 | 0 | 1 | 1.7 | -34.02 | ||||||||||||||||||||||||
| c.1508A>C | Q503P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; the remaining tools (FoldX, premPS, AlphaMissense‑Default) are inconclusive. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta both predict pathogenic. Because the majority of evidence points to a deleterious effect, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -10.915 | Likely Pathogenic | 0.414 | Ambiguous | Likely Benign | 1.06 | Ambiguous | 0.7 | 5.94 | Destabilizing | 3.50 | Destabilizing | 0.75 | Ambiguous | 0.860 | Likely Pathogenic | -5.20 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | -1.53 | Pathogenic | 0.03 | Affected | 0.2076 | 0.3610 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.1946T>G | M649R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M649R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.360413 | Uncertain | 0.962 | 0.345 | 0.000 | -14.827 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 5.02 | Destabilizing | 0.1 | 5.97 | Destabilizing | 5.50 | Destabilizing | 2.09 | Destabilizing | 0.595 | Likely Pathogenic | -5.98 | Deleterious | 0.985 | Probably Damaging | 0.464 | Possibly Damaging | 3.33 | Benign | 0.00 | Affected | 0.1635 | 0.1228 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||
| c.1982A>C | Q661P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q661P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, whereas the remaining 12 tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score) all classify the change as pathogenic or likely pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a pathogenic effect. No prediction is inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.117089 | Uncertain | 0.924 | 0.309 | 0.000 | -17.549 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 4.11 | Destabilizing | 0.1 | 5.97 | Destabilizing | 5.04 | Destabilizing | 0.45 | Likely Benign | 0.531 | Likely Pathogenic | -4.58 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 3.41 | Benign | 0.01 | Affected | 0.1811 | 0.3850 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.1133G>C | G378A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G378A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as “Likely Benign.” High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus confirms a benign likelihood, while Foldetta—combining FoldX‑MD and Rosetta outputs—predicts a pathogenic effect on protein folding stability. Overall, the majority of evidence points toward a benign impact, and this conclusion is consistent with the absence of ClinVar annotation and gnomAD data. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.767246 | Disordered | 0.432858 | Uncertain | 0.341 | 0.915 | 0.625 | -6.450 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 5.06 | Destabilizing | 1.3 | 6.00 | Destabilizing | 5.53 | Destabilizing | -0.04 | Likely Benign | 0.497 | Likely Benign | -0.55 | Neutral | 0.999 | Probably Damaging | 0.981 | Probably Damaging | 1.33 | Pathogenic | 0.18 | Tolerated | 0.4062 | 0.4576 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.913A>C | T305P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T305P 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of tools (7 pathogenic vs. 5 benign) lean toward a pathogenic impact, and this assessment does not contradict the lack of ClinVar annotation. 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. | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -5.203 | Likely Benign | 0.177 | Likely Benign | Likely Benign | 3.64 | Destabilizing | 1.1 | 6.02 | Destabilizing | 4.83 | Destabilizing | 0.71 | Ambiguous | 0.293 | Likely Benign | -2.83 | Deleterious | 0.997 | Probably Damaging | 0.929 | Probably Damaging | 1.72 | Pathogenic | 0.06 | Tolerated | 0.2206 | 0.5333 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||
| c.1450T>G | F484V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -15.492 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 6.08 | Destabilizing | 0.1 | 6.07 | Destabilizing | 6.08 | Destabilizing | 1.28 | Destabilizing | 0.455 | Likely Benign | -6.70 | Deleterious | 0.859 | Possibly Damaging | 0.526 | Possibly Damaging | 2.75 | Benign | 0.00 | Affected | 0.1696 | 0.1902 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1030G>A | G344S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344S is listed in ClinVar (ID 981240.0) as Pathogenic and is not reported in gnomAD. Prediction tools that assess pathogenicity all agree: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic; the only inconclusive result is premPS, which is marked Uncertain. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | Pathogenic | 5 | -11.254 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 9.02 | Destabilizing | 0.7 | 6.08 | Destabilizing | 7.55 | Destabilizing | 0.98 | Ambiguous | 0.790 | Likely Pathogenic | -5.28 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.45 | Pathogenic | 0.04 | Affected | 3.37 | 25 | 0.2735 | 0.5324 | 1 | 0 | -0.4 | 30.03 | 217.3 | -51.7 | 0.0 | 0.1 | 0.2 | 0.1 | X | X | Potentially Pathogenic | Because Gly344 lacks a proper side chain, it allows the anti-parallel β sheet strand (res. Gly341-Pro349) to have a slight twist. Within a β strand, side chains normally alternate between outward and inward positions, but glycine is an exception as it allows the alternating pattern to skip a residue. Introducing serine or any other residue with a side chain at position 344 prevents this unique skip in the alternating pattern, causing structural strain or likely preventing correct folding altogether. Additionally, Tyr342 shields Gly344 from the solvent, contributing to twist formation in the β sheet and stabilizing the β-strand.In the variant simulations, the side chain of Ser344 assumes the inward position. However, the hydrophobic niche formed by multiple C2 domain residues (e.g., Val365, Val343, Leu327) is not accommodating for its hydroxyl group. The outward position, not seen in the simulations, would be equally disadvantageous due to the presence of hydrophobic residues on that side as well (e.g., Leu345, Tyr342). Serine is also not well-suited for twist formation, as it tends to suppress twisting and bending in β sheets. At this position, the hydroxyl group of Ser344 could also form hydrogen bonds with the backbone atoms of the Gly-rich Ω loop in the C2 domain (e.g., Thr366, Leu367, Gly378; res. Pro364-Pro398), potentially adversely affecting membrane-loop dynamics and ultimately compromising the stability of the SynGAP-membrane association. | |||||||||||||||
| c.2071A>C | T691P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T691P is listed in ClinVar (ID 648126.0) as Pathogenic and is not reported in gnomAD. Across the broad panel of in‑silico predictors, three tools (REVEL, SIFT, FATHMM) classify the change as benign, whereas the remaining 11 predictors (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score) report it as pathogenic. High‑accuracy assessments further support a deleterious effect: the AlphaMissense‑Optimized model is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and the Foldetta stability analysis (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the preponderance of evidence indicates that T691P is most likely pathogenic, which is consistent with its ClinVar classification and does not contradict the database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.271308 | Uncertain | 0.941 | 0.232 | 0.000 | Likely Pathogenic | 1 | -13.801 | Likely Pathogenic | 0.905 | Likely Pathogenic | Ambiguous | 5.04 | Destabilizing | 0.4 | 6.09 | Destabilizing | 5.57 | Destabilizing | 1.27 | Destabilizing | 0.214 | Likely Benign | -3.43 | Deleterious | 1.000 | Probably Damaging | 0.952 | Probably Damaging | 3.43 | Benign | 0.06 | Tolerated | 3.43 | 14 | 0.1466 | 0.4236 | 0 | -1 | -0.9 | -3.99 | 188.9 | 33.0 | 0.1 | 0.0 | -0.6 | 0.0 | X | X | Potentially Pathogenic | The hydroxyl side chain of Thr691, located in an α-helix (res. Leu696-Leu685), can form hydrogen bonds with the backbone carbonyl and the side chain guanidinium group of Arg687. This interaction facilitates the simultaneous formation of salt bridges between Arg687 and Glu688 on the same α-helix. Additionally, Thr691 occasionally interacts with the thioether side chain of Met409 in an anti-parallel β-sheet of the C2 domain (res. Ile411-Ala399), although this interaction is not consistently maintained throughout the WT simulations. In the variant simulations, the pyrrolidine side chain of Pro691 lacks hydrogen bond donors, making a similar setup impossible. Moreover, proline lacks a free amide group necessary for hydrogen bonding with the carbonyl group of Arg687, introducing a slight bend in the α-helix and compromising its integrity. | |||||||||||||||
| c.2078A>C | H693P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are limited to FATHMM, which classifies the variant as benign. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -16.281 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.54 | Destabilizing | 0.2 | 6.09 | Destabilizing | 5.82 | Destabilizing | 1.06 | Destabilizing | 0.600 | Likely Pathogenic | -9.97 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.09 | Benign | 0.01 | Affected | 0.2080 | 0.3210 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.2167A>C | T723P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723P is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity are SGM Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. premPS is uncertain and does not influence the overall assessment. Overall, the majority of tools and the high‑accuracy methods support a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.476583 | Structured | 0.458243 | Uncertain | 0.945 | 0.447 | 0.375 | -9.231 | Likely Pathogenic | 0.741 | Likely Pathogenic | Likely Benign | 3.98 | Destabilizing | 0.1 | 6.10 | Destabilizing | 5.04 | Destabilizing | 0.54 | Ambiguous | 0.085 | Likely Benign | -2.51 | Deleterious | 0.995 | Probably Damaging | 0.929 | Probably Damaging | 3.49 | Benign | 0.04 | Affected | 0.1826 | 0.4406 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.2042G>T | G681V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G681V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—classify the change as pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; SGM‑Consensus predicts a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic outcome. No other high‑confidence predictions are available. Taken together, the consensus of pathogenic predictions outweighs the single benign call, indicating that G681V is most likely pathogenic. This assessment 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 | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | -14.043 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 3.21 | Destabilizing | 2.0 | 6.12 | Destabilizing | 4.67 | Destabilizing | 0.64 | Ambiguous | 0.572 | Likely Pathogenic | -8.98 | Deleterious | 0.999 | Probably Damaging | 0.928 | Probably Damaging | 3.33 | Benign | 0.01 | Affected | 0.1350 | 0.3840 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1763T>G | L588R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L588R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity uniformly classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy methods corroborate this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. All available evidence points to a deleterious impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.082229 | Uncertain | 0.887 | 0.214 | 0.000 | -15.602 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 6.96 | Destabilizing | 0.4 | 6.14 | Destabilizing | 6.55 | Destabilizing | 2.07 | Destabilizing | 0.942 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.42 | Pathogenic | 0.00 | Affected | 0.1209 | 0.0530 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2135G>T | G712V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G712V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, while the majority of tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.384858 | Uncertain | 0.947 | 0.365 | 0.000 | -10.466 | Likely Pathogenic | 0.877 | Likely Pathogenic | Ambiguous | 3.79 | Destabilizing | 0.0 | 6.18 | Destabilizing | 4.99 | Destabilizing | 0.79 | Ambiguous | 0.410 | Likely Benign | -7.55 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.32 | Benign | 0.00 | Affected | 0.1395 | 0.3712 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1051G>C | A351P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are Foldetta, PROVEAN, SIFT, FATHMM, and Rosetta. FoldX and premPS give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the lack of ClinVar reporting; thus the variant is most likely benign rather than pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -6.559 | Likely Benign | 0.147 | Likely Benign | Likely Benign | -0.89 | Ambiguous | 0.2 | 6.19 | Destabilizing | 2.65 | Destabilizing | 0.62 | Ambiguous | 0.051 | Likely Benign | -3.08 | Deleterious | 0.016 | Benign | 0.007 | Benign | 1.67 | Pathogenic | 0.03 | Affected | 0.1862 | 0.5472 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||
| c.1714T>A | W572R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W572R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while no tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.150080 | Structured | 0.039626 | Uncertain | 0.935 | 0.256 | 0.000 | -17.511 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.84 | Destabilizing | 0.1 | 6.19 | Destabilizing | 5.52 | Destabilizing | 1.79 | Destabilizing | 0.894 | Likely Pathogenic | -12.81 | Deleterious | -1.25 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.4059 | 0.0212 | 2 | -3 | -3.6 | -30.03 | 312.6 | -37.6 | 0.0 | 0.0 | -1.0 | 0.0 | X | X | Potentially Pathogenic | The indole ring of Trp572, located in an α-helix (res. Arg563-Glu578), lies in a hydrophobic inter-helix space, where it makes extensive hydrophobic interactions with nearby residues such as Met470, Phe569, Leu588, and Ile589. The guanidinium group of Arg572 is similarly sized to the tryptophan it replaced; however, it is also positively charged. In the variant simulations, Arg572 forms hydrogen bonds with other residues in the inter-helix space, such as Ser592 and the backbone carbonyl atom of Leu465. Additionally, Arg572 hydrophobically packs its carbon chain with surrounding residues such as Phe569 and Ile589.However, the introduced residue arginine is too hydrophilic and charged for the hydrophobic space, disrupting the hydrophobic packing of the inter-helix space. Indeed, in the second simulation, Arg572 successfully escapes the hydrophobic niche completely, causing the whole protein to partially unfold.Overall, the residue swap is highly likely to cause critical protein folding problems, as evidenced by the effects seen in the variant simulations. | |||||||||||||||||||||
| c.1714T>C | W572R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W572R is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, which is consistent with its ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.150080 | Structured | 0.039626 | Uncertain | 0.935 | 0.256 | 0.000 | Not provided | 1 | -17.511 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.84 | Destabilizing | 0.1 | 6.19 | Destabilizing | 5.52 | Destabilizing | 1.79 | Destabilizing | 0.894 | Likely Pathogenic | -12.81 | Deleterious | -1.25 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.4059 | 0.0212 | 2 | -3 | -3.6 | -30.03 | 312.6 | -37.6 | 0.0 | 0.0 | -1.0 | 0.0 | X | X | Potentially Pathogenic | The indole ring of Trp572, located in an α-helix (res. Arg563-Glu578), lies in a hydrophobic inter-helix space, where it makes extensive hydrophobic interactions with nearby residues such as Met470, Phe569, Leu588, and Ile589. The guanidinium group of Arg572 is similarly sized to the tryptophan it replaced; however, it is also positively charged. In the variant simulations, Arg572 forms hydrogen bonds with other residues in the inter-helix space, such as Ser592 and the backbone carbonyl atom of Leu465. Additionally, Arg572 hydrophobically packs its carbon chain with surrounding residues such as Phe569 and Ile589.However, the introduced residue arginine is too hydrophilic and charged for the hydrophobic space, disrupting the hydrophobic packing of the inter-helix space. Indeed, in the second simulation, Arg572 successfully escapes the hydrophobic niche completely, causing the whole protein to partially unfold.Overall, the residue swap is highly likely to cause critical protein folding problems, as evidenced by the effects seen in the variant simulations. | |||||||||||||||||||
| c.1946T>A | M649K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M649K is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign calls are limited to polyPhen‑2 (HumVar) and FATHMM. High‑accuracy methods reinforce the pathogenic consensus: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.360413 | Uncertain | 0.962 | 0.345 | 0.000 | -14.533 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.42 | Destabilizing | 0.0 | 6.19 | Destabilizing | 4.81 | Destabilizing | 1.79 | Destabilizing | 0.614 | Likely Pathogenic | -5.98 | Deleterious | 0.968 | Probably Damaging | 0.382 | Benign | 3.34 | Benign | 0.01 | Affected | 0.1438 | 0.1079 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.2140C>G | L714V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L714V has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Overall, the majority of predictions (10 pathogenic vs. 4 benign) indicate a likely pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no record for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.314870 | Structured | 0.402311 | Uncertain | 0.961 | 0.369 | 0.000 | -4.966 | Likely Benign | 0.781 | Likely Pathogenic | Likely Benign | 3.91 | Destabilizing | 0.1 | 6.19 | Destabilizing | 5.05 | Destabilizing | 1.21 | Destabilizing | 0.259 | Likely Benign | -2.76 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.16 | Benign | 0.00 | Affected | 0.1421 | 0.2689 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.1640G>A | C547Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547Y (ClinVar ID 1404191.0) is listed as Pathogenic in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Taken together, the overwhelming majority of computational evidence indicates a pathogenic effect, which is in agreement with the ClinVar classification. Thus, the variant is most likely pathogenic and does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | Pathogenic | 1 | -15.871 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 8.53 | Destabilizing | 1.8 | 6.20 | Destabilizing | 7.37 | Destabilizing | 0.62 | Ambiguous | 0.874 | Likely Pathogenic | -10.57 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.33 | Pathogenic | 0.06 | Tolerated | 3.37 | 35 | 0.1393 | 0.2742 | 0 | -2 | -3.8 | 60.04 | 280.1 | -54.8 | 0.0 | 0.0 | 0.0 | 0.0 | X | X | X | Potentially Pathogenic | Cys547 is located in an α-helix (res. Ala533-Val560). The thiol side chain of Cys547 is situated in a hydrophobic inter-helix space, where it packs hydrophobically with other residues such as Ile626, Leu551, and Phe652. Additionally, the thiol side chain of Cys weakly hydrogen bonds with the carbonyl group of Leu543 in the same α-helix. In the variant simulations, the bulkier phenol ring of Tyr547, with its polar hydroxyl group, is less suited for the hydrophobic space. Consequently, it moves outside and forms a hydrogen bond with the carbonyl group of Phe652 in the neighboring α-helix (res. Glu666-Asp644). This causes the two helices to slightly separate, negatively affecting the secondary structure integrity of the latter helix. These negative structural effects could be more pronounced during protein folding and are likely to be undermined in the MD simulations. | ||||||||||||||
| c.1247T>C | L416P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L416P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and the SGM Consensus). High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, which is consistent with the lack of ClinVar reporting and gnomAD absence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.336105 | Uncertain | 0.935 | 0.227 | 0.000 | -8.859 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 2.59 | Destabilizing | 0.1 | 6.23 | Destabilizing | 4.41 | Destabilizing | 1.27 | Destabilizing | 0.284 | Likely Benign | -3.56 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.35 | Benign | 0.21 | Tolerated | 0.3589 | 0.1353 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1571G>A | C524Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic, while premPS is the sole tool predicting a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. With the overwhelming majority of evidence pointing to a damaging effect and no ClinVar annotation to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.024729 | Uncertain | 0.916 | 0.385 | 0.125 | -11.032 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.20 | Destabilizing | 1.4 | 6.24 | Destabilizing | 4.72 | Destabilizing | 0.18 | Likely Benign | 0.863 | Likely Pathogenic | -10.94 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.36 | Pathogenic | 0.00 | Affected | 0.1496 | 0.3911 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.680G>T | G227V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining twelve tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The high‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.106997 | Structured | 0.329995 | Uncertain | 0.800 | 0.329 | 0.250 | -9.329 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 3.57 | Destabilizing | 0.4 | 6.24 | Destabilizing | 4.91 | Destabilizing | 0.78 | Ambiguous | 0.839 | Likely Pathogenic | -7.58 | Deleterious | 0.952 | Possibly Damaging | 0.521 | Possibly Damaging | 5.67 | Benign | 0.01 | Affected | 0.1130 | 0.4703 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.634T>C | S212P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX and FATHMM, whereas the remaining tools—REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic. High‑accuracy methods give consistent pathogenic results: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. With the overwhelming majority of tools supporting pathogenicity and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -13.051 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.02 | Likely Benign | 0.9 | 6.30 | Destabilizing | 3.16 | Destabilizing | 0.90 | Ambiguous | 0.809 | Likely Pathogenic | -4.13 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 5.75 | Benign | 0.01 | Affected | 0.1859 | 0.5679 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.2170G>C | A724P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A724P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: REVEL predicts a benign effect, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS [uncertain], PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a pathogenic score; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, classifies the variant as pathogenic. No tool suggests a benign outcome, and the single benign prediction (REVEL) is outweighed by the consensus of pathogenic predictions. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this mutation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.476583 | Structured | 0.458050 | Uncertain | 0.923 | 0.483 | 0.250 | -12.817 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.90 | Destabilizing | 0.3 | 6.35 | Destabilizing | 4.63 | Destabilizing | 0.52 | Ambiguous | 0.391 | Likely Benign | -3.88 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.04 | Pathogenic | 0.04 | Affected | 0.1642 | 0.4273 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.652T>G | F218V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; pathogenic predictions arise from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Pathogenic.” High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus agrees on a likely pathogenic outcome, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenicity. No predictions or stability results are missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion aligns with the absence of a ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -10.081 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 4.18 | Destabilizing | 0.2 | 6.35 | Destabilizing | 5.27 | Destabilizing | 1.15 | Destabilizing | 0.691 | Likely Pathogenic | -4.14 | Deleterious | 0.300 | Benign | 0.066 | Benign | 5.81 | Benign | 0.08 | Tolerated | 0.2173 | 0.2258 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1312G>C | A438P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A438P missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas those that predict a pathogenic impact are FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv), SIFT, and AlphaMissense‑Default; premPS and ESM1b are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as pathogenic. Overall, six tools predict pathogenicity versus four predicting benign, and the high‑accuracy consensus is split, but the majority of evidence points toward a deleterious effect. Thus, 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. | GAP | 0.147574 | Structured | 0.290154 | Uncertain | 0.929 | 0.293 | 0.000 | -7.955 | In-Between | 0.721 | Likely Pathogenic | Likely Benign | 2.21 | Destabilizing | 0.1 | 6.36 | Destabilizing | 4.29 | Destabilizing | 0.83 | Ambiguous | 0.158 | Likely Benign | -2.46 | Neutral | 0.815 | Possibly Damaging | 0.137 | Benign | 4.09 | Benign | 0.05 | Affected | 0.1624 | 0.4150 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||
| c.1736G>C | R579P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R579P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar or gnomAD evidence to the contrary, the variant is most likely pathogenic. 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 | -14.826 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.00 | Destabilizing | 0.2 | 6.36 | Destabilizing | 4.68 | Destabilizing | 0.93 | Ambiguous | 0.821 | Likely Pathogenic | -6.26 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.41 | Pathogenic | 0.01 | Affected | 0.2207 | 0.3081 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1909T>C | S637P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S637P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls arise from FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments give a pathogenic signal: the SGM Consensus predicts likely pathogenic, Foldetta predicts destabilizing pathogenic effects, whereas AlphaMissense‑Optimized remains uncertain. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -11.455 | Likely Pathogenic | 0.793 | Likely Pathogenic | Ambiguous | 6.73 | Destabilizing | 0.1 | 6.36 | Destabilizing | 6.55 | Destabilizing | 0.44 | Likely Benign | 0.192 | Likely Benign | -3.12 | Deleterious | 0.946 | Possibly Damaging | 0.360 | Benign | 3.36 | Benign | 0.03 | Affected | 0.2374 | 0.4094 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.857T>C | L286P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L286P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.122885 | Structured | 0.385647 | Uncertain | 0.932 | 0.260 | 0.000 | -14.982 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.43 | Destabilizing | 0.9 | 6.38 | Destabilizing | 5.91 | Destabilizing | 2.10 | Destabilizing | 0.878 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.47 | Pathogenic | 0.00 | Affected | 0.3719 | 0.1182 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.2123T>C | L708P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708P is not reported in ClinVar and is absent from gnomAD. Consensus among most in‑silico predictors is strongly pathogenic: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a deleterious effect. Only REVEL and FATHMM predict a benign outcome, while AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, SGM Consensus reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic change. Taken together, the preponderance of evidence points to a pathogenic impact for L708P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.250310 | Structured | 0.365875 | Uncertain | 0.931 | 0.378 | 0.000 | -10.268 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 4.29 | Destabilizing | 0.1 | 6.43 | Destabilizing | 5.36 | Destabilizing | 1.62 | Destabilizing | 0.298 | Likely Benign | -4.47 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 3.39 | Benign | 0.04 | Affected | 0.2800 | 0.0825 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1160G>T | G387V 2D 3DClick to see structure in 3D Viewer AISynGAP1 G387V is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438065-G-T). Functional prediction tools that report a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as likely benign, while the Foldetta stability assessment (combining FoldX‑MD and Rosetta) indicates a pathogenic change. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as pathogenic. Overall, the majority of predictions favor a benign impact, and this consensus does not contradict the ClinVar uncertain status; thus the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.642678 | Disordered | 0.422910 | Uncertain | 0.293 | 0.861 | 0.750 | Uncertain | 1 | 6-33438065-G-T | 22 | 1.37e-5 | -6.199 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 5.13 | Destabilizing | 1.8 | 6.44 | Destabilizing | 5.79 | Destabilizing | -0.33 | Likely Benign | 0.390 | Likely Benign | -0.54 | Neutral | 0.069 | Benign | 0.077 | Benign | 1.32 | Pathogenic | 0.01 | Affected | 4.32 | 3 | 0.1586 | 0.3708 | -1 | -3 | 4.6 | 42.08 | 207.7 | -68.4 | -0.7 | 0.8 | -0.5 | 0.1 | Uncertain | Gly387 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. This loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play significant roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Val387 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.1814C>G | P605R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains inconclusive. Grouping by consensus, the benign category is empty and the pathogenic category contains all available predictions. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields pathogenic; and Foldetta, integrating FoldX‑MD and Rosetta outputs, reports a destabilizing, pathogenic effect. Consequently, the variant is most likely pathogenic, which does not contradict its current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | Uncertain | 1 | -13.745 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 8.71 | Destabilizing | 2.5 | 6.46 | Destabilizing | 7.59 | Destabilizing | 0.92 | Ambiguous | 0.845 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.69 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.1458 | 0.3131 | 0 | -2 | -2.9 | 59.07 | 281.7 | -118.1 | -0.2 | 0.0 | 0.5 | 0.1 | X | X | X | X | Potentially Pathogenic | Pro605 is located in a short turn between an α helix (res. Glu582-Met603) and a short α helical section (res. Ser606-Phe608). The pyrrolidine side chain of Pro605 packs hydrophobically with nearby hydrophobic residues (e.g., Ile514, Leu623, Leu610) in the inter-helix space. Additionally, proline lacks a free backbone amide group, which breaks the α helix and facilitates the turn in the WT structure.In the variant simulations, the guanidinium side chain of Arg605 is bulkier than proline, and its positively charged guanidinium group faces mostly hydrophobic residues (e.g., Ile514, Leu623, Leu610). As a result, it needs to rotate away from the hydrophobic niche. The residue swap could have a more profound effect on the actual folding process, for example, by preventing the bending at the α helix end.Moreover, due to its location at the GAP-Ras interface, the residue swap could affect the GAP-Ras association. | |||||||||||||
| c.1273A>C | T425P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as deleterious, while only FATHMM predicts a benign outcome; premPS is uncertain. High‑accuracy tools reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. Taken together, the overwhelming majority of evidence supports a pathogenic classification, 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 | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -12.318 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 2.81 | Destabilizing | 0.3 | 6.49 | Destabilizing | 4.65 | Destabilizing | 0.77 | Ambiguous | 0.512 | Likely Pathogenic | -5.16 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.37 | Benign | 0.03 | Affected | 0.1815 | 0.3469 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1964T>C | L655P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L655P is catalogued in gnomAD (ID 6‑33441223‑T‑C) but has no ClinVar entry. Functional prediction tools show a split: benign calls come from REVEL, PROVEAN, SIFT, and FATHMM, whereas pathogenic calls are made by Rosetta, Foldetta, both polyPhen‑2 versions, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are uncertain. High‑accuracy assessments give AlphaMissense‑Optimized as pathogenic, Foldetta as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Overall, the majority of evidence points to a pathogenic effect. 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. | GAP | 0.015344 | Structured | 0.268808 | Uncertain | 0.961 | 0.274 | 0.000 | 6-33441223-T-C | 1 | 6.20e-7 | -9.771 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 1.33 | Ambiguous | 0.5 | 6.52 | Destabilizing | 3.93 | Destabilizing | 0.57 | Ambiguous | 0.126 | Likely Benign | -1.36 | Neutral | 0.981 | Probably Damaging | 0.772 | Possibly Damaging | 3.47 | Benign | 0.32 | Tolerated | 3.39 | 24 | 0.3598 | 0.1274 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.2150T>C | L717P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L717P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL and FATHMM, while the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) all classify the variant as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. No predictions are missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.429342 | Uncertain | 0.969 | 0.397 | 0.000 | -10.214 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.96 | Destabilizing | 0.2 | 6.56 | Destabilizing | 5.26 | Destabilizing | 1.66 | Destabilizing | 0.447 | Likely Benign | -5.32 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.28 | Benign | 0.00 | Affected | 0.3065 | 0.1053 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.791T>C | L264P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset reports a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.323473 | Uncertain | 0.939 | 0.264 | 0.000 | Uncertain | 1 | -12.285 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.73 | Destabilizing | 0.3 | 6.57 | Destabilizing | 6.15 | Destabilizing | 2.65 | Destabilizing | 0.767 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.49 | Pathogenic | 0.00 | Affected | 0.3239 | 0.1053 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||
| c.1652T>C | L551P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L551P (ClinVar ID 547942.0) is classified as Pathogenic in ClinVar and is not reported in gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is Pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009977 | Structured | 0.006653 | Uncertain | 0.960 | 0.254 | 0.000 | Likely Pathogenic | 1 | -14.620 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.66 | Destabilizing | 0.1 | 6.58 | Destabilizing | 6.62 | Destabilizing | 2.66 | Destabilizing | 0.953 | Likely Pathogenic | -4.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.60 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.3377 | 0.1353 | -3 | -3 | -5.4 | -16.04 | 208.6 | 60.9 | 0.1 | 0.0 | -0.3 | 0.0 | X | Potentially Pathogenic | L551 is located on an α-helix (res. Ala533-Val560). The iso-butyl side chain of Leu551 hydrophobically packs with nearby hydrophobic residues such as Cys547, Phe652, Leu633, and Ile630 in the inter-helix space. In the variant simulations, the pyrrolidine side chain of Pro551 is not as optimal as leucine for hydrophobic packing with the nearby residues. Moreover, Pro551 lacks the amide group, and thus, it cannot form a hydrogen bond with the backbone carbonyl group of Cys547, which disrupts the continuity of the secondary structure element. | ||||||||||||||||
| c.1100T>G | L367R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L367R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Those that predict a pathogenic effect are SIFT, FATHMM, and Rosetta. Tools with uncertain or inconclusive results are FoldX, 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 (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of evidence points to a benign impact, with a minority of pathogenic predictions. The variant’s status is not contradicted by ClinVar, as it is not yet classified there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.370445 | Structured | 0.441805 | Uncertain | 0.790 | 0.657 | 0.250 | -6.527 | Likely Benign | 0.515 | Ambiguous | Likely Benign | 0.68 | Ambiguous | 0.4 | 6.63 | Destabilizing | 3.66 | Destabilizing | 0.70 | Ambiguous | 0.196 | Likely Benign | -0.39 | Neutral | 0.146 | Benign | 0.057 | Benign | 1.66 | Pathogenic | 0.02 | Affected | 0.1608 | 0.1173 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||
| c.2060G>C | R687P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R687P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas the remaining eleven tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also indicates pathogenicity. With the overwhelming majority of evidence pointing to a damaging effect and no conflicting ClinVar annotation, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.191060 | Uncertain | 0.914 | 0.259 | 0.000 | -15.697 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.31 | Destabilizing | 0.3 | 6.63 | Destabilizing | 4.47 | Destabilizing | 0.89 | Ambiguous | 0.553 | Likely Pathogenic | -6.12 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.87 | Benign | 0.01 | Affected | 0.1811 | 0.3159 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1145G>A | G382E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G382E is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438050‑G‑A). Prediction tools that agree on a benign effect include premPS, PROVEAN, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts pathogenic. Overall, the majority of evidence points to a pathogenic impact for G382E, 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 | 0.728858 | Disordered | 0.429690 | Uncertain | 0.315 | 0.951 | 0.750 | 6-33438050-G-A | -9.570 | Likely Pathogenic | 0.564 | Ambiguous | Likely Benign | 4.86 | Destabilizing | 1.7 | 6.64 | Destabilizing | 5.75 | Destabilizing | 0.48 | Likely Benign | 0.594 | Likely Pathogenic | -0.96 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 1.32 | Pathogenic | 0.03 | Affected | 4.32 | 9 | 0.1775 | 0.3932 | -2 | 0 | -3.1 | 72.06 | |||||||||||||||||||||||||||
| c.1814C>A | P605H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605H is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. All available predictions are consistent and indicate a deleterious effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | -13.846 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 8.80 | Destabilizing | 2.7 | 6.69 | Destabilizing | 7.75 | Destabilizing | 0.87 | Ambiguous | 0.828 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.68 | Pathogenic | 0.00 | Affected | 0.1778 | 0.4142 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||
| c.1648G>C | A550P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A550P is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar or gnomAD evidence to the contrary, the variant is most likely pathogenic and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | -18.578 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 6.15 | Destabilizing | 0.3 | 6.75 | Destabilizing | 6.45 | Destabilizing | 0.67 | Ambiguous | 0.872 | Likely Pathogenic | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.971 | Probably Damaging | -1.32 | Pathogenic | 0.02 | Affected | 0.1476 | 0.3417 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1151G>T | G384V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G384V is catalogued in gnomAD (ID 6‑33438056‑G‑T) but has no entry in ClinVar. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. 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 benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a pathogenic effect on protein stability. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.427831 | Uncertain | 0.323 | 0.934 | 0.750 | 6-33438056-G-T | -6.968 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 3.69 | Destabilizing | 0.4 | 6.77 | Destabilizing | 5.23 | Destabilizing | -0.11 | Likely Benign | 0.460 | Likely Benign | -1.01 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 4.32 | 2 | 0.1599 | 0.3708 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||
| c.1694T>C | L565P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L565P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. No prediction or folding‑stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.045819 | Uncertain | 0.922 | 0.205 | 0.000 | -13.369 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.59 | Destabilizing | 0.4 | 6.82 | Destabilizing | 5.21 | Destabilizing | 2.33 | Destabilizing | 0.546 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.74 | Benign | 0.00 | Affected | 0.3825 | 0.0877 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1454G>C | R485P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485P is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic or likely pathogenic scores. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.377409 | Uncertain | 0.805 | 0.246 | 0.125 | -16.356 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.26 | Destabilizing | 0.3 | 6.86 | Destabilizing | 6.06 | Destabilizing | 0.56 | Ambiguous | 0.692 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.94 | Pathogenic | 0.00 | Affected | 0.2059 | 0.3941 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.703T>C | S235P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235P is listed in ClinVar as Pathogenic (ClinVar ID 1067856.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. No predictions or stability results are missing or inconclusive. **Based on the collective predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | Likely Pathogenic | 1 | -14.857 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.02 | Destabilizing | 0.1 | 6.91 | Destabilizing | 5.47 | Destabilizing | 1.23 | Destabilizing | 0.870 | Likely Pathogenic | -4.24 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 5.47 | Benign | 0.01 | Affected | 3.40 | 14 | 0.2432 | 0.5307 | 1 | -1 | -0.8 | 10.04 | 201.5 | 17.0 | 0.1 | 0.0 | -0.6 | 0.0 | X | Potentially Pathogenic | In the WT, the hydroxyl group of Ser235, located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Phe231) and an α helix (residues Ala236-Val250), forms hydrogen bonds with the GAP domain loop residue Glu680 and with the backbone amide groups of Ala237 and Glu238 from the α helix. In the variant simulations, the pyrrolidine ring of Pro235 cannot stabilize the α helix end or maintain tertiary bonding interactions between the PH and GAP domains via hydrogen bonding as effectively as serine. | ||||||||||||||||
| c.1673A>C | H558P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H558P 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 SIFT and AlphaMissense‑Optimized; those that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain predictions come from FoldX and premPS. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts Likely Pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Overall, the majority of tools, including the high‑accuracy ones, indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.011039 | Uncertain | 0.897 | 0.200 | 0.000 | -13.706 | Likely Pathogenic | 0.675 | Likely Pathogenic | Likely Benign | 0.63 | Ambiguous | 0.2 | 6.93 | Destabilizing | 3.78 | Destabilizing | 0.94 | Ambiguous | 0.782 | Likely Pathogenic | -6.28 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | -1.25 | Pathogenic | 0.09 | Tolerated | 0.2061 | 0.2405 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.1820T>C | L607P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L607P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while the SGM‑Consensus score is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome; the only inconclusive result is FoldX, which is listed as uncertain and therefore does not influence the overall assessment. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Consequently, the variant is most likely pathogenic based on the available 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 | 0.048328 | Structured | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | -14.059 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.11 | Ambiguous | 0.7 | 6.93 | Destabilizing | 4.02 | Destabilizing | 1.29 | Destabilizing | 0.922 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.54 | Pathogenic | 0.00 | Affected | 0.3710 | 0.1274 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.916G>T | V306F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306F is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, and AlphaMissense‑Optimized, whereas the remaining tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a pathogenic effect. Overall, the majority of evidence supports a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.363090 | Structured | 0.315026 | Uncertain | 0.896 | 0.287 | 0.125 | -9.311 | Likely Pathogenic | 0.700 | Likely Pathogenic | Likely Benign | 13.59 | Destabilizing | 1.4 | 6.99 | Destabilizing | 10.29 | Destabilizing | 0.23 | Likely Benign | 0.336 | Likely Benign | -3.28 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.74 | Pathogenic | 0.01 | Affected | 0.0535 | 0.3318 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||
| c.1123G>T | G375W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G375W is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438028‑G‑T). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of evidence, including the high‑accuracy tools, points to a pathogenic effect for G375W. 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. | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | 6-33438028-G-T | -9.654 | Likely Pathogenic | 0.464 | Ambiguous | Likely Benign | 4.33 | Destabilizing | 2.0 | 7.01 | Destabilizing | 5.67 | Destabilizing | 0.22 | Likely Benign | 0.450 | Likely Benign | -1.26 | Neutral | 0.992 | Probably Damaging | 0.869 | Possibly Damaging | 1.31 | Pathogenic | 0.01 | Affected | 4.32 | 12 | 0.0992 | 0.4368 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||||||
| c.1358A>C | H453P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H453P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM. The majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -15.704 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 3.29 | Destabilizing | 0.4 | 7.04 | Destabilizing | 5.17 | Destabilizing | 0.84 | Ambiguous | 0.488 | Likely Benign | -9.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.04 | Affected | 0.2115 | 0.3938 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.2105A>C | Q702P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q702P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; FoldX is uncertain and therefore not counted. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, more tools predict pathogenicity (7) than benignity (5), and the high‑accuracy pathogenic prediction from Foldetta further supports this. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.074921 | Structured | 0.397258 | Uncertain | 0.907 | 0.345 | 0.000 | -10.361 | Likely Pathogenic | 0.324 | Likely Benign | Likely Benign | 1.76 | Ambiguous | 0.1 | 7.05 | Destabilizing | 4.41 | Destabilizing | -0.04 | Likely Benign | 0.369 | Likely Benign | -4.71 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.42 | Benign | 0.05 | Affected | 0.1877 | 0.3371 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||
| c.1297G>C | A433P 2D 3DClick to see structure in 3D Viewer AISynGAP1 A433P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, SIFT, and FATHMM. Those that predict pathogenicity comprise FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. The remaining tools, premPS and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the lack of ClinVar annotation and gnomAD absence. Therefore, 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 | 0.098513 | Structured | 0.352258 | Uncertain | 0.938 | 0.302 | 0.000 | -9.887 | Likely Pathogenic | 0.883 | Likely Pathogenic | Ambiguous | 2.48 | Destabilizing | 0.0 | 7.09 | Destabilizing | 4.79 | Destabilizing | 0.55 | Ambiguous | 0.217 | Likely Benign | -2.64 | Deleterious | 0.998 | Probably Damaging | 0.820 | Possibly Damaging | 3.37 | Benign | 0.07 | Tolerated | 0.1471 | 0.4150 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1621G>C | A541P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. No predictions are inconclusive or missing. Overall, the collective evidence points to a pathogenic effect for A541P, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | Uncertain | 1 | -14.733 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.47 | Destabilizing | 0.3 | 7.26 | Destabilizing | 4.87 | Destabilizing | 0.86 | Ambiguous | 0.594 | Likely Pathogenic | -3.16 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.34 | Pathogenic | 0.07 | Tolerated | 3.37 | 35 | 0.1706 | 0.2707 | 1 | -1 | -3.4 | 26.04 | 170.4 | -11.2 | 0.1 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | Ala541 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala541 is on the surface and does not form any interactions. Proline lacks a free backbone amide group, and thus, Pro541 is unable to form a hydrogen bond with the carbonyl group of Ala537 in the variant simulations. Consequently, Pro541 disrupts the continuity of the secondary structure element, causing the α-helix to bend slightly in the variant simulations. | ||||||||||||||||
| c.974T>C | L325P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325P is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.352862 | Structured | 0.424577 | Uncertain | 0.955 | 0.436 | 0.000 | -16.130 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.49 | Destabilizing | 0.3 | 7.27 | Destabilizing | 6.38 | Destabilizing | 1.89 | Destabilizing | 0.607 | Likely Pathogenic | -4.37 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 1.33 | Pathogenic | 0.00 | Affected | 0.3393 | 0.1903 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1771G>C | A591P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A591P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely converge on a pathogenic effect: pathogenic predictions come from FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). Benign predictions are limited to REVEL and FATHMM. High‑accuracy assessments reinforce the pathogenic view: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. Consequently, the variant is most likely pathogenic, a conclusion that contrasts with its ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.018787 | Structured | 0.093848 | Uncertain | 0.882 | 0.185 | 0.000 | Uncertain | 1 | -14.479 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 3.78 | Destabilizing | 0.3 | 7.29 | Destabilizing | 5.54 | Destabilizing | 1.45 | Destabilizing | 0.404 | Likely Benign | -4.41 | Deleterious | 0.995 | Probably Damaging | 0.853 | Possibly Damaging | 3.35 | Benign | 0.01 | Affected | 3.37 | 35 | 0.1872 | 0.3087 | 1 | -1 | -3.4 | 26.04 | 191.5 | -10.1 | 0.2 | 0.1 | 0.4 | 0.1 | X | Potentially Pathogenic | The methyl group of the Ala591 side chain, located in the middle of an α helix (res. Glu582-Met603), packs against hydrophobic residues (e.g., Ile483, Phe484) of an opposing partially helical loop (res. Phe476-Asn487).In the variant simulations, Pro591 lacks a free backbone amide group and, therefore, cannot form a hydrogen bond with the backbone carbonyl of Arg587 as Ala591 does in the WT. This notably weakens the α helix integrity and compromises the continuity of the helix. In reality, the effect on the structure during protein folding could be more severe. | ||||||||||||||||
| c.641T>C | L214P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L214P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and the consensus of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the overwhelming agreement among predictive algorithms, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.372604 | Uncertain | 0.818 | 0.302 | 0.125 | -11.348 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.38 | Destabilizing | 1.3 | 7.51 | Destabilizing | 5.45 | Destabilizing | 1.30 | Destabilizing | 0.930 | Likely Pathogenic | -5.98 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 0.3448 | 0.1553 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1030G>T | G344C 2D AIThe SynGAP1 missense variant G344C is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic outcome include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy methods specifically show pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No tool predicts a benign effect. Based on the unanimous pathogenic predictions and the absence of any ClinVar or gnomAD evidence, the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | -12.880 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 8.52 | Destabilizing | 2.9 | 7.52 | Destabilizing | 8.02 | Destabilizing | 0.59 | Ambiguous | 0.794 | Likely Pathogenic | -8.02 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.47 | Pathogenic | 0.01 | Affected | 0.1184 | 0.4788 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.2141T>G | L714R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L714R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.314870 | Structured | 0.402311 | Uncertain | 0.961 | 0.369 | 0.000 | -12.763 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.38 | Destabilizing | 0.2 | 7.54 | Destabilizing | 5.96 | Destabilizing | 2.09 | Destabilizing | 0.402 | Likely Benign | -5.62 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 0.1186 | 0.0558 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1124G>T | G375V 2D AIThe SynGAP1 missense variant G375V is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions (premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Benign) and pathogenic predictions (REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, and FATHMM). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also benign, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a pathogenic effect. No prediction is missing or inconclusive. Overall, the majority of tools and the consensus score suggest a benign effect, but the Foldetta result introduces uncertainty. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | -6.149 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 3.93 | Destabilizing | 3.5 | 7.55 | Destabilizing | 5.74 | Destabilizing | 0.02 | Likely Benign | 0.547 | Likely Pathogenic | -0.92 | Neutral | 0.845 | Possibly Damaging | 0.186 | Benign | 1.32 | Pathogenic | 0.06 | Tolerated | 0.1653 | 0.4193 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1714T>G | W572G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W572G is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the uniform pathogenic predictions from both general and high‑accuracy tools, the variant is most likely pathogenic, a conclusion that contradicts its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.150080 | Structured | 0.039626 | Uncertain | 0.935 | 0.256 | 0.000 | Uncertain | 1 | -17.692 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 6.57 | Destabilizing | 0.2 | 7.57 | Destabilizing | 7.07 | Destabilizing | 1.83 | Destabilizing | 0.900 | Likely Pathogenic | -11.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.24 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.4128 | 0.1285 | -7 | -2 | 0.5 | -129.16 | 195.2 | 127.9 | 0.0 | 0.0 | -1.0 | 0.0 | X | Potentially Pathogenic | The introduced residue Gly572, located in an α-helix (res. Arg563-Glu578), is considerably smaller than the tryptophan it replaced. The indole ring of the Trp572 side chain lies in a hydrophobic inter-helix space, where it makes extensive hydrophobic interactions with nearby residues such as Met470, Phe569, Leu588, and Ile589. In the variant simulations, all these favorable packing interactions are completely removed, as the introduced residue Gly572 essentially lacks a side chain altogether. Although not observed in the simulations, the residue swap could also weaken the integrity of the helix (res. Arg563-Glu578), as glycine is known as an “α-helix breaker.” Overall, the residue swap is highly likely to cause critical protein folding problems that are underestimated based on the effects seen in the variant simulations. | ||||||||||||||||
| c.1280A>C | H427P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H427P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. Two tools are uncertain: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both indicate a pathogenic effect. Overall, the preponderance of evidence points to a pathogenic classification for H427P, 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 | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -11.098 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 4.74 | Destabilizing | 0.1 | 7.61 | Destabilizing | 6.18 | Destabilizing | 0.68 | Ambiguous | 0.324 | Likely Benign | -4.22 | Deleterious | 0.993 | Probably Damaging | 0.819 | Possibly Damaging | 3.51 | Benign | 0.01 | Affected | 0.2061 | 0.3442 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.1316T>C | L439P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L439P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic view: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | -9.929 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 6.30 | Destabilizing | 0.2 | 7.62 | Destabilizing | 6.96 | Destabilizing | 1.28 | Destabilizing | 0.539 | Likely Pathogenic | -5.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.21 | Benign | 0.02 | Affected | 0.3426 | 0.1192 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1525G>C | A509P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign effect, so the benign‑prediction group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports a pathogenic effect; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a pathogenic impact. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status (no report). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -13.234 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 5.82 | Destabilizing | 0.6 | 7.70 | Destabilizing | 6.76 | Destabilizing | 1.13 | Destabilizing | 0.884 | Likely Pathogenic | -4.15 | Deleterious | 0.987 | Probably Damaging | 0.844 | Possibly Damaging | -1.39 | Pathogenic | 0.01 | Affected | 0.1940 | 0.4570 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1900G>C | A634P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A634P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.052058 | Uncertain | 0.932 | 0.242 | 0.000 | -15.372 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 4.17 | Destabilizing | 0.2 | 7.72 | Destabilizing | 5.95 | Destabilizing | 1.39 | Destabilizing | 0.745 | Likely Pathogenic | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.50 | Benign | 0.01 | Affected | 0.2090 | 0.3429 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1132G>A | G378S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G378S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as pathogenic, giving a mixed outcome. Because the predictions are evenly split and the high‑accuracy methods are contradictory, the variant’s functional impact is uncertain. Based on the available evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.767246 | Disordered | 0.432858 | Uncertain | 0.341 | 0.915 | 0.625 | -5.331 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 6.75 | Destabilizing | 2.2 | 7.81 | Destabilizing | 7.28 | Destabilizing | 0.12 | Likely Benign | 0.565 | Likely Pathogenic | -0.63 | Neutral | 1.000 | Probably Damaging | 0.986 | Probably Damaging | 1.33 | Pathogenic | 0.08 | Tolerated | 0.3013 | 0.4724 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.740A>C | Q247P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact; premPS is uncertain and therefore treated as unavailable. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -14.361 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.43 | Destabilizing | 0.2 | 7.83 | Destabilizing | 5.63 | Destabilizing | 0.81 | Ambiguous | 0.770 | Likely Pathogenic | -3.56 | Deleterious | 0.995 | Probably Damaging | 0.795 | Possibly Damaging | 5.69 | Benign | 0.02 | Affected | 0.1768 | 0.3631 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.1879G>C | A627P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A627P is not reported in ClinVar and is absent from gnomAD. Prediction tools were grouped by consensus: Benign – none; Pathogenic – SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized. High‑accuracy methods specifically: AlphaMissense‑Optimized predicts pathogenicity; SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a deleterious effect. Therefore, the variant is most likely pathogenic, and this 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 | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -15.404 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.78 | Destabilizing | 0.3 | 7.84 | Destabilizing | 6.81 | Destabilizing | 1.13 | Destabilizing | 0.740 | Likely Pathogenic | -4.96 | Deleterious | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.43 | Pathogenic | 0.01 | Affected | 0.1752 | 0.3422 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1550T>C | L517P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517P is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: pathogenic predictions are returned by REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -15.546 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.88 | Destabilizing | 0.8 | 7.96 | Destabilizing | 6.92 | Destabilizing | 1.92 | Destabilizing | 0.937 | Likely Pathogenic | -6.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | 0.3570 | 0.1963 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1628T>G | L543R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L543R is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a pathogenic impact. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.020918 | Uncertain | 0.963 | 0.314 | 0.000 | -18.563 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.47 | Destabilizing | 1.2 | 8.02 | Destabilizing | 5.75 | Destabilizing | 1.64 | Destabilizing | 0.739 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.89 | Pathogenic | 0.00 | Affected | 0.1229 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1144G>A | G382R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G382R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include premPS, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts a benign change, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta stability outputs) both predict pathogenicity. Overall, the majority of evidence points to a pathogenic effect, 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 | C2 | 0.728858 | Disordered | 0.429690 | Uncertain | 0.315 | 0.951 | 0.750 | -8.997 | Likely Pathogenic | 0.654 | Likely Pathogenic | Likely Benign | 4.53 | Destabilizing | 1.6 | 8.03 | Destabilizing | 6.28 | Destabilizing | 0.23 | Likely Benign | 0.595 | Likely Pathogenic | -0.95 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.02 | Affected | 0.1295 | 0.4346 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1144G>C | G382R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G382R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include premPS, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts a benign change, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta stability outputs) both predict pathogenicity. Overall, the majority of evidence points to a pathogenic effect, 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 | C2 | 0.728858 | Disordered | 0.429690 | Uncertain | 0.315 | 0.951 | 0.750 | -8.997 | Likely Pathogenic | 0.654 | Likely Pathogenic | Likely Benign | 4.53 | Destabilizing | 1.6 | 8.03 | Destabilizing | 6.28 | Destabilizing | 0.23 | Likely Benign | 0.570 | Likely Pathogenic | -0.95 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.02 | Affected | 0.1295 | 0.4346 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1202G>C | R401P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining twelve tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.314870 | Structured | 0.424277 | Uncertain | 0.961 | 0.419 | 0.000 | -14.090 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 9.69 | Destabilizing | 0.3 | 8.07 | Destabilizing | 8.88 | Destabilizing | 0.77 | Ambiguous | 0.892 | Likely Pathogenic | -6.45 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.42 | Benign | 0.00 | Affected | 0.2265 | 0.4064 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1829T>C | L610P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L610P is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classifies the substitution as pathogenic; no tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic effect. Because all evidence points to a deleterious impact and there is no ClinVar entry to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.209504 | Uncertain | 0.888 | 0.253 | 0.000 | -14.863 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 6.02 | Destabilizing | 0.2 | 8.15 | Destabilizing | 7.09 | Destabilizing | 1.99 | Destabilizing | 0.934 | Likely Pathogenic | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.59 | Pathogenic | 0.00 | Affected | 0.3599 | 0.1113 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.2132T>C | L711P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L711P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and FATHMM; all other evaluated algorithms—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.377436 | Uncertain | 0.950 | 0.364 | 0.000 | -12.128 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.70 | Destabilizing | 0.1 | 8.15 | Destabilizing | 6.93 | Destabilizing | 2.09 | Destabilizing | 0.375 | Likely Benign | -6.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.28 | Benign | 0.00 | Affected | 0.3300 | 0.0986 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1348G>C | A450P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A450P missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, and FATHMM, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM Consensus score all classify the change as pathogenic. The high‑accuracy predictors give consistent pathogenic results: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. premPS remains uncertain. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which is consistent with the absence of a benign ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -15.378 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.75 | Destabilizing | 0.3 | 8.32 | Destabilizing | 5.54 | Destabilizing | 0.72 | Ambiguous | 0.459 | Likely Benign | -4.67 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.40 | Benign | 0.08 | Tolerated | 0.1494 | 0.4309 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1810T>C | S604P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy methods give consistent results: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also labels the variant as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. Taken together, the overwhelming majority of computational evidence supports a pathogenic classification for S604P, 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 | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -10.953 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.76 | Destabilizing | 0.3 | 8.40 | Destabilizing | 6.08 | Destabilizing | 0.04 | Likely Benign | 0.512 | Likely Pathogenic | -4.98 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 3.10 | Benign | 0.01 | Affected | 0.2524 | 0.4829 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.745G>C | A249P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is therefore pathogenic (3 pathogenic vs. 1 benign). High‑accuracy assessments are consistent: AlphaMissense‑Optimized indicates pathogenicity; the SGM‑Consensus (majority vote) is pathogenic; and Foldetta, integrating FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. **Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -10.727 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.76 | Destabilizing | 0.4 | 8.40 | Destabilizing | 5.58 | Destabilizing | 1.04 | Destabilizing | 0.756 | Likely Pathogenic | -3.32 | Deleterious | 0.176 | Benign | 0.039 | Benign | 5.57 | Benign | 0.03 | Affected | 0.1429 | 0.3537 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1367A>C | Q456P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q456P is listed in ClinVar with an uncertain significance (ClinVar ID 2697090.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are made by FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. High‑accuracy methods specifically report pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are inconclusive. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, which contradicts the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | Uncertain | 1 | -15.250 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.68 | Destabilizing | 0.2 | 8.43 | Destabilizing | 6.06 | Destabilizing | 0.82 | Ambiguous | 0.469 | Likely Benign | -5.66 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.34 | Benign | 0.07 | Tolerated | 3.37 | 34 | 0.2256 | 0.3631 | -1 | 0 | 1.9 | -31.01 | |||||||||||||||||||||||||
| c.1708G>C | A570P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A570P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods corroborate this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.046336 | Structured | 0.054494 | Uncertain | 0.932 | 0.263 | 0.000 | -15.178 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.21 | Destabilizing | 0.5 | 8.45 | Destabilizing | 6.83 | Destabilizing | 1.19 | Destabilizing | 0.832 | Likely Pathogenic | -4.55 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.31 | Pathogenic | 0.02 | Affected | 0.1965 | 0.2578 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.968T>C | L323P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L323P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.268042 | Structured | 0.428564 | Uncertain | 0.956 | 0.369 | 0.000 | Uncertain | 1 | -12.507 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.39 | Destabilizing | 0.6 | 8.46 | Destabilizing | 5.93 | Destabilizing | 2.20 | Destabilizing | 0.762 | Likely Pathogenic | -4.80 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 0.59 | Pathogenic | 0.01 | Affected | 4.29 | 398 | 0.3678 | 0.1221 | -3 | -3 | -5.4 | -16.04 | 201.9 | 68.2 | 0.0 | 0.1 | 0.6 | 0.3 | X | Potentially Pathogenic | The iso-butyl side chain of Leu323, located at the beginning of an anti-parallel β sheet strand (res. Ala322-Asp330), packs against multiple hydrophobic leucine residues (e.g., Leu264, Leu266, Leu284, Leu286). In contrast, in the variant simulations, the less bulky cyclic five-membered pyrrolidine ring of Pro323 cannot fill the hydrophobic space as effectively as the branched hydrocarbon side chain of leucine. Notably, the backbone amide group of Leu323 forms a hydrogen bond with the backbone carbonyl group of Cys285. Pro323 cannot form this bond due to the absence of the backbone amide group, resulting in partial unfolding of the anti-parallel β sheet end in the variant simulations. | ||||||||||||||||
| c.1352T>C | L451P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451P is reported in ClinVar as Pathogenic (ClinVar ID 3064222.0) and is not found in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on these predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | Likely Pathogenic | 1 | -14.549 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.92 | Destabilizing | 0.2 | 8.57 | Destabilizing | 7.75 | Destabilizing | 2.58 | Destabilizing | 0.750 | Likely Pathogenic | -6.81 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 3.37 | 34 | 0.2823 | 0.1221 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1718G>C | R573P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R573P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic impact. Based on the uniform predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.032433 | Uncertain | 0.934 | 0.235 | 0.000 | -16.684 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.76 | Destabilizing | 1.1 | 8.58 | Destabilizing | 7.17 | Destabilizing | 1.21 | Destabilizing | 0.831 | Likely Pathogenic | -5.78 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.47 | Pathogenic | 0.01 | Affected | 0.1961 | 0.3239 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1190G>A | C397Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and the combined Foldetta method. Uncertain results come from AlphaMissense‑Default and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as pathogenic. Overall, the majority of tools and the high‑accuracy consensus lean toward a benign interpretation, and this does not contradict any ClinVar classification (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -7.213 | In-Between | 0.397 | Ambiguous | Likely Benign | 2.01 | Destabilizing | 2.3 | 8.64 | Destabilizing | 5.33 | Destabilizing | 0.12 | Likely Benign | 0.455 | Likely Benign | -1.82 | Neutral | 0.952 | Possibly Damaging | 0.497 | Possibly Damaging | 4.64 | Benign | 0.07 | Tolerated | 0.1299 | 0.5084 | 0 | -2 | -3.8 | 60.04 | ||||||||||||||||||||||||||||||
| c.737T>C | L246P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L246P is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from FATHMM, while all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -16.581 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.42 | Destabilizing | 0.3 | 8.72 | Destabilizing | 7.57 | Destabilizing | 1.79 | Destabilizing | 0.944 | Likely Pathogenic | -6.30 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.67 | Benign | 0.00 | Affected | 0.3731 | 0.1582 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1342G>C | A448P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect, while only FATHMM predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized returns a pathogenic prediction; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a likely pathogenic result; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -13.706 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.42 | Destabilizing | 0.0 | 8.74 | Destabilizing | 7.08 | Destabilizing | 1.16 | Destabilizing | 0.650 | Likely Pathogenic | -4.94 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.13 | Benign | 0.01 | Affected | 0.1758 | 0.3626 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1261G>C | A421P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A421P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL, FATHMM, and polyPhen‑2 HumVar, whereas pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, reports a pathogenic effect. Taken together, the overwhelming majority of evidence points to a pathogenic impact for A421P, 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 | 0.067594 | Structured | 0.404927 | Uncertain | 0.965 | 0.257 | 0.000 | -13.126 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.51 | Destabilizing | 0.2 | 8.77 | Destabilizing | 6.64 | Destabilizing | 1.17 | Destabilizing | 0.371 | Likely Benign | -4.31 | Deleterious | 0.855 | Possibly Damaging | 0.420 | Benign | 3.39 | Benign | 0.04 | Affected | 0.1963 | 0.3343 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1669T>C | S557P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S557P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also labels it pathogenic. Based on the uniform predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). 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 | -15.383 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 6.91 | Destabilizing | 0.4 | 8.79 | Destabilizing | 7.85 | Destabilizing | 1.09 | Destabilizing | 0.934 | Likely Pathogenic | -4.60 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | -1.76 | Pathogenic | 0.01 | Affected | 0.2222 | 0.6239 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1405G>C | A469P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only SIFT, whereas all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Based on the overwhelming consensus of these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -16.072 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.06 | Destabilizing | 0.3 | 8.83 | Destabilizing | 6.95 | Destabilizing | 1.02 | Destabilizing | 0.774 | Likely Pathogenic | -2.69 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.33 | Pathogenic | 0.21 | Tolerated | 0.1606 | 0.4092 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1801G>C | A601P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining 12 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify it as pathogenic. The high‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta outputs)—all report pathogenicity. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. 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 | -14.584 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 4.90 | Destabilizing | 0.6 | 8.84 | Destabilizing | 6.87 | Destabilizing | 0.87 | Ambiguous | 0.713 | Likely Pathogenic | -4.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.56 | Benign | 0.01 | Affected | 0.2176 | 0.4328 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1558T>C | S520P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome, while premPS remains inconclusive. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Overall, the evidence strongly supports a pathogenic impact for S520P, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | Uncertain | 1 | -12.707 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.72 | Destabilizing | 0.8 | 8.86 | Destabilizing | 6.29 | Destabilizing | 0.83 | Ambiguous | 0.855 | Likely Pathogenic | -4.57 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 0.2154 | 0.4776 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||
| c.1544G>C | R515P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R515P has no ClinVar entry and is absent from gnomAD. In silico prediction tools uniformly indicate a deleterious effect: benign‑predicting algorithms are not reported, while pathogenic‑predicting tools—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—all classify the substitution as pathogenic. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. Consequently, the variant is most likely pathogenic based on the collective computational evidence, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | -14.291 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.69 | Destabilizing | 0.1 | 8.87 | Destabilizing | 6.28 | Destabilizing | 1.02 | Destabilizing | 0.823 | Likely Pathogenic | -4.24 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.36 | Pathogenic | 0.03 | Affected | 0.2223 | 0.2725 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.743G>C | R248P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R248P is listed in ClinVar as Pathogenic (ClinVar ID 1065478.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the overwhelming consensus of pathogenic predictions and the high‑accuracy tool results, the variant is most likely pathogenic, which aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | Likely Pathogenic | 1 | -10.751 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.09 | Destabilizing | 0.6 | 8.87 | Destabilizing | 5.98 | Destabilizing | 1.21 | Destabilizing | 0.848 | Likely Pathogenic | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.878 | Possibly Damaging | 5.64 | Benign | 0.00 | Affected | 3.41 | 14 | 0.1943 | 0.4528 | 0 | -2 | 2.9 | -59.07 | 223.8 | 126.6 | 0.0 | 0.0 | -0.2 | 0.1 | X | X | Potentially Pathogenic | The guanidinium group of Arg248, located on an α helix (residues Ala236-Val250), forms two very stable salt bridges with Asp255 (from a short α helical section, res. Lys254-Asn256) and Glu244 (from a nearby loop) in the WT simulations. In the variant simulations, the pyrrolidine side chain of Pro248 cannot form any salt bridges, which could negatively affect the tertiary structure assembly of the PH domain. Additionally, Pro248 lacks a free amide group needed for hydrogen bonding with the backbone carbonyl group of Asn245, disrupting the continuity of the α helix. | |||||||||||||||
| c.1499T>C | L500P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500P is listed in ClinVar (ID 2708686.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | Pathogenic | 1 | -15.898 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 5.91 | Destabilizing | 0.3 | 8.90 | Destabilizing | 7.41 | Destabilizing | 1.92 | Destabilizing | 0.894 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.37 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.3103 | 0.0625 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1864A>C | T622P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T622P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. No tool predicts a benign outcome; the only inconclusive result is premPS, which is listed as uncertain. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) also indicates pathogenic. 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 | 0.268042 | Structured | 0.071403 | Uncertain | 0.957 | 0.198 | 0.000 | -16.410 | Likely Pathogenic | 0.964 | Likely Pathogenic | Likely Pathogenic | 2.81 | Destabilizing | 0.4 | 8.90 | Destabilizing | 5.86 | Destabilizing | 0.78 | Ambiguous | 0.924 | Likely Pathogenic | -5.57 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.57 | Pathogenic | 0.01 | Affected | 0.1700 | 0.3876 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.2174T>C | L725P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L725P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. **Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.557691 | Disordered | 0.455613 | Uncertain | 0.911 | 0.491 | 0.625 | -15.390 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 4.91 | Destabilizing | 0.1 | 9.02 | Destabilizing | 6.97 | Destabilizing | 1.82 | Destabilizing | 0.396 | Likely Benign | -6.08 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 0.3796 | 0.1664 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||
| c.1570T>C | C524R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524R is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Across the evaluated in‑silico tools, all pathogenic‑predicating algorithms—REVEL, SGM‑Consensus, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—return a pathogenic or likely pathogenic verdict. The only tool with an inconclusive result is FoldX, which is treated as unavailable. High‑accuracy predictors reinforce this assessment: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.024729 | Uncertain | 0.916 | 0.385 | 0.125 | -14.337 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | -0.53 | Ambiguous | 0.5 | 9.04 | Destabilizing | 4.26 | Destabilizing | 1.62 | Destabilizing | 0.917 | Likely Pathogenic | -11.93 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.40 | Pathogenic | 0.00 | Affected | 0.2031 | 0.1463 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.1870A>C | T624P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T624P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.052894 | Uncertain | 0.962 | 0.217 | 0.000 | -15.681 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 3.64 | Destabilizing | 0.2 | 9.04 | Destabilizing | 6.34 | Destabilizing | 0.83 | Ambiguous | 0.914 | Likely Pathogenic | -5.94 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.55 | Pathogenic | 0.01 | Affected | 0.1500 | 0.3569 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.878G>C | R293P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R293P is listed in ClinVar as Pathogenic (ClinVar ID 571092.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL and premPS, whereas the remaining tools—FoldX, Rosetta, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as Pathogenic; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, classifies it as Pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is concordant with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.338192 | Uncertain | 0.924 | 0.269 | 0.125 | Likely Pathogenic | 1 | -16.275 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.62 | Destabilizing | 0.4 | 9.06 | Destabilizing | 6.34 | Destabilizing | 0.47 | Likely Benign | 0.497 | Likely Benign | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.45 | Pathogenic | 0.01 | Affected | 3.38 | 23 | 0.2162 | 0.4778 | 0 | -2 | 2.9 | -59.07 | 202.3 | 132.0 | 0.1 | 0.0 | 0.1 | 0.1 | X | X | X | Potentially Pathogenic | The guanidinium group of the Arg293 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), packs against the phenol ring of the Tyr281 side chain or forms a salt bridge with the carboxylate group of Glu283 on the outer side of the C2 domain. In the WT simulations, the positively charged side chain of arginine remains outside the hydrophobic C2 domain, resulting in a twist in the β strand. The backbone amide bond of Arg293 potentially maintains this twist by forming a hydrogen bond with the carbonyl group of His210 or the hydroxyl group of Ser211 in the anti-parallel β sheet.Although this twist is also maintained in the variant simulations, replacing the positively charged residue with proline, which lacks the backbone amide group altogether, causes the β strand to unfold. Because Arg293 is positioned at the C2 and PH domain interface, the residue swap could significantly impact the tertiary structure assembly. Notably, Arg293 is located at the SynGAP-Ras interface, and its role in complex formation cannot be fully understood through solvent-only simulations. | ||||||||||||||
| c.1616A>C | H539P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H539P missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include only FoldX, whereas all other evaluated algorithms—REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Taken together, the overwhelming majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.031398 | Uncertain | 0.948 | 0.360 | 0.000 | -15.182 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.22 | Likely Benign | 0.3 | 9.08 | Destabilizing | 4.65 | Destabilizing | 1.03 | Destabilizing | 0.913 | Likely Pathogenic | -9.18 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 0.1900 | 0.2794 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.1721T>C | L574P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L574P is not reported in ClinVar and is present in gnomAD (6-33440773‑T‑C). Prediction tools that indicate a benign effect include REVEL, PROVEAN, and SIFT, whereas the majority of tools predict a pathogenic impact: FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM Consensus score (likely pathogenic). High‑accuracy methods specifically give a pathogenic verdict: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.026427 | Uncertain | 0.927 | 0.246 | 0.000 | 6-33440773-T-C | -13.394 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.95 | Destabilizing | 0.5 | 9.19 | Destabilizing | 6.07 | Destabilizing | 0.59 | Ambiguous | 0.442 | Likely Benign | -1.05 | Neutral | 1.000 | Probably Damaging | 0.971 | Probably Damaging | -1.29 | Pathogenic | 0.26 | Tolerated | 3.38 | 32 | 0.3811 | 0.0953 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||
| c.1958T>C | L653P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L653P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.335213 | Uncertain | 0.963 | 0.332 | 0.000 | -17.675 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.02 | Destabilizing | 0.8 | 9.20 | Destabilizing | 7.61 | Destabilizing | 2.56 | Destabilizing | 0.700 | Likely Pathogenic | -6.51 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 0.3251 | 0.1874 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1411T>C | S471P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only polyPhen‑2 HumVar, whereas the remaining evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -12.379 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 3.65 | Destabilizing | 0.2 | 9.24 | Destabilizing | 6.45 | Destabilizing | 0.84 | Ambiguous | 0.530 | Likely Pathogenic | -4.03 | Deleterious | 0.552 | Possibly Damaging | 0.141 | Benign | -1.31 | Pathogenic | 0.05 | Affected | 0.2007 | 0.4769 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1145G>T | G382V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G382V has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split opinion: benign predictions come from PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions are returned by REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM, while premPS is uncertain. High‑accuracy assessments give a mixed signal: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, but Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy Foldetta result supports this. Therefore, the variant is most likely pathogenic based on current 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 Benign | C2 | 0.728858 | Disordered | 0.429690 | Uncertain | 0.315 | 0.951 | 0.750 | -5.988 | Likely Benign | 0.155 | Likely Benign | Likely Benign | 6.40 | Destabilizing | 1.6 | 9.28 | Destabilizing | 7.84 | Destabilizing | -0.53 | Ambiguous | 0.571 | Likely Pathogenic | -0.54 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.03 | Affected | 0.1631 | 0.3708 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1985A>C | Q662P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q662P 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 are made by SGM‑Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy methods give a consistent pathogenic signal: the SGM‑Consensus score (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. AlphaMissense‑Optimized returns an uncertain result, which is treated as unavailable. Overall, the majority of evidence points to a pathogenic impact for Q662P, 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 | 0.046336 | Structured | 0.103446 | Uncertain | 0.932 | 0.323 | 0.000 | -13.174 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 2.15 | Destabilizing | 0.0 | 9.37 | Destabilizing | 5.76 | Destabilizing | 0.36 | Likely Benign | 0.268 | Likely Benign | -3.42 | Deleterious | 0.999 | Probably Damaging | 0.962 | Probably Damaging | 3.40 | Benign | 0.08 | Tolerated | 0.2621 | 0.4364 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.2108T>C | L703P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic, while only FATHMM predicts it benign. The SGM‑Consensus, which is a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Pathogenic” result (3 pathogenic vs. 1 benign). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus is likely pathogenic; and Foldetta, integrating FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -13.766 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 4.44 | Destabilizing | 0.1 | 9.38 | Destabilizing | 6.91 | Destabilizing | 1.54 | Destabilizing | 0.559 | Likely Pathogenic | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.11 | Benign | 0.00 | Affected | 0.3698 | 0.1186 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1862G>C | R621P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R621P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas the remaining eleven tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The high‑accuracy subset further supports this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. No prediction is inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently contains no entry for R621P. 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 | -17.022 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.94 | Destabilizing | 0.4 | 9.39 | Destabilizing | 7.17 | Destabilizing | 0.96 | Ambiguous | 0.745 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.81 | Benign | 0.01 | Affected | 0.2143 | 0.3692 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1124G>A | G375E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G375E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, FATHMM, and AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenic, and Foldetta also predicts pathogenic. Overall, the majority of tools, including the high‑accuracy ones, indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | -7.780 | In-Between | 0.600 | Likely Pathogenic | Likely Benign | 2.89 | Destabilizing | 1.4 | 9.47 | Destabilizing | 6.18 | Destabilizing | 0.45 | Likely Benign | 0.545 | Likely Pathogenic | -1.07 | Neutral | 0.845 | Possibly Damaging | 0.244 | Benign | 1.32 | Pathogenic | 0.09 | Tolerated | 0.1619 | 0.4299 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.2153T>C | L718P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L718P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign effect, so the benign‑prediction group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Consequently, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.438417 | Uncertain | 0.966 | 0.385 | 0.000 | -15.643 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.56 | Destabilizing | 0.1 | 9.69 | Destabilizing | 8.13 | Destabilizing | 2.35 | Destabilizing | 0.660 | Likely Pathogenic | -6.64 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 0.3854 | 0.1221 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.874G>C | A292P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely converge on a deleterious effect: only REVEL classifies it as benign, whereas FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a destabilizing, pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -16.897 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.37 | Destabilizing | 0.3 | 9.80 | Destabilizing | 7.09 | Destabilizing | 1.23 | Destabilizing | 0.471 | Likely Benign | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.67 | Pathogenic | 0.01 | Affected | 0.2101 | 0.5988 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1572C>G | C524W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524W is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: benign predictions are absent, while pathogenic predictions are made by REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.024729 | Uncertain | 0.916 | 0.385 | 0.125 | -12.351 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.03 | Destabilizing | 1.2 | 9.88 | Destabilizing | 6.46 | Destabilizing | 0.93 | Ambiguous | 0.675 | Likely Pathogenic | -10.94 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.41 | Pathogenic | 0.00 | Affected | 0.1953 | 0.3920 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1729G>C | A577P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A577P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only SIFT, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic outcome; premPS is inconclusive and is therefore not counted. 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 (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the consensus of these predictions, the variant is most likely pathogenic, and this conclusion does not contradict 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 | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | -9.009 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.93 | Destabilizing | 0.2 | 9.88 | Destabilizing | 6.91 | Destabilizing | 0.87 | Ambiguous | 0.585 | Likely Pathogenic | -2.72 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.34 | Pathogenic | 0.20 | Tolerated | 0.2256 | 0.4600 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1235T>G | L412W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L412W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -13.436 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 8.44 | Destabilizing | 0.4 | 9.91 | Destabilizing | 9.18 | Destabilizing | 1.65 | Destabilizing | 0.503 | Likely Pathogenic | -5.53 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 0.0586 | 0.2664 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.1670C>T | S557F 2D AIThe SynGAP1 missense variant S557F is not reported in ClinVar and has no gnomAD entry. Prediction tools cluster into two groups: the single benign prediction from premPS versus a consensus of pathogenic predictions from the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized). High‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta—all indicate pathogenicity. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic based on the aggregate computational evidence, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.010261 | Uncertain | 0.924 | 0.215 | 0.000 | -12.523 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 15.55 | Destabilizing | 5.2 | 9.95 | Destabilizing | 12.75 | Destabilizing | 0.08 | Likely Benign | 0.958 | Likely Pathogenic | -5.38 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.77 | Pathogenic | 0.00 | Affected | 0.1073 | 0.5931 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.1619A>C | Q540P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q540P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic, while premPS is uncertain. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a pathogenic effect. No tool predicts a benign outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.029522 | Uncertain | 0.958 | 0.371 | 0.000 | -16.096 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.95 | Destabilizing | 0.3 | 10.06 | Destabilizing | 7.01 | Destabilizing | 0.73 | Ambiguous | 0.922 | Likely Pathogenic | -5.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 0.1882 | 0.3654 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.1504G>C | G502R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the only inconclusive result is from premPS, which is listed as uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -15.571 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 8.80 | Destabilizing | 0.3 | 10.07 | Destabilizing | 9.44 | Destabilizing | 0.88 | Ambiguous | 0.917 | Likely Pathogenic | -7.73 | Deleterious | 1.000 | Probably Damaging | 0.985 | Probably Damaging | -1.65 | Pathogenic | 0.00 | Affected | 0.1014 | 0.3317 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1898T>C | L633P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L633P (ClinVar ID 858973.0) is listed as Pathogenic and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it as Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts Pathogenic. Based on the overwhelming consensus of pathogenic predictions and the ClinVar designation, the variant is most likely pathogenic, with no contradiction to its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.045407 | Uncertain | 0.952 | 0.252 | 0.000 | Pathogenic/Likely path. | 2 | -15.669 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.60 | Destabilizing | 0.2 | 10.15 | Destabilizing | 8.38 | Destabilizing | 2.42 | Destabilizing | 0.693 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.70 | Benign | 0.00 | Affected | 3.37 | 34 | 0.3528 | 0.0953 | -3 | -3 | -5.4 | -16.04 | 193.2 | 65.1 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | The iso-butyl side chain of Leu633, located in the middle of an α helix (res. Glu617-Asn635), packs hydrophobically with nearby residues (e.g., Leu653, Val629, Leu551) in the WT simulations.In the variant simulations, the pyrrolidine side chain of Pro633 is not as optimal for hydrophobic packing as Leu633 in the WT. Additionally, proline lacks a free backbone amide group, so Pro633 cannot form a hydrogen bond with the backbone carbonyl group of Val629, which disrupts the continuity of the secondary structure element. | ||||||||||||||||
| c.1058T>C | L353P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L353P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a strong bias toward pathogenicity: REVEL predicts benign, whereas FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all predict pathogenic. Two tools report uncertainty: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Overall, the majority of evidence points to a pathogenic impact, which is consistent with the ClinVar designation of uncertain significance but leans toward pathogenicity rather than benign. Thus, the variant is most likely pathogenic, and this prediction does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.137348 | Structured | 0.373584 | Uncertain | 0.926 | 0.315 | 0.000 | Uncertain | 1 | -7.913 | In-Between | 0.936 | Likely Pathogenic | Ambiguous | 4.63 | Destabilizing | 0.1 | 10.19 | Destabilizing | 7.41 | Destabilizing | 2.17 | Destabilizing | 0.464 | Likely Benign | -3.70 | Deleterious | 0.947 | Possibly Damaging | 0.454 | Possibly Damaging | 1.29 | Pathogenic | 0.02 | Affected | 3.37 | 25 | 0.3582 | 0.1645 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1517T>C | L506P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506P is listed in ClinVar (ID 975474.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, which aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | Likely Pathogenic | 1 | -12.088 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.48 | Destabilizing | 0.7 | 10.19 | Destabilizing | 7.84 | Destabilizing | 2.50 | Destabilizing | 0.737 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.55 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.3047 | 0.0625 | -3 | -3 | -5.4 | -16.04 | 182.6 | 64.9 | 0.1 | 0.0 | 0.2 | 0.1 | X | Potentially Pathogenic | Leu506 is located in the middle of an α-helix (res. Gly502-Tyr518) within the inter-helix space of two helices (res. Gly502-Tyr518 and res. Glu582-Met603). In the WT simulations, the iso-butyl side chain of Leu506 hydrophobically packs with residues in the inter-helix space (e.g., Ile510, Phe597, Leu598, Ala601). In the variant simulations, the cyclic five-membered pyrrolidine ring of Pro506 is not as optimal as Leu506 for hydrophobic packing with nearby residues. Additionally, Pro506 cannot maintain the hydrogen bond with the backbone oxygen of Gly502 as Leu506 does in the WT, which disrupts the secondary structure element. | ||||||||||||||||
| c.1778T>C | L593P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L593P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic outcome. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, a conclusion that contradicts its current ClinVar “Uncertain” status. 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 | Uncertain | 1 | -13.961 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.75 | Destabilizing | 0.9 | 10.77 | Destabilizing | 8.26 | Destabilizing | 2.43 | Destabilizing | 0.777 | Likely Pathogenic | -6.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | 0.3783 | 0.1274 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||
| c.1477G>C | A493P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A493P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact all converge on a pathogenic interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict deleterious effects. No tool in the dataset indicates a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -15.797 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.96 | Destabilizing | 0.1 | 10.79 | Destabilizing | 7.88 | Destabilizing | 1.32 | Destabilizing | 0.883 | Likely Pathogenic | -4.54 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.41 | Pathogenic | 0.02 | Affected | 0.1490 | 0.2907 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.2087T>C | L696P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L696P is listed in ClinVar as Pathogenic (ClinVar ID 1699350.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM; all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—report it as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a pathogenic effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote) is pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a destabilizing, pathogenic outcome. Taken together, the overwhelming majority of predictions and the high‑accuracy tools classify the variant as pathogenic, fully consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | Likely Pathogenic | 1 | -16.926 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.66 | Destabilizing | 0.2 | 10.84 | Destabilizing | 8.75 | Destabilizing | 2.13 | Destabilizing | 0.678 | Likely Pathogenic | -6.58 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | 3.46 | 13 | 0.3065 | 0.1995 | -3 | -3 | -5.4 | -16.04 | 180.6 | 65.9 | 0.1 | 0.0 | -0.6 | 0.1 | X | Potentially Pathogenic | The isobutyl side chain of Leu696, located in the middle of an α-helix (res. Leu685-Gln702), engages in hydrophobic packing with nearby residues (e.g., Leu441, Leu431, Leu692, Leu714) in the inter-helix space. Prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Leu692 in the same manner as Leu696 in the WT. Consequently, the residue swap with proline disrupts the continuity of the secondary structure element in the variant simulations. Additionally, the side chain of Pro696 is not as optimal as Leu696 for hydrophobic packing in the inter-helix space. | ||||||||||||||||
| c.1394T>C | L465P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465P is listed in ClinVar as Pathogenic (ClinVar ID 1067821.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | Likely Pathogenic | 1 | -14.824 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 7.18 | Destabilizing | 0.3 | 10.85 | Destabilizing | 9.02 | Destabilizing | 2.73 | Destabilizing | 0.778 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 3.37 | 34 | 0.3387 | 0.1582 | -3 | -3 | -5.4 | -16.04 | 211.1 | 65.9 | 0.1 | 0.0 | -0.2 | 0.0 | X | Potentially Pathogenic | The iso-butyl side chain of Leu465, located in the middle of an α helix (res. Ala461–Phe476), packs with hydrophobic residues (e.g., Phe464, Met468, Tyr497, Ile494) in an inter-helix space formed with two other α helices (res. Ala461–Phe476 and res. Thr488-Gly502). In the variant simulations, the cyclic five-membered pyrrolidine ring of Pro465 is not as optimal as the side chain of Leu465 for filling the three α helix hydrophobic niche. Although the residue swap does not cause a large-scale conformational shift during the simulations, the H-bond between the backbone amide group of Leu465 and the backbone carbonyl group of Ala461 is lost. This, in turn, breaks the continuity of the α helix secondary structure element. | ||||||||||||||||
| c.1445T>C | L482P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482P is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the substitution as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a pathogenic impact. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -12.866 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.59 | Destabilizing | 0.1 | 10.87 | Destabilizing | 7.23 | Destabilizing | 1.55 | Destabilizing | 0.896 | Likely Pathogenic | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.30 | Pathogenic | 0.01 | Affected | 0.2756 | 0.0825 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.2002T>C | S668P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668P has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the only benign predictor, while the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify it as pathogenic or likely pathogenic. The premPS score is uncertain and therefore not used as evidence. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -13.452 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.40 | Destabilizing | 1.1 | 10.90 | Destabilizing | 8.65 | Destabilizing | 0.61 | Ambiguous | 0.612 | Likely Pathogenic | -4.82 | Deleterious | 0.998 | Probably Damaging | 0.790 | Possibly Damaging | 3.16 | Benign | 0.02 | Affected | 0.1979 | 0.5137 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1546G>C | A516P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A516P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; premPS is inconclusive. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized scores it as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies it as pathogenic. Based on the consensus of these predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -15.348 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.67 | Destabilizing | 0.3 | 10.96 | Destabilizing | 6.82 | Destabilizing | 0.83 | Ambiguous | 0.750 | Likely Pathogenic | -4.41 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.29 | Pathogenic | 0.06 | Tolerated | 0.2214 | 0.4328 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.2003C>T | S668F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668F is reported in ClinVar as Pathogenic (ClinVar ID 1309930.0) and is not found in gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, while the remaining 12 tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also Pathogenic. No predictions are inconclusive. Overall, the computational evidence strongly supports a pathogenic effect, consistent with the ClinVar classification. Therefore, the variant is most likely pathogenic based on the consensus of prediction tools, and this assessment aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | Likely Pathogenic | 1 | -15.047 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 16.72 | Destabilizing | 5.0 | 11.07 | Destabilizing | 13.90 | Destabilizing | 0.00 | Likely Benign | 0.643 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 3.38 | 28 | 0.0656 | 0.5849 | -3 | -2 | 3.6 | 60.10 | 250.9 | -59.6 | -0.1 | 0.1 | 0.0 | 0.1 | X | X | X | Potentially Pathogenic | In the WT simulations, the hydroxyl side chain of Ser668, located on an α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), forms hydrogen bonds with the backbone carbonyl groups of Leu664, Tyr665, and Glu666, as well as the guanidinium group of Arg573 on a nearby α-helix (res. Arg563-Glu578). In the variant simulations, the side chain of Phe668 cannot maintain the same hydrogen-bond network. Due to its larger size, it moves away to avoid steric hindrance. In the WT simulations, a network of hydrogen bonds between several residues (e.g., Asn669, Lys566, and Glu666) keeps both α-helices and the proceeding loop (res. Asn669-Asp684) tightly connected, but this setup is not present in the variant simulations. Additionally, in the variant simulations, the side chain of Arg573 shifts to form a more stable salt bridge with the carboxylate group of Glu582 instead of hydrogen bonding with Ser668 as in the WT simulations. | ||||||||||||||
| c.1868T>C | L623P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L623P is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: pathogenic predictions are returned by REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.060667 | Uncertain | 0.962 | 0.211 | 0.000 | -12.385 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.70 | Destabilizing | 0.2 | 11.18 | Destabilizing | 8.94 | Destabilizing | 2.26 | Destabilizing | 0.788 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.56 | Pathogenic | 0.00 | Affected | 0.3961 | 0.1474 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1892A>C | Q631P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q631P is not reported in ClinVar and has no entry in gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining eleven tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all classify the change as pathogenic. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates pathogenic. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). 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 | -16.914 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 4.98 | Destabilizing | 0.3 | 11.18 | Destabilizing | 8.08 | Destabilizing | 0.56 | Ambiguous | 0.641 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.75 | Benign | 0.00 | Affected | 0.1999 | 0.2982 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.1031G>A | G344D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the unanimous pathogenic predictions and the absence of benign calls, the variant is most likely pathogenic, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | -12.527 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 14.53 | Destabilizing | 1.5 | 11.36 | Destabilizing | 12.95 | Destabilizing | 1.13 | Destabilizing | 0.897 | Likely Pathogenic | -6.30 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.49 | Pathogenic | 0.01 | Affected | 0.1572 | 0.1574 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.1292T>C | L431P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L431P (ClinVar ID 661045.0) is reported as Pathogenic and is not present in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the overwhelming consensus of pathogenic predictions and the ClinVar designation, the variant is most likely pathogenic, with no contradiction to its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | Likely Pathogenic | 1 | -14.222 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 6.78 | Destabilizing | 0.3 | 11.59 | Destabilizing | 9.19 | Destabilizing | 2.29 | Destabilizing | 0.659 | Likely Pathogenic | -6.39 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.91 | Benign | 0.05 | Affected | 3.37 | 29 | 0.3484 | 0.2163 | -3 | -3 | -5.4 | -16.04 | 222.4 | 62.8 | 0.1 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | The iso-butyl side chain of Leu431, located in an α helix (res. Met414-Glu436), packs against other hydrophobic residues in an interhelix space (e.g., Val434, Leu435, Leu696, Leu711) in the WT simulations. While the backbone amide group of Leu431 forms an H-bond with the carbonyl group of His427, the cyclic five-membered pyrrolidine ring of Pro431, lacking the necessary amide group, cannot do the same. Thus, although the cyclic five-membered pyrrolidine ring of Pro431 packs almost as favorably as the side chain of Leu431 in the hydrophobic niche, the residue swap causes the α helix to partially unfold in the variant simulations. | ||||||||||||||||
| c.1133G>A | G378D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G378D is not reported in ClinVar (ClinVar ID: None) but is present in gnomAD (ID 6‑33438038‑G‑A). Prediction tools that classify the variant as benign include premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. ESM1b is uncertain, and no other high‑accuracy predictions are available. Overall, the majority of evidence supports a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.767246 | Disordered | 0.432858 | Uncertain | 0.341 | 0.915 | 0.625 | 6-33438038-G-A | 1 | 6.97e-7 | -7.767 | In-Between | 0.576 | Likely Pathogenic | Likely Benign | 11.41 | Destabilizing | 5.0 | 11.84 | Destabilizing | 11.63 | Destabilizing | 0.50 | Likely Benign | 0.619 | Likely Pathogenic | -0.63 | Neutral | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 1.32 | Pathogenic | 0.08 | Tolerated | 4.32 | 12 | 0.2130 | 0.2035 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||
| c.1364T>C | L455P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -14.150 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 7.45 | Destabilizing | 0.2 | 11.99 | Destabilizing | 9.72 | Destabilizing | 2.19 | Destabilizing | 0.695 | Likely Pathogenic | -6.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | 0.3211 | 0.1221 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1793T>C | L598P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L598P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates it is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also classifies it as pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.007259 | Structured | 0.147872 | Uncertain | 0.953 | 0.154 | 0.000 | -12.621 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 8.31 | Destabilizing | 0.5 | 12.04 | Destabilizing | 10.18 | Destabilizing | 2.02 | Destabilizing | 0.705 | Likely Pathogenic | -6.87 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.10 | Benign | 0.00 | Affected | 0.2742 | 0.1192 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1937T>C | L646P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -12.956 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 7.34 | Destabilizing | 0.5 | 12.08 | Destabilizing | 9.71 | Destabilizing | 2.72 | Destabilizing | 0.604 | Likely Pathogenic | -4.55 | Deleterious | 0.999 | Probably Damaging | 0.926 | Probably Damaging | 3.17 | Benign | 0.00 | Affected | 0.3481 | 0.1874 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1132G>T | G378C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G378C is 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools (8/12) predict pathogenicity, and the high‑accuracy consensus leans toward benign only for AlphaMissense‑Optimized and SGM Consensus, while Foldetta indicates instability. Thus, the variant is most likely pathogenic based on the preponderance of evidence, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.767246 | Disordered | 0.432858 | Uncertain | 0.341 | 0.915 | 0.625 | -7.981 | In-Between | 0.203 | Likely Benign | Likely Benign | 7.63 | Destabilizing | 2.7 | 12.14 | Destabilizing | 9.89 | Destabilizing | 0.26 | Likely Benign | 0.635 | Likely Pathogenic | -1.18 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 0.1595 | 0.4240 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||
| c.1858T>C | S620P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S620P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly favor a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while premPS remains uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.100377 | Uncertain | 0.936 | 0.219 | 0.000 | -12.208 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 4.89 | Destabilizing | 0.5 | 12.23 | Destabilizing | 8.56 | Destabilizing | 0.73 | Ambiguous | 0.834 | Likely Pathogenic | -3.62 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.35 | Pathogenic | 0.02 | Affected | 0.2147 | 0.4776 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1874T>C | L625P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L625P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | -14.819 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.47 | Destabilizing | 0.6 | 12.49 | Destabilizing | 8.98 | Destabilizing | 1.98 | Destabilizing | 0.746 | Likely Pathogenic | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | 0.3294 | 0.1313 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1123G>A | G375R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G375R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized, whereas tools that predict pathogenicity are FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions (7 pathogenic vs. 5 benign) indicate a likely pathogenic effect, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | -8.955 | Likely Pathogenic | 0.609 | Likely Pathogenic | Likely Benign | 2.97 | Destabilizing | 1.3 | 12.66 | Destabilizing | 7.82 | Destabilizing | 0.36 | Likely Benign | 0.497 | Likely Benign | -1.15 | Neutral | 0.845 | Possibly Damaging | 0.523 | Possibly Damaging | 1.32 | Pathogenic | 0.11 | Tolerated | 0.1335 | 0.4513 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1123G>C | G375R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G375R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, whereas Foldetta indicates a destabilizing, pathogenic change, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as likely pathogenic. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | -8.955 | Likely Pathogenic | 0.609 | Likely Pathogenic | Likely Benign | 2.97 | Destabilizing | 1.3 | 12.66 | Destabilizing | 7.82 | Destabilizing | 0.36 | Likely Benign | 0.497 | Likely Benign | -1.15 | Neutral | 0.845 | Possibly Damaging | 0.523 | Possibly Damaging | 1.32 | Pathogenic | 0.11 | Tolerated | 0.1335 | 0.4513 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.2003C>A | S668Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and FATHMM, whereas the remaining 12 tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict it to be pathogenic or likely pathogenic. High‑accuracy methods give consistent results: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions are missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -14.833 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 18.34 | Destabilizing | 6.2 | 12.69 | Destabilizing | 15.52 | Destabilizing | 0.06 | Likely Benign | 0.641 | Likely Pathogenic | -5.95 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 0.0647 | 0.5693 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.2099T>C | L700P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L700P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while only FATHMM predicts it benign. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Pathogenic” verdict (3 pathogenic vs. 1 benign). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this 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 | 0.113710 | Structured | 0.416255 | Uncertain | 0.927 | 0.331 | 0.000 | -13.092 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 7.29 | Destabilizing | 0.5 | 12.85 | Destabilizing | 10.07 | Destabilizing | 1.84 | Destabilizing | 0.541 | Likely Pathogenic | -4.31 | Deleterious | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 0.3603 | 0.1025 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1763T>C | L588P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L588P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All available in silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.082229 | Uncertain | 0.887 | 0.214 | 0.000 | Uncertain | 2 | -14.771 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.61 | Destabilizing | 0.5 | 12.91 | Destabilizing | 9.26 | Destabilizing | 2.33 | Destabilizing | 0.932 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.42 | Pathogenic | 0.00 | Affected | 3.38 | 34 | 0.3533 | 0.0992 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1132G>C | G378R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G378R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, and SIFT, while pathogenic predictions arise from REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also indicates pathogenicity. Overall, the preponderance of evidence points to a pathogenic impact for G378R. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.767246 | Disordered | 0.432858 | Uncertain | 0.341 | 0.915 | 0.625 | -8.863 | Likely Pathogenic | 0.745 | Likely Pathogenic | Likely Benign | 12.27 | Destabilizing | 6.3 | 13.17 | Destabilizing | 12.72 | Destabilizing | 0.12 | Likely Benign | 0.653 | Likely Pathogenic | -0.96 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.32 | Pathogenic | 0.06 | Tolerated | 0.1343 | 0.4356 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.2075T>C | L692P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692P is listed in ClinVar with an “Uncertain” status (ClinVar ID 847082.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | Uncertain | 1 | -16.447 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 9.19 | Destabilizing | 0.1 | 13.20 | Destabilizing | 11.20 | Destabilizing | 1.69 | Destabilizing | 0.668 | Likely Pathogenic | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 3.42 | 17 | 0.3642 | 0.1025 | -3 | -3 | -5.4 | -16.04 | 186.2 | 62.8 | -0.2 | 0.1 | -0.7 | 0.3 | X | Potentially Pathogenic | The isobutyl side chain of Leu692, located in the middle of an α-helix (res. Leu685-Gln702), engages in hydrophobic packing with nearby residues (e.g., Leu441, Leu431, Leu696) in the inter-helix space. Prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Glu688 in the same manner as Leu692 in the WT. Consequently, the residue swap with proline disrupts the continuity of the secondary structure element in the variant simulations. Additionally, the side chain of Pro692 is not as optimal as Leu692 for hydrophobic packing in the inter-helix space. | ||||||||||||||||
| c.2066T>C | L689P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -17.900 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.76 | Destabilizing | 0.2 | 13.35 | Destabilizing | 10.06 | Destabilizing | 2.29 | Destabilizing | 0.631 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.17 | Benign | 0.00 | Affected | 0.3668 | 0.1353 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1628T>C | L543P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L543P (ClinVar ID 4540554) is classified as Pathogenic in ClinVar and is not reported in gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. All available predictions and stability analyses support a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.020918 | Uncertain | 0.963 | 0.314 | 0.000 | Likely Pathogenic | 1 | -15.958 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 8.56 | Destabilizing | 0.6 | 13.44 | Destabilizing | 11.00 | Destabilizing | 1.54 | Destabilizing | 0.770 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.89 | Pathogenic | 0.00 | Affected | 0.3457 | 0.0992 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||
| c.2141T>C | L714P 2D AIThe SynGAP1 missense variant L714P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the preponderance of evidence from these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.314870 | Structured | 0.402311 | Uncertain | 0.961 | 0.369 | 0.000 | -12.562 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 7.48 | Destabilizing | 1.9 | 13.54 | Destabilizing | 10.51 | Destabilizing | 2.26 | Destabilizing | 0.441 | Likely Benign | -6.44 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.08 | Benign | 0.00 | Affected | 0.3572 | 0.1253 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1030G>C | G344R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while the only inconclusive result is premPS, which is listed as uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. Consequently, the variant is most likely pathogenic, and this assessment is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | -12.609 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 14.84 | Destabilizing | 0.8 | 13.66 | Destabilizing | 14.25 | Destabilizing | 0.81 | Ambiguous | 0.801 | Likely Pathogenic | -7.17 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.49 | Pathogenic | 0.01 | Affected | 0.0844 | 0.4614 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1031G>T | G344V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344V is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while the only inconclusive result is premPS, which is listed as uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | -14.913 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 13.33 | Destabilizing | 1.5 | 14.51 | Destabilizing | 13.92 | Destabilizing | 0.53 | Ambiguous | 0.889 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.48 | Pathogenic | 0.03 | Affected | 0.1244 | 0.4744 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1133G>T | G378V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G378V is catalogued in gnomAD (ID 6‑33438038‑G‑T) but has no ClinVar submission. Functional prediction tools split in their assessment: benign calls come from premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls arise from REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy analyses further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts pathogenic. Overall, the balance of evidence, especially from the high‑accuracy tools, points to a benign effect for G378V, and this conclusion does not conflict with ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.767246 | Disordered | 0.432858 | Uncertain | 0.341 | 0.915 | 0.625 | 6-33438038-G-T | 1 | 6.97e-7 | -6.837 | Likely Benign | 0.168 | Likely Benign | Likely Benign | 12.88 | Destabilizing | 5.0 | 21.64 | Destabilizing | 17.26 | Destabilizing | 0.04 | Likely Benign | 0.606 | Likely Pathogenic | -0.98 | Neutral | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 1.32 | Pathogenic | 0.04 | Affected | 4.32 | 12 | 0.1686 | 0.3708 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||
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